Nineteenth Century Foundations of Cancer Research Origins of Experimental Research*

VICTORA. TRIÃ“LO (McArdle Memorial Laboratory, University of Wisconsin, The Medical School, Madison, Wis.)

CONTENTS Caroline Brewer Croft Cancer Commission 22 Huntington Cancer Research Fund 22 INTRODUCTION 4 REFERENCES 23 Unit Concept of Structural Organization 5 Unit Concept of Disease 5 INTRODUCTION THE CLASSICINFECTION THEORY OF CANCER 5 Bacterial Theory 5 This review will discuss the origins of experimental Protozoan and Yeast Theories 6 cancer research through three selected topics: (a) the Mycetozoan Theory 7 classic infection theory of cancer, (6) studies on tumor Virus Theory 7 STUDIES ON TUMOR TRANSMISSION 8 transmission, and (c) studies on tumor growth. No Precursal Implantation Research 8 attempt will be made to appraise these subjects from a Doutrelepont 8 scientific or formally historical viewpoint, since several Discovery of Transmissible Canine and Rodent Neoplasms 9 excellent surveys of this kind are available (79, 175, 259, Novinsky and Hanau 9 263).' Moreover, critical evaluations in terms of recent Morau 9 Velich 9 trends can be made only by experts in each field. A few Establishment of the First Rodent Tumor Lines 9 of the earlier conceptual attitudes which have been Loeb and Jensen 9 distinctly altered by modern research will be pointed out Borrel 10 in footnotes. This paper, and others which are projected, Michaelis and Ehrlich 11 Bashford, Murray, and Cramer 11 is designed principally as a guide to nineteenth century Gay lord, Clowes, and Baeslack 11 cancer research, surveyed along the broadest lines. Its Tyzzer 12 scope includes the presentation of a more comprehensive Cumulative Results 12 bibliography than is now available in the English literature Canine neoplasms 12 on the history of cancer. Rat neoplasms 12 Mouse neoplasms 12 When the specific scientific relations of a previous era The Infection Theory in Tumor Transplantation Research 13 are examined it is correct to avoid a technical vocabulary STUDIES ON TUMOR GROWTH 13 not appropriate to that era. For example, terms such The Experimental Production of Tumors 13 as 'homologous,' 'heterologous,' 'isologous,' and 'autol- Cell transfer theory 14 ogous,' and their precise import for modern transplan Cell irritation theory 14 Growth mechanisms 15 tation work, cannot be applied to a few roughly Resistance and Immunity in Experimental Cancer 15 analogous procedures of 60 years ago. To the investigator Transmissible rodent neoplasms 15 working at the turn of the century the term 'cancer' Transmissible canine neoplasms 16 implied 'a malignant growth of epidermal origin,' and Further studies on immunologie protection 17 Physical and Chemical Research on Tumor Cells 17 frequent distinctions among cancer, sarcoma, and the Temperature and chemicals 17 other major categories of neoplastic growths are found in Radiations 17 the scientific communications of these times.2 Archaic Biologic implications 17 terminology where it appears will be qualified for the Biochemical Characteristics of Tumor Cells 18 sake of clarity. Protein constituents 18 The 'infectious' nature of cancer was first suggested in Enzymes 19 Nucleic acid constituents 19 the seventeenth century (79, p. 34), but with the rise of Inorganic constituents 20 modern bacteriology in the 1870's and 1880's the exact Immunologie Relationships 20 means were provided whereby the infection theory of Cytolytic and cytotoxic agents 20 CONCLUSIONS 21 cancer could be empirically tested. The possibility of Parasite Theory 21 this etiological breakthrough was entirely dependent upon Theories of Biological Origins 21 1A new history of cancer, Geschichte der Krebskrankheit, by Cell Autonomy Concept 21 Juraj KÃ¶rbler (Zagreb), issued by Verlag Palm & Enke, Erlangen, Tumor Growth Research 21 is scheduled to appear in the near future. Tumor Metabolism Research 22 2Before 1855, the histogenic period of cancer research, all Research Programs in the United States 22 malignant tumors were designated as 'cancer' or 'carcinoma'. New York State Cancer Laboratory 22 The etymological relationship between the term 'cancer' (Gr. karkinos, crab) and the term 'carcinoma' (Gr. karkioma, from * This work was supported by grant CRTY 5002 of the National karkinos, crab) appears to have carried over so that 'cancer' and Institutes of Health, U. S. Public Health Service. 'carcinoma' retained equivalent meanings.

the results of prior, systemic, and descriptive research. imbalance' (239, p. 78), nor Cohnheim's theory of These prior developments may be classed under (a) the 'embryonic rests' (1875 [59]) presented entirely convincing unit concept of structural organization and (6) the unit answers to the question of etiology.3 Cohnheim's argu concept of disease. The events which resulted in the ment was acceptable as an explanation for the occurrence formation of each concept were in many instances inter of certain complex tumors such as teratomas, but it was related. unsatisfactory for explaining the formation of carcinomas. Unit concept of structural organization.â€”The unit Thiersch's theory was palpably contradicted by Waldeyer concept of structural organization is based on the cell (1867 [250], 1872 [251]). Notwithstanding their limita theory, and Johannes MÃ¼llerin 1838, the year in which tions, these theories, and others which appeared later, SchwÃ¤rmproposed the Cell Doctrine, first reported the provided the incentive for highly productive research. cellular structure of certain tumors (164). MÃ¼ller's The rapidity with which microbiological research was work suggested the possibility of identifying malignant taken up by European and American medical departments tissues through different proportions and groupings of shortly after 1880 (53) reflects the broad medical aware cells. Subsequent research on cellular differentiation ness of its implications for every area of pathology. In pursued in the 1840's and 1850's by MÃ¼ller,Remak, and microbiology a clear opportunity was presented for a others (192) repudiated a popular hypothesis that new solution of the cancer problem. This outlook channeled cells were formed from the intercellular matrix and research into the first widespread experimental attack on replaced it with the theory that all animal cells originate cancer. from pre-existing cells (Omnia cellula e cellula). Virchow, using this principle as the cornerstone of his Cellular THE CLASSIC INFECTION THEORY Pathology, formulated by 1858 (248), established the OF CANCER cell as the focus of tumor growth, but he misinterpreted Bacterial theory.â€”The existence of a cancer microbe the nature of endogenous cell formation (80, 259, pp. 4-5). was postulated as early as 1872 by Nepveu, and this Thiersch (1865 [239]) advanced decisive evidence for the assumption was again advanced in 1881 by Nedopil and epithelial (glandular) cell origins of epithelioma, through Cripps, but these authors offered no empirical evidence to the use of improved histological technics, and Waldeyer support their contention (263, p. 549). From a report (250), in 1867, produced further proof that all carcinomas read in 1886 before the New York County Medical were derived from the epithelial strata. These con Association by Laurence McNamara (151) it appears that clusions (a) corrected Virchow's belief that connective the subject was being actively pursued through the early tissue elements were capable of transformation into 1880's. McNamara announced that clinical and experi cancer cells and (6) established through analogy that the mental efforts thus far had failed to link a bacterium dictum'Omnis cellula e cellula,' had to be amended to 'Omnis with the cause of tumors and that tumors had never been cellula e cellula ejusdem generis' (A tumor is analogous to successfully inoculated, nor had they ever infected the any other new formation and results from the prolifera surgeon. He suggested that rapidly growing sarcomas tion of cells, of the same general character as the tumor). showed 'reactive' changes analogous to vegetable cells This conception provided a sound taxonomic and morpho infected with actinomycetesâ€”namely, the production logical basis for cancer research in the 1870's. of small round cells in the earlier stages and giant cells in Unit concept of disease.â€”Between 1820 and 1860, the later stages resembling the inflammatory actions of largely through the initiative of the Paris Clinical School, the fungus in vegetable growths. Nevertheless, McNa a long established system of clinical diagnosis based upon mara conceded that if sarcomas were caused by a generalized symptoms gave way to concepts of disease, microorganism, it would be necessary to suppose that the each related to a localized, structural pathology (230). process required very favorable conditions. For example, the recognition of 'specific disease entities,' Concerning the microbic source of carcinoma McNamara such as 'pneumonia,' 'pleurisy,' and 'bronchitis' sup stated that the misplaced epithelial elements could account planted the vague nosonomic 'inflammation of the chest' for all the reactive changes in the cells of the matrix. If of earlier times. With the identification of local sites of a microorganism were to be considered the cause of this disease, research programs were able to pass to a con class of tumors, it was not clear why it should affect only sideration of the etiological stage (231). By 1885 the the epithelial cells. There was no direct evidence that role of microorganisms (the contagium vivum) was impli pathogens could induce anything more than inflammatory cated in a considerable number of specific diseases: hyperplasias (151, pp. 136-137). The great advantage malarial fevers, pneumonia, consumption, cholera, typhoid of the infection theory, McNamara concluded, was that it fever, anthrax, erysipelas, septicemia, and pyÃ«mia. did not have to go beyond the organism and its cellular The work of MÃ¼llerand his successors, between 1850 elements to explain the occurrence of malignant growth. and 1870, made it possible to differentiate malignant from In 1887 Scheurlen (218) described a bacillus 'isolated' benign and inflammatory lesions and to recognize from human carcinoma. He reported that culture-grown malignant growths not only in terms of symptoms but specimens of these organisms when inoculated into dogs also in terms of lesions. It was thus possible to establish produced epitheliomas in which spores of the bacilli a category of clinically identifiable malignant diseases. could be readily identified. Similar results were described The next step was to determine the cause or causes of this class of diseases. Neither Virchow's 'irritation' theory 8That these theories merely specified possible stimuli for neoplastic growth and not exact etiological conditions inciting un of 1863 (249), Thiersch's 1865 theory of 'growth energy limited cellular proliferation was fully recognized by 1900.

almost simultaneously by other investigators (95, 219). inocula from his cultures or with pieces of human cancer These reports were immediately challenged (28, 201)â€”for tissue. example, by Ballance and Shattock (1887 [10]), who In 1894 Simon Flexner (90) reported the presence of reported that they were unable to isolate any but 'naturally cellular inclusions in clinical lymphosarcoma. Flexner occurring' (saphrophytic) microorganisms from cultures of indicated that these bodies could not be regarded as carcinoma, sarcoma, lipoma, and myxoma. Many of the bacteria, but he suggested that they might be protozoa. early efforts to inoculate fragments of malignant tissues Priority for the discovery of an alleged cancer parasite into laboratory animals and humans were motivated by by an American investigator belongs to Gustav Eisen, the intent to isolate and identify, according to Koch's who in 1900 described (77, 78) a parasitic amoeba, 'Cancri- Postulates, a suspected etiological agent. (Several amoeba macroglossa,' which he proposed as the etiological significant exceptions are discussed in the following agent of epithelial carcinoma in humans. Eisen as section.) Senger (1888 [225]), in an attempt to demon sociated the spores of these amoebae with 'yeast' forms strate the cancer microbe under strict antiseptic conditions, described by Plimmer in 1899 (186), and he presented implanted nodules of human carcinoma into various elaborate morphological descriptions of the adult cancri- animals, but in every case the transplant was absorbed or amoeba. In common with other workers, Eisen failed to disappeared. Similar experiments in the United States satisfy the fundamental conditions of Koch's Rules in were performed by Nicholas Senn (1883 [226]) who establishing an etiological connection between a micro concluded that the rarity of spontaneous tumors in organism and a specific pathological state. laboratory animals and the difficulty of inoculating such By the turn of the century most investigators agreed tumors presented almost insurmountable obstacles. that cancer resulted through an external or internal A reappraisal of the microbial theory of cancer in the stimulus, probably a 'potent living influence' such as a late 1880's was prompted by (a) the general failure to parasite (179), and that its discovery would depend culture suspected infectious agents upon nutrient media, upon the adoption and employment of scrupulous technics (6) the inability to reproduce new growths from inocula, (180). and (c) the lack of success in transmitting cancer through Accordingly, in 1901 Harvey Gaylord (98) of the New transplants within the same species or among different York State Cancer Laboratory, reported that the parasite species; exceptions, such as the work of Novinsky and of cancer had been identifiedâ€”an announcement which Hanau, appeared to have little influence upon the situa received wide acclaim (69). He cited the discovery, in tion. human cancer tissues, of undifferentiated parasites which, Protozoan and yeast theories.â€”The infection theory when inoculated into a guinea pig, produced 'adeno- continued to be an active issue after 1889 through suc carcinoma' nodules. Gaylord pointed out that the guinea cessive reports of other parasitic species in carcinoma and pig was not particularly susceptible to the development of sarcoma tissues from humans. Numerous protozoan spontaneous tumors. Subsequently, the morphology of forms were reported (3, 63, 93, 185, 217, 232, 240) on the the parasite was worked out; infective particles at various basis of elaborate morphological evidence obtained through stages of their life cycle obtained from a broad spectrum a variety of staining technics. The reliability of many of of tumors appeared to fall into four classes: (a) typical these descriptive studies was questioned by Cazin (1890 Plimmer's bodies, (6) modified Plimmer's bodies, (c) [50] and Ohlmacher (1893 [177]), whose investigations Russell's bodies, and (d) intranuclear protozoan forms. clearly showed that the normal processes of cellular Culture experiments on the suspected agent gave uniformly degeneration or artifacts resulting from the staining negative results. methods were commonly misinterpreted as alleged A part of Gay lord's study was specifically aimed at protozoan parasites. determining the nature of animal resistance to cancer. Russell's discovery (1890 [206]) of yeast-like 'fuchsin Preliminary evidence definitely implicated the reactions of bodies' in 43 cases of epithelioma opened an intensive the 'protozoan inclusions' in malignant tissues with those search for blastomycetes parasites in cancer. The of vaccinia, the virus of which by 1900 had been isolated considerable experimental efforts associated with this and successfully grown upon rabbit cornea (97, 107). phase of the classic infection theory began with Busse Following this lead, the Buffalo group demonstrated that (1894 [45]), who described inclusions which resembled the virulence of the suspected cancer parasite increased yeast organisms in the cells of human sarcoma tissues. after one passage through an animal, and the average Between 1895 and 1898 Sanfelice (208-215) attempted to survival time of rabbits inoculated at various sites with relate the inclusions in cancer cells to the pathogenic the different forms of infectious material suggested that saccharomyces. Sanfelice reported the occurrence in this animal was more resistant to infection than other dogs and guinea pigs of tumors induced through injections species. Gaylord considered that the nature and role of of 'Saccharomyces neoformans,' a species of air-borne the suspected virus principle in cancer were not unlike blastomycetes, which he obtained in pure cultures. those postulated by Borrel for epithelioma. Sanfelice accounted for his failure to culture these Gay lord's claim fell short of being the decisive stroke in organisms from tumor specimens on the grounds that the favor of the parasite theory. There were still wide infective saccharomyces were unable to re-acclimate to discrepancies in the morphological record. Moreover, artificial media. Flimmer (1899 [186]), who reported with the exception of a few dubious claims, pure cultures of results approximating those of Sanfelice, was unable to infective organisms, especially under circumstances in obtain malignant growths in laboratory animals with which protozoan forms appeared to be involved, had not

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1964 American Association for Cancer Research. TRIÃ“LOâ€”Foundationsof Cancer Research been obtained (263, pp. 595-97, 627). Attempts to agent was found to be the mycetozoan Plasmodiophora reproduce true cancer in experimental animals through brassicae, and in 1899 Behla (35) suggested its infectious infectivity studies proved to be entirely unconvincing. action in animal tissues. Experiments by Podwyssotzki These problems were given special consideration by the (1900 [187]) indicated that fragments of clubroot Caroline Brewer Croft Cancer Commission at Harvard inoculated into rabbits and guinea pigs gave rise to University and by other laboratories. tumors of mesodermal origin ; he also reported the presence A report of the Croft Commission by E. H. Nichols of plasmodiophora spores in certain elements of these (1900 [169]) stated that preliminary work had pointed to tumors resembled the inclusions seen in several human the existence of 'typical' cancer bodies in several human sarcomas. Feinberg (1902 [84]) examined the spore, neoplasms, but attempts to produce cancer in animals ameboid, and plasmodial forms of the organism, and through inoculations of these bodies were entirely unsuc subsequently (85) associated several of its appearances cessful. Culture experiments with cancer tissues, car with the cell inclusions implicated in the etiology of ried out by O. Richardson, failed to reveal anything that carcinoma. could be regarded as a specific infecting organism (194, The problem of mycetozoan parasitism in cancer was 195), although R. B. Greenough confirmed the presence of taken into active consideration by Gaylord (1901 [99-101]), Plimmer's bodies in a few cases of human carcinoma who pursued the analogy suggested by Podwyssotzki and (108). A more detailed report by Nichols in 1902 (171) Feinberg. This analogy stressed the similar appearances suggested the following conclusions: (a) The lesion produced through Plasmodiophora spore infections in produced by the coccidium oviforme was essentially a animals and the 'inclusions' (Plimmer's bodies, 'Bird's- process of chronic inflammation and not analogous to the eye' inclusion, etc.) of cancer as well as the similarities of lesion seen in cancer (E. E. Tyzzer [243]); (6) the lesion in the host-parasite relationship in both plant and animal molluscum contagiosum, characterized by certain changes in tumors. His conclusions were drawn from inoculation the epidermis, was not due to the action of a protozoan studies in which pieces of the tumor-like growths of (C. J. White and W. H. Robey [257]); (c) the so-called cabbage roots implanted in animal tissues resulted in the 'blastomycetes' ('saccharomycetes') of Sanfelice and in situ production of nodules of granulation tissue. Histo- Plimmer were actually torulae (J. D. Weis [256]); (d) the logical comparison of plant and animal tumor tissues led lesions produced by these 'blastomycetes,' or torulae, Gaylord (100) to assume that Plasmodiophora was an were essentially nodules of peculiar granulation tissue and agent which fulfilled many of the conditions requisite to were not in any sense true tumors (Nichols [170]); (Ã¨) the establishment of an etiological relationship between a blastomycetes were not constantly present in human parasite and cancer. cancer (Nichols [170]); (/) the peculiar bodies seen in the Although Gaylord did not go beyond this analogical protoplasm of cancer cells were not parasites, or the cause suggestion, the issue was carried a step further by of the lesions, but apparently atypical stages of the Robertson and Wade (1905 [98]), who reported the glandular epithelial secretory processes (Greenough [109]). discovery in human cancers of parasites closely resembling The opinion that blastomycetes were incidentally Plasmodiophora brassicae. Furthermore, these investiga present in cancer had been advanced by Mafucci and tors claimed success in culturing from these tumors an Sirleo (1898 [148]) and Messer (1901 [152]), and these organism which appeared to represent several successive reports also weakened the claims of Sanfelice. When phases of a parasite from this class. Their conclusions Darier in 1904 repudiated his 'psorosperm' and Foa, about were never substantiated. In addition, the criticisms of the same time, rejected his previous assumptions on the von Trubeuf and others (79, p. 43) (a) that the histology 'Bird's-eye' inclusion, the protozoan and yeast questions of club-root was not that of a true neoplasm, (f>)that were fast becoming dying issues (79, p. 43). Neither Plasmodiophora tumors resulted principally from disten- Busse nor Plimmer had succeeded in proving that inocula tion and degeneration of infected cells surrounded by an tions of their organisms produced other than inflammatory area of inflammatory overgrowth, and (c) that the behavior lesions, and the same held true of Sanfelice's 'expÃ©rimentai' of this organism in plants was widely different from that of sarcomas in guinea pigs. In the case of Sanfelice's any suspicious structure in malignant tumors, severely allegedly induced canine adenocarcinomas, Nichols (169, damaged the mycetozoan theory of cancer. pp. 44-45) pointed out that spontaneous cancers commonly Virus theory.â€”Aconsideration of subsequent accounts occurred in dogs, and it was possible, in view of the large of cancer parasites (i.e., the spirochetes of Gaylord (1907 number of dogs involved in Sanfelice's experiments, [102]) and Calkins (1907 [49]) are beyond our proposed that these tumors developed coincidentally. Lastly, scope. However, the beginnings of a new phase of the Koch's Rules had not as yet been satisfied in efforts to infection theory should be mentioned. As indicated, by relate intracellular parasites to cancer or any other 1900 an etiological agent of cancer similar to the vaccinia autonomous new growth. virus had been hypothesized by Gaylord and others Mycetozoan theory.â€”After 1900 the infection theory was (Gorini, 1900 [107]). In 1904 Borrel, largely on the basis temporarily sustained by the advancement of claims for a of his work on contagious avian epithelioses (39, 40), mycetozoan agent of cancer. Organisms of this group, suggested that the causative agent of cancer and of a described by Woronin in 1876, were discovered in various number of highly infectious diseases, all with specific species of the cabbage family in which they produce yet homologous cell inclusions, might be a factor commonly root tumors variously known as 'club-root,' 'finger-and- associated with these products of cellular decomposition. toe disease,' 'Kohlhernie,' and 'Kohlkropf.' The causative In the case of the bird epithelioses these agents were

described by Borrel as congeries or masses of minute cocci TABLE 1 lying adjacent to the specific cell inclusions. Borrel ALLEGEDETIOLOGICALAGENTSOF CANCEBREPORTEDBY 1905 proposed the existence of an analogous factor, a virus Based in part upon Ewing's compilation (79, p. 41) cancÃ©reuse,whichbore a similar causal connection to the processes of malignant epithelioma. Bacteria: Bacillus of Rappin, 1887 (189); Scheurlen, 1887 (218); Lampiasi, 1887 (131); Francke, 1888 (95); A weakness of this hypothesis, pointed out by Borrel, Koubassof, 1890 (128); Micrococcus neoformans,* was the obvious dissimilarity between the infectious epithelioses and true cancers. The lesions of 'vaccinia,' Doyen, 1903 (65).

Molluscum conlagiosum, and related infectious epithelioses Coccidia: Coccidium of Darier, 1889 (63); Malassez, 1889 lacked that capacity for unlimited infiltrative growth (149); Albarran, 1889 (3); Thoma, 1889 (240); which was the specific distinguishing feature of malignant Sjobring, 1890 (232); Soudakiewitsch-Metchnikoff, tumors. Moreover, the immunity conferred by the 1892 (235); Coccidium sarcolyticum, Adamkiewicz, epithelioses and the filtrability of their viruses had no 1893 (2); Monsarrat, 1904 (160). apparent counterparts in cancer.4 However, the virus theory has significant implications in work on the trans- Sporozoa: (unclassified): Bosc, 1888 (42); Bird's eye inclu sion, Foa, 1892 (93) ; Plimmer's bodies, 1892 (185); plantable rodent neoplasms. A partial list of the Sawtschenko, 1892 (217); Sporozoen, Ruffer, organisms which have been suggested as the agents of Walker, and Flimmer 1893 (203-205); Amoeba- cancer appears in Table 1. sporidium, L. Pfeiffer, 1893 (184) ; Rhopalocephalus STUDIES ON TUMOR TRANSMISSION carcinomatosus, Korotneff, 1893 (127); Sporozoon, Kourloff, 1894 (129); Haematozoon, Kahane, 1894 PRECURSALIMPLANTATIONRESEARCH (124) ; Leydenia gemmipara, Schaudinn, 1896 (79, The conception of cancer as a transmissible disease p. 84); Cancriamoeba macroglossia, Eisen, 1900 parallels the early popular beliefs of its contagiousness, (77); Intranuclear parasite, Schuller, 1901-a (222). found in numerous reports of its accidental transfer from one individual to another (the so-called cancer Ã deux and Blastomycetes : Russell's fuchsin bodies, 1890 (206); Busse, 1894 the phenomena of 'cancer houses' (259, pp. 39-42)), as well (45); Corselli and Frisco, 1895 (199, 200); Curtis, 1895 (62); Saccharomyces neoformans, Sanfelice, as many alleged instances of its transfer from patient to 1895 (208); Flimmer, 1899 (186); Leopold, 1900 physician (179). Attempts to verify this hypothesis (134) ; Steckson, 1900 (98, p. 524) ; Mucor racemosus, include the effort of Senn (1901 [227]) to inoculate him Schmidt, 1906 (220). self with pieces of cancerous lymph node, and other investigations involving tumor transplantations in humans Mycetozoa: Plasmodiophora brassicae, Behla, 1899 (35); (60, 112, 226). Podwyssotzki, 1900 (187); Feinberg, 1902 (85); Inoculations of human cancer into laboratory animals, Gaylord, 1903 (100); Robertson and Wade, 1905 as well as implantation experiments within the same or (198). different species, also have a direct bearing upon the * Italicized items refer to specific types. cancer parasite question throughout the 1880-1900 period. Among more objective efforts in these areas are of cancer from the watchdog. Both wounds healed without sup those of Duplay and Cazin (1892 [67]), in which fragments puration. On the 15th of September a nodule, firm to the touch, of human tumors and of tumors occurring spontaneously about half the size of a dove's egg was found in the wound de in dogs were inoculated into a variety of laboratory pression of the left thigh. On the right side, in the region of the animals. These investigators (52) claimed only one earlier operation on which now only a fine scar was present, a positive result in dogs. The doubtful nature of their new piece of tumor was implanted in another muscle wound. data led them (68) to question the validity of trans This wound also healed without suppuration. On the 3rd of plantation studies, especially transfers of human tumors to October the animal which had been washed two days previously animals and transfers between animals of different species, was found dead. Autopsy pointed to double pneumonia as the as confirmatory evidence for the infection theory of cause of death. The other internal organs were normal. On the cancer. operation sites of both thighs very thick scar tissue was found Doutrelepont.â€”The tumor transplantation studies do which, under microscopic examination, proved to be only young connective tissue without specific elements. Under the muscle not take their origins in the cancer parasite question. of the left thigh, in the region of the scar, a little nodule was There are reports of implantation experiments before found, the remainder of the aforementioned nodule. Micro 1880 (89), one of which is of particular interest. In scopic examination of this revealed only young, rapidly growing 1868 Doutrelepont, working at Bonn, discovered a canine connective tissue enveloping fat globules, among the cells of tumor in the vicinity of the vagina, a neoplasm which which rapidly proliferating connective tissue nuclei were appar he identified as an epithelial carcinoma of the mammae. ent. In the middle of the nodule, round cells were still to be Fragments of this tumor were implanted into three dogs, found and these became spindle cells along the peripheries, and two rabbits, and a guinea pig. Doutrelepont reported the the outer limits already had the (usual) appearances of fibrous connective tissue. The inguinal glands were slightly swollen, following, result translated from the German : but they merely showed the products of a simple inflammation" "On the 31st of August (1868) a few-months-old dog was im (64). planted in muscle wounds made on both thighs with small pieces 4The early descriptive studies by Borrel foreshadow the later The two other dogs died as a result of postoperative experimental demonstration of viral agents in cancer by Rous peritonitis, and the rabbits and guinea pig absorbed the (1909) and other investigators. tumor materials transferred to them.

Doutrelepont considered his experiments as failures, by Morau in his paper of 1894 (163), are worthy of re and in the experiment described above he designated the production, as translated from the French: (a) cylindrical nodule, "a simulated tumorâ€”'ein Knoten, welcher ein epitheliomas of the white mouse are inoculable into animals GeschwÃ¼lstvortÃ¤uschte'â€”which diminished to such an of the same species; (o) heredity plays a considerable role extent that it amounted to no more than a small tissue in the development of these neoplasms and prepares the rest merely presenting the histological appearances of soil for their evolution; (c) the neoplasms become general young connective tissue" (64, p. 508). His own conclusions ized, and this process is hastened by trauma; (d) gestation were accepted by his contemporaries, and his work has accelerates the evolution of these tumors; (e) the neo faded almost entirely from the annals of cancer. Wolff plasms possess a variable virulence (differ as to rates of (263, pp. 534-35) refers only to the fact that two of growth) which may eventually lead to the destruction of Doutrelepont's dogs succumbed to infection incurred in the host; (/) the neoplasms become progressively less the operationâ€”no mention is made of the third dogâ€”and inoculable and virulent in other hosts, provided these are he adds that the first successful tumor transfer within the of a similar species; (g) when these neoplasms are not same species (by Novinsky) was achieved after the ulcerated they are devoid of bacteria. appearance of antiseptic surgery. In the light of modern The significance of these initial rodent-tumor trans knowledge there are provocative features to the above plantation studies did not escape the notice of experi cited experiment5 by Doutrelepont which perhaps merit mental pathologists; they stimulated the search for spon him some recognition as a pioneer in tumor transplantation taneous animal tumors and led to more accurate research. histological surveys of these growths (Cadiot and Cadiot, 1894 [48]). At Johns Hopkins L. E. Livingood (1895 DISCOVERYOFTRANSMISSIBLECANINEAND [138]), spurred by the success of Morau and other en RODENTNEOPLASMS couraging reports, studied a series of spontaneous tumors Novinsky and Hanau.-â€”-Priorityfor the first successful occurring in laboratory mice. He described four spon taneous tumors, and, although several of these neoplasms tumor transplantation is accorded to Novinsky (228, 229), who from 1875 to 1877 succeeded in obtaining the grossly resembled sarcoma, his microscopic findings led passage through two generations of a nasal anaplastic him to conclude that true carcinoma, with structural tumor and a venereal myxosarcoma ('transmissible elements and patterns of growth differing in no way from lymphosarcoma') in dogs (173, 174). Greater notoriety those occurring in humans, was the predominant type of neoplasm appearing in mice. From the standpoint of was attached to the reports of Wehr (253, 254) and homology and analogy Livingood concluded that these particularly Hanau (113, 114), the latter of whom suc tumors made suitable experimental materials for studying ceeded between 1888 and 1889 in propagating a carcinoma of the vulva through several generations in rats. Wehr's the mechanisms of human carcinoma. He did not attempt work on the transfer of genital tumors (venereal sarcomas to propagate the tumors. or 'transmissible lymphosarcomas') in dogs, which just Velich.â€”In 1898 Velich (247) reported the transfer of a rodent neoplasm, a subperiosteal sarcoma of a rat, through preceded the studies of Hanau, lacks the circumspect histological confirmation of Hanau's results: Jenny (1896 eight generations, all in rats of the same origins except for [119]) analyzed Hanau's data so thoroughly as to leave no the last generation. The tumors in successive generations presented all the characteristics of spindle-cell sarcomas doubt that the tumors produced in his experiments were true cancers. (Jenny's supportive evidence has given and were similar in every respect to the primary growth, the greatest weight to earlier claims for the priority of but underwent a progressive decrease of proliferative Hanau's work in the area of tumor transplantation.) energy. However, Velich interpreted his results as a Hanau (114), although he regarded his experiments suc transfer of microorganisms and not as a transplantation cessful in every detail, stressed that they did not of tumor cells, thus obscuring the more significant bio necessarily demonstrate an infective property of the logical implications of his experiments. tumor but merely that the epithelial cells were capable of ESTABLISHMENTOFTHE FIRST RODENT proliferating in their new environment in a manner similar TUMORLINES to skin grafts. M orau.â€”Adecisive step was taken in 1889 by Morau Loeb and Jensen.â€”Even though relatively few animal (161-163), who began a series of transfers of cylinder-cell tumors had been successfully transplanted by 1900, the epitheliomas in mice. This appears to be the first utility of the transplantation work as an experimental tool systematic survey of tumor-host relationships from almost was becoming apparent. A survey of the literature (1900), a purely biological standpoint. By 1893 Morau carried relating to the inoculability of carcinoma, by Joseph Sailer his transfer experiments through seventeen generations in suggests the newer emphasis : which he observed the effects of age, sex, and predisposition "It will perhaps not be out of place to suggest in what direction to tumor growth in first-generation offspring of tumor- subsequent investigation upon the subject of the etiology of bearing mice. The conclusions of these studies, presented malignant neoplasm should apparently be pursued. It seems 6There is the possibility that Doutrelepont was working with a useless to continue inoculating lower animals with fragments of canine venereal sarcomaâ€”the so-called 'transmissible lymphosar human cancers; it is criminal to use human beings as subjects coma'â€”the class of tumors to which that described by Duplay for these experiments, and we are, therefore, restricted to inocu and Cazin belongs, and about which little was known until the lation experiments with such malignant tumors as may develop turn of the century. These tumors are known to regress especially spontaneously in the lower animals. These tumors are not un in young, vigorous hosts. common in dogs, and probably are more frequent than is ordi-

narily supposed in the ordinary laboratory animals. It is tissue preparations from the same species. Mayet's urgently necessary that a number of investigators undertake the hypothesis that some active principle, 'a parasite or a elucidation of this subject and determine under what conditions ferment,' was capable of inciting tumor growth indepen and by what methods the transmission of the tumor actually takes place" (207). dently of the neoplastic cell remained unverified, although Herzog specified that tumor-producing 'ultra-microscopic' This appeal was answered by the research of two inves organism might be so strictly parasitic they could not exist tigators, the first of whom was Leo Loeb. Loeb's earlier outside the living cells (117, p. 81). experiences at Ribbert's Institute of Pathology at Zurich, Carl 0. Jensen's discoveries, reported from the Agricul where he carried out skin transplantation studies (1897), ture and Veterinary Institute at Copenhagen, appear to be and his subsequent work in tissue culture at Chicago, had the actual starting point for most of the experimental an important part in directing his later approach to the mouse tumor research in Europe and the United States. subject of tumor transplantation. Through a personal Jensen's first accounts, presented in an obscure Danish conviction that "not only cancer cells and embryonal cells, medical journal (120, 121), passed entirely unnoticed, but also normal adult tissue cells may be potentially im and only after he published an exhaustive experimental mortal (146)," he concerned himself primarily with growth report in the Cenlralblatt fÃ¼rBakteriologie (1903 [122]) phenomena. Loeb (142) cited as precedents for his own did his work achieve wide notoriety. In this communica studies only Morau and the doubtful experiments of JÃ¼rgen tion Jensen announced that he succeeded, from 1901 to (1899 [123]), who claimed a successful transfer of human 1903, in propagating a spontaneous alveolar carcinoma of sarcoma to a rabbit. Attempts by Loeb to transplant the white mouse through nineteen generations. Trans carcinomas of the cow and mouse in the respective species plantations to various species of mice were unsuccessful, failed, but subsequently (1901) he succeeded at 150 con except in gray mice in which the tissue structure of im secutive transfers of a cystic sarcoma of the thyroid in rats. plants varied from those observed in white mice. (Both Loeb (140) established that growth of the transplant oc Loeb and Herzog had successfully given implants of a curred through proliferation of its peripheral cells, and sarcoma of the white rat to gray rats.) these usually took on the characteristic spindle-cell ap Jensen found that the histological features of the tumor pearance of the primary tumor tissue. Neither the remained constant throughout successive transfers in the original tumor nor any of the transplanted pieces were white mouse, and the growths remained mostly localized. accompanied by distant mÃ©tastases,although local or In agreement with Loeb's observation, Jensen discovered contact mÃ©tastaseswere frequently found. The rate of that the daughter tumors grew from peripheral nests of tumor growth remained relatively constant over the course cells of the transferred material, with the original mass of the experiments. Loeb (1902 [142]) subsequently re undergoing progressive ulcÃ©rationand degeneration. The ported the transfer of a rat thyroid sarcoma through 40 growth of these tumor islets was usually characterized by generations and the transfer of an adenocarcinosarcoma of typical mitotic figures, and the rate of growth remained the thyroid in rats through eight generations. He deter fairly constant throughout his experiments. mined that the transplantable sarcomas must be regarded Jensen also concerned himself with the question whether as true sarcomas and not as granulomas; the 48 successive he had actually demonstrated the transmission of cancer transfers of the first and second series showed that, except cells or merely an infective neoplastic agent. His data for a few minor structural variations based upon individual indicated only that a genuine transplantation of malignant cell differences, the qualitative character of the tumor tissue from animal to animal had been accomplished. As remained unchanged in each series. in the case of Loeb, Jensen did not eliminate the possibility Loeb's studies made it possible to assume that the tumor of a transmissible agent of cancer. Although he detected cells themselves were transplanted, whether or not they the presence of 'cellular inclusions' in most of his experi were accompanied by some unrecognized tumor-producing mental tumors (differing from Loeb's reports), he was un agency (141). The occurrence of bacteria within trans able to culture a bacterial or blastomycetic factor, nor planted tumors had no etiological bearing on the trans could he establish any evidence for the infection theory of mission of tumors. For example, inoculations of filtered cancer (122, p. 144). tumor fluids into normal rats were ineffective; culture Barrel.â€”Ina 1903 paper on the infectious epithelioses experiments and differential staining to detect the presence and epitheliomas Borrel (39) reported six passages through of cellular inclusions proved as unrewarding. In the inoculation of a spontaneous cylinder-cell epithelioma of case of the mammary adenoma, pregnancy was found to mice, a tumor similar to that reported by Morau more than induce a considerable increase in the tumor growth rate, 10 years earlier. Borrel found that the structure of this in agreement with Morau's finding. tumor remained constant throughout its passage, and each Similar studies were pursued by Maximilian Herzog in daughter tumor grew peripherally from the original im 1902. Herzog (117), who supplied Loeb with his original plant. Metastatic deposits frequently appeared in the sarcoma material, carried his transplantations over eight lungs (Livingood [138] first described pulmonary mÃ©tas generations, and he also noted that gestation appeared to tases in one of his adenocarcinomatous mice) and also in promote the growth of his sarcoma implants. In view of the lymph glands. Borrel proposed that the secondary Mayet's (1902 [150]) alleged production of epithelial lesions in the lungs established themselves through floating tumors in rats with inocula of human carcinoma extracts, masses of malignant cells which became trapped in the Herzog unsuccessfully attempted to induce tumors in pulmonary vessels. This conclusion was subsequently normal rats through inoculations of cell-free sarcoma supported by Haaland's studies (1905 [110, p. 184]) in

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1964 American Association for Cancer Research. TRIÃ“LOâ€”Foundationsof Cancer Research 11 which the dissemination of mÃ©tastasesthrough the general species various spontaneous carcinomas and sarcomas circulation was for the first time definitely demonstrated. occurring in rats, dogs, cats, and horses. Their experi Borrel concerned himself primarily with the 'parasitic' ments with mouse tumors involved twelve spontaneous and aspect of the transplant question. Within the cells of four established lines, chiefly those of Jensen and Borrel certain of the pulmonary mÃ©tastasesin mice Borrel al (1905 [18]). By 1904 the new scope of this research was legedly detected small, irregularly shaped, chromatin-like given concrete form through Bashford's conviction that, inclusions in the protoplasm adjacent to the nuclei. These "the problem of the genesis of a malignant new growth cellular bodies apparently resembled those which appeared must be distinguished from that of the circumstances in bronchial pustules caused by certain types of infectious which permit of its continued existence" (16). epithelioses, but at this time Borrel omitted further details The details of this conception constitute the subject of on the nature of these particles. (Borrel's work of 1904, the next section, but a few of its broader implications in which he claimed to have demonstrated the existence of should be stated. The work of Loeb and Jensen estab these cellular inclusions as the virus cancÃ©reuse,hasbeen lished that significant differences existed between the cited above.) Borrel urged immediate steps in securing re problems of tumor induction and tumor perpetuation by liable data on the production of experimental cancer in demonstrating that a transmitted growth stemmed directly mice which appeared to be particularly susceptible to from viable, transferred cells. Since tumor propagation, spontaneous tumors, possibly by virtue of cage infections under these circumstances, could no longer be considered or possibly through some hereditary predisposition (39, synonymous with the processes of infection, the hypothesis p. 116). that tumor growth required a continuous neoplastic stim Michaelis and Ehrlich.â€”The early work of the German ulus through a special cancer agent lost much of its appeal. cancer investigators largely involves the biological map The initiation of the neoplastic processes through the ac ping of the mouse tumor materials. Michaelis (155, 156) tion of some indirect excitatory influence still remained as at the Berlin Cancer Research Institute investigated the a clear possibility. Although the cause of hyperplasia tumor growth patterns in miceâ€”namely, 'Copenhagen' might depend, to some extent, upon cellular irritants, the and 'Berlin' mice, using the Jensen tumor and several nature of its transition into a malignant growth remained spontaneous growths which he discovered. As a result, unexplained. By 1905 investigators were turning toward Michaelis (157) devised the first nomenclature scheme for the new experimental rodent tumors to furnish answers these tumor materials as follows: Type 1â€”simple but oc for this problem, as summed by Bashford (1904 [16, p. 15]): casionally tubular, alveolar carcinoma; Type 2â€”adenocar- "... the nature of the transmissibility of cancer reduces cinoma, frequently characterized by the formation of cysts the field of inquiry to the cell again, and leads one to seek and papillae ; Type 3â€”unnamed, consisting of groupings of for the peculiarities in the cell-life of normal and cancer alveoli within the parenchyma, corresponding in gross ap tissues which limit the power of independent existence in pearance with the first type but with each alveolus con the former, and raise this power to the level of being the taining cells which wreathed the lumen in single layers, a chief characteristic of the cells of the latter." type comparable to the malignant adenomas. Gaylord, Clowes, and Baeslack.â€”In the spring of 1902 At Ehrlich's Institute for Experimental Therapy at rats bearing cystic sarcoma of the thyroid were brought by Frankfurt, where various aspects of the cancer problem had Loeb to the New York State Cancer Laboratory, but been under consideration as early as 1901, the introduction studies with this tumor were discontinued in October, 1902. of the first transplantable mouse tumors (the Jensen strain) From December, 1902, until the summer of 1903 rats were in the spring of 1903 significantly broadened the research not used in experimental work at the Buffalo laboratory. perspective (7). In 2J years, or up to 1905, 71 spontan Between July, 1904, and October, 1905, cystic sarcomas of eous cancers in mice were examined, only ten of which were the thyroid were discovered in three rats obtained for found to be transplantable, and of these four (Stamm studies other than tumor implantation, but kept in one of seven, eleven, sixteen, and eighteen) were passed through the cages formerly housing Loeb's tumor animals. Sub 60, 42, 42, and 40 generations, respectively (74). By cutaneous implantations of macerated tumor tissue and 1906 Ehrlich arid his associates (71) were working with a inoculations of serum found in the cystic cavity of these total of eleven transplantable mouse tumors from among a three animals gave rise to identical tumors in other rats, total of 94 spontaneous growths appearing in their labora and the tumor was subsequently propagated through ten tory stocks. Among other results, Ehrlich (70) described generations with mounting virulence through each trans a new species of transplantable mouse tumor, a spontan fer (104). The starting materials appeared to stem from eous chondroma. Simultaneously, Apolant (6) carried an endemic occurrence of sarcoma through a cage infection, out exhaustive studies on the tissue derivatives which gave a situation similar to that in which Loeb obtained his rise to the majority of epithelial tumors in mice. original tumor in 1900â€”i.e.,from an endemic outbreak of Bashford, Murray, and Cramer.â€”The initial efforts of sarcoma in Herzog's rats at the Chicago Polyclinic. The English cancer investigators, under the auspices of the possibility of tumor transmission through cage infections Imperial Cancer Research Fund (1902), reflect the same had been pointed out by Borrel (39), who noted the singu outlook as their colleagues in other lands. As early as lar frequency of adenocarcinoma in mice of one cage, and October 1903 Jensen's results were corroborated by the by Michaelis (157), who detected an unusual number of investigators of this Fund (15). With his associates, E. malignant adenomas in mice of the same cage. This prob F. Bashford, after 2J years' work, reported the complete lem was pursued by the Buffalo Laboratory in conjunction failure of over 900 attempts to transplant within the same with its attempts to localize a source of cancer infectivity.

In 1904 the first mouse carcinoma studies were taken up comprised several, well defined propagable growths. Two at the New York State Cancer Laboratory. Tumor- other rat neoplasms were described in 1906â€”atransplant- bearing mice obtained from Jensen's stocks led to the es able mammary carcinoma by Michaelis (158) and a sar tablishment of a tumor line at this laboratory (55), and by coma found by Flexner and Jobling (91)â€”which subse 1905 the 'Buffalo' adenocarcinoma had been propagated quently (1908) devolved into an adenocarcinoma. The through more than 30 generations. This category of rat neoplasms proved useful materials for research on tumor formed the basis of immunity experiments which several phases of tumor histogenesis. For example, Loeb will be considered in the following section. (141) observed various cellular alterations, such as alveolar Tyzzer.â€”1905also marks the date at which various in sarcoma, endothelioma, or myxoma, etc., through success oculable mouse tumor materials were made available to ive transfers of a diffuse spindle-cell sarcoma of the rat. the Harvard Cancer Commission. The Jensen tumor was He also noted the predominance of the sarcomatous ele received from England and the New York State Cancer ment, through suppression of the carcinomatous parts in Laboratory, a tumor strain was obtained from Borrel, successive passages, of the rat thyroid adenocarcinosar- and another from Ehrlich ('Stamm 11'); each of these, coma; this constitutes one of the earliest observations on with the exception of the Borrel tumor, was successfully the transformation of carcinoma into sarcoma in rodents. propagated (244). Ten transplant generations were se The rat tumors also provided materials for resistance cured with both the Jensen carcinoma and the Ehrlich studies. tumor by 1907. Spontaneous regressions occurred more Mouse neoplasms.â€”The most extensive experimental frequently in the Jensen than in the Ehrlich strain (which results in the field of tumor transplantation were achieved showed a greater regularity of growth). Significant through use of the mouse. Morau and, particularly, growth variations were noted in different breeds of mice; Jensen are responsible for the origins of these studies, and the inoculation of mice from one source always gave nega rapid succession of reports on diverse spontaneous mouse tive results. Pulmonary mÃ©tastasesoccurred in both neoplasms followed in the wake of Jensen's 1903 publica Jensen and Ehrlich tumor animals, but the lymph nodes tion. Together with the tumors discovered by Borrel and adjacent to tumors of both types were never involved. In Ehrlich, the discoveries of Haaland (1905 [110, p. 188]) of this respect inoculated tumors appeared to behave differ a squamous-cell carcinoma of the lower jaw of the mouse ently from spontaneous tumors found in animals in which and of Bashford, Murray, and Cramer (1905 [23]) of a pri invasive growths of the lymph glands commonly occurred. mary adenocarcinoma of the small intestines are additional These investigations were pursued by Tyzzer (245) in evidence of this development. Before the utility of the conjunction with other studies on the inoculability of spon mouse tumorsâ€”and the same applies to rat growthsâ€” taneous tumors. could be fully employed in various research capacities it was necessary to resolve two problemsâ€”namely (a) the CUMULATIVERESULTS structural origins of these tumors and (6) their authenticity Canine neoplasms.â€”The number of transplantable ani as neoplasms. mal tumors available to the cancer investigator by 1905 The first question was given detailed consideration by was small yet substantial. In dogs the observations of Apolant (6), and also by Bashford, Murray, and Cramer Novinsky and Wehr were followed by other reports of (19). All these investigators advanced histological proof transmissible canine tumors, each of which was becoming for the alveolar (mammary) origins of many of the mouse recognized as a species of the so-called infectious lympho- tumors reported from various laboratories through 1905. sarcoma. Knowledge of this tumor was materially ad Research on the histological differentiation of the neo- vanced from 1904 to 1906 by Sticker (236-238), Beebe and plastic tissues, as well as the transformation of tumor types Ewing (33), and others. The puzzling histological6 and in the course of successive passages through various species growth characteristics, as well as the irregular resistance of mice, was actively pursued by Ehrlich and Apolant (8, and immunity reactions associated with its passage, ap 75). Michaelis' classification marks the beginnings of a peared, at first, to limit the usefulness of this tumor for mouse tumor nomenclature, subsequently extended (i.e., research. The canine lymphosarcoma will be discussed by Apolant [6, p. 11]), and this work provided descriptive more fully in the next section. standards far more exact than the initial designations of Rat neoplasms.â€”In rats the epithelioma described by 'Jensen's' tumor, 'Borrel's' tumor, etc. Proof that the Hanau and the sarcomas reported by Velich and Loeb mouse neoplasms were true cancers was first advanced by Livingood's 1896 study (138). His observations were ex * Novinsky and Wehr described the canine tumor as a carci noma. Geissler (106) at first regarded the canine tumor as a tended by Borrel (39), who discovered lung and lymph carcinoma, but he later accepted the diagnosis of sarcoma. Du- node mÃ©tastasesin tumor-bearing mice, and by Haaland play and Cazin were uncertain as to the nature of their canine (110, 111), who investigated the modes of metastatic in tumor, but Smith and Washbourne (233, 234), Sanfelice (216), filtration. Bashford and Murray (17 [footnote]), at first and Sticker were certain that the canine tumors which they dis covered must be regarded as round-cell sarcomas. However, unable to corroborate these findings, subsequently (1905 Bashford, Murray, and Cramer (21) referred to the canine tumor as [22]) described mÃ©tastasesinthe lungs of mice given inocu an infectious granuloma. Sticker secured specimens of the lations of the Jensen tumor. Another criterion of malig tumors studied by Wehr, Geissler, Smith and Washbourn, San nancy, infiltrative growth, was reported in 1905 for the felice, and Bashford, and submitted them, together with his own specimens, to a large number of German pathologists, all of whom Jensen tumor by Bashford, Murray, and Cramer (22, pp. agreed upon the diagnosis of round-cell sarcoma. (See Beebe 23, 39), and also by F. W. Baeslack (9). Similar studies and Ewing (33, pp. 221-22)). were carried out on other tumor strains. The evidence

TABLE 2 TUMORSEXPERIMENTALLYPROPAGATEDWITHINTHE SAMESPECIES(TO 1905) The doubtful experiment of Doutrelepont (64) is not included in this list

transfer identification of AuthorNovinskyWehrPfeifferHanauMorauv. typeAnaplastic gener parent and ations211217121181401986t15tHistologicaldaughtergrowths*+-?+

174253, venerealsarcomaepithelial carcinoma; lymphosarcoma)fVaginal(transmissible 254183113-115161-163768652, and prepucial carcinoma (trans missiblelymphosarcoma)tMelanotic carcinoma?Squamous-cell carcinomaCylinder-cell ratWhite , Jenny(119)+++--+++++++â€”++ epitheliomaSpindle-cell mouseRatRatDogDogWhite EiselbergFirketDuplay fibrosarcomaSpindle-cell sarcomaVaginal andCazinGeisslerVelichSmith67,68106247233, (transmissiblelymphosarcoma)epithelial tumor tVenereal papilloma (transmissible lympho sarcoma)!Subperiosteal sarcomaVenereal ratDogWhite andWashbourneLoebJensenHerzogBorrelMichaelisSani234140-142120-12211739153-157216236, sarcoma (transmissible lympho sarcoma)!Cystic adenocar-cinosarcomasarcoma of the thyroid; ratMouseWhite mammaryadenocarcinomaAlveolarof the thyroid;

carcinomaCystic thyroidCylinder-cellsarcoma of the ratMouseMouseDogDogMouseNo. epitheliomaMammary adenocarcinomaVenereal eliceStickerEhrlich papilloma (transmissible lympho sarcoma)!Venereal 237,23871-75Year1875-771887-881888?1888-891889-931890189218921895189818981900-011901-03190219031904-190419041904-Tumorsarcoma (transmissible lympho sarcoma)!Alveolar andApolantRef.173, carcinomaAnimalDogDogMouseWhite

* Microscopic confirmation that the growth has been transmitted. ! The transmissible lymphosarcomas of dogs have been variously interpreted as carcinomas before the work of Smith and Wash- bourne (233, 234) and particularly Sticker (236-238) and Beebe and Ewing (33). ÃŽTumorline subsequently continued. for the malignant character and heterogeneous distribu for this perhaps follows Herzog's idea that the cancer virus tion of the mouse neoplasms now established a firm basis represented parasitism so highly adapted to the cell that for a comparative experimental approach to the problem its reactions could be approached only through those of of malignant new growths in humans. the cancer cell itself, a view which necessitated a closer scrutiny of tumor growth. A partial list of tumors trans THE INFECTIONTHEORYIN TUMORTRANSPLANTATION planted within the same species appears in Table 2. RESEARCH The reports of 'cage infections' promoted continued STUDIES ON TUMOR GROWTH7 arguments on the contagious influences of neoplastic THE EXPERIMENTALPRODUCTIONOFTUMORS diseases, and in a few institutes, such as the New York The problem of tumor growth has been approached in a State Cancer Laboratory, the issue continued to be actively variety of ways, many of which go back to the formative pursued. Borrel argued that the transplanted tumor years of cancer research (80, p. 127). Before the turn of represented only a secondary stage of cancer, malignant growth, whereas the actual solution to the cancer problem 7The title selected for this section is valid only in a limited was to be found in an analysis of the viral-induced proc historical sense. Several of the topics discussed are no longer esses of cellular transformation from the normal to the meaningful. Moreover, the etiology of the neoplastic process is malignant state. Borrel's virus, viewed merely as a trig not clearly distinguished from the processes of cellular growth. For example, the two theories on the nature of the neoplastic ger of malignant processes, was able to withstand many of process referred to in the opening paragraphs differ in kind from the objections to the other alleged types of cancer para the remaining topics which deal with the growth of already es tablished tumors. This dichotomy would be mandatory in a sitism. Their etiological beliefs notwithstanding, the modern review of tumor induction, but it was not apparent to an interests of the virus adherents coincided largely with those earlier generation. The topic heading simply reflects the older of investigators who remained uncommitted. The reason perspective.

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1964 American Association for Cancer Research. 14 Cancer Research Vol. 24, January 1964 the century the possibility of understanding the nature of The cell transfer studies gave Ribbert's and related malignancy by finding means whereby the power of malig theories only partial experimental support. The fact that nant growth could be conferred upon normal tissue sug a few nonmalignant tumors and dermoid cysts could be gested itself to the cancer investigator. The objectives induced experimentally, as well as the fact that fetal pursued in these studies usually followed two conceptions : tissues were found to have a much greater inherent power (a) tumor induction through cell transfer and (6) tumor of growth than adult tissues, appeared to conform to cer induction through cell irritation (259, p. 20). tain conditions imposed by one or another of these hy Cell transfer theory.â€”The cell transfer studies, which potheses (172, p. 219). However, cellular proliferation most commonly involved the implantation of normal could be explained without resorting to the growth-restrict tissues into animals of the same or similar species, are part ing capacity of the structural medium. The factor respon of the early record of transplantation research. As early sible for unlimited growth might exist as a direct stimulus as 1874 Zahn (264) implanted various tissues of adult on the cells. This assumption underlies the experimental rabbits into other rabbits with no apparent result except approaches to tumor induction through cell irritation. when embryonal cartilage and bone were substituted, in Cell irritation theory.â€”Theessentials of the modern cell which cases the grafts proliferated. Similar studies were irritation theory are found in Virchow's views, and the pursued in other laboratories (89, 125, 133, 258). The role of environmental 'trauma' (external functional stimuli) most dramatic of these appears to be the widely publicized as a cause of cancer was suggested by various authors after case of Lack (1900 [130]), who reported that fragments of 1870. The occurrence of epithelial cancer among workers germinal epithelium from the rabbit's ovary retained in in the coal tar and paraffin industries was first noted in the peritoneal cavity of the same animal gave rise to 1875 by Volkmann, and Tillmanns in 1880 discussed from masses of new growth resembling typical ovarian cancer. a clinico-theoretical standpoint the possible carcinogenic However, Lack's data could not be duplicated (94). effects of tar, soot, and tobacco smoke (241). Martin's Isaac Levin, beginning in 1897 (135), treated rabbits work of 1882-83 ranks among the first experimental at and dogs with implants of normal adult tissues of the same tempts to produce cancer through irritative stimulus. species without success except for skin grafts. Similar This investigator (132) administered injections of oil of experiments were performed by Nichols (1904 [172]), who sweet almonds converted into an irritant by the addition concluded that (a) misplaced epidermal tissue (both adult of croton oil to a rabbit, and he found that the animal had and fetal) maintains its 'potentiality of growth,' its dis developed lung lesions which corresponded exactly to the tinctive characteristics, and its capacities to produce form of epithelioma designated by Malessez as epithelioma nodules analogous to dermoid cysts or more complicated muquoide. Hanau (1889 [114, pp. 115, 338]) painted teratomas, (6) epithelium of highly differentiated function preparations of gas and coal tar upon the scrotum of white is not able to maintain its power of growth and prolifer rats as well as upon the skin, vulvae, nipples, and secreting ation, (c) fetal tissue shows greater 'potentiality of growth' and nonsecreting mammae of dogs, maintaining the than does adult tissue, (d) epithelial infiltration and epi applications for several months, but this treatment re thelial mÃ©tastasesare never observed in the implants, (e) sulted only in local inflammatory changes. Hanau's implanted fetal cartilage retains the same 'potentiality of experiment was repeated without success by Cazin (1894 growth' as adult epithelium, and (/) transplanted fetal [51]). tissues tend to reproduce the ultimate stage of their normal In 1900 Brosch (44) reported the development of atypi development. cal epithelial growth when he applied a xylol-paraffin solu The cell displacement work largely developed from tion to the crushed skin of a guinea pig. Successive appli various early theories on the biological origin of cancer, cations were made after wound infiltration had receded, several of which have been outlined in the "Introduction." and growths appeared within 10 weeks after the begin A later concept, Ribbert's hypothesis (1894 [196], 1896 ning of the experiment. No particular interest was given [197]), shows the influence of Cohnheim's and Thiersch's these studies until the investigations of Fischer (87,88), be thinking. Ribbert postulated that the tissue environ gun about 1905, implicated the organic stains Scharlach ment limited the proliferative activity of its cellular com R, Sudan III, and indophenol in the etiology of carci ponents by means of growth restrictions imposed by the noma. By the turn of the century a number of experi structural organization. Cells that became separated mentalists believed that external stimuli induced an 'ana- from these restraining influences ('tissue tension') were was foreshadowed by Weigert (1882 [255]) and Roux (1888 [202]), capable of unlimited growth; benign growth resulted if both of whom asserted that the regenerative capacities of cells the cells were partly dislocated from their normal tissue are fixed at the time of their derivation from the ovum and cannot strata ; malignant growth resulted if they became completely be subsequently increased by any external stimulus, although they detached. Ribbert's concept of 'tissue tension,' and the are constantly restrained by the organization. Other contem porary opinions are consonant with the Weigert-Roux Theory. views which preceded it, suggested that rapid cell pro Thus, Klebs (1887[126])proposed that tumor cells were fertilized liferation resulted through a break-down of the growth- cells conjoined with leukocytes; Waldeyer (1887 [252]) explained controlling mechanisms.8 their origins through the mechanism of parthenogenesis; Reckling- hausen (1896 [190])postulated that cancer cells were established 8Actually this assumption subsequently grew out of Ribbert's through the conjunction of endothelium and fibroblasts, and concept. Ribbert himself insisted that cancer cells do not pos Bashford (1904 [17]) assumed that tumor cells occurred through sess special powers of proliferation, but that these cells, freed from the nuclear conjunction of equivalent cells. The development the restraints of tissue tension, merely exhibit those powers of of the above-mentioned implication of Ribbert's theory, the cell growth with which they are endowed from the ovum. This view autonomy idea, will be discussed elsewhere.

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1964 American Association for Cancer Research. TRIÃ“LOâ€”Foundationsof Cancer Research 15 plastic' process of the cell which involved no change in its vidual predisposition or immunity'9 to transplanted position or its relationship with neighboring cells. Sup tumors. porting this view, Levin (135, p. 154) pointed to (a) In 1905 Loeb (145) presented further results on the Ziegler and Oblensky, who demonstrated that applica 'energy' of tumor growth and on experimentally produced tions of small amounts of phosphorus and arsenic to the variations of the rate of growth. These results affirmed epithelial cells of the bile duct caused the proliferation of the conclusion that not only species differences but varia these cells, (6) to Yakimowitch, who had shown that ultra tions among individuals or families markedly influenced violet light induced cellular proliferation in the triton, and the rate of tumor growth. Loeb also demonstrated that (c) to the experiments of Hertwig, Morgan, and J. Loeb, it was possible to obtain experimental growth variations whose studies on pathogenesis established that chemical through reinoculation. Etiological investigations of this stimuli initiated partial development of the unfertilized progressive increase of tumor growth in subsequent genera egg- tions led him (145, pp. 266-67) to assume that enhanced Growth mechanisms.â€”Despite the many inconclusive growth 'energy' might occur (a) through injury to the attempts to produce cancer in the laboratory, these efforts connective tissue capsule surrounding the tumor in which promoted an intensification of interest on the mechanisms the tension inhibiting further growth of the tumor would of normal and malignant growth. In 1903 L. Loeb (144) be removed ; (6) through the direct removal of the tension pointed out the importance of research on embryonic de imposed by the surrounding capsule, in which case the velopment with reference to tumor production from the 'energy' of tumor growth would be directly increased; or viewpoint of Cohnheim's and Ribbert's theories. Loeb (c) through the augmentation of tumor nutrition as a argued that a solution of the problem could stem only from consequence of an improved vascular supply. Immunity a knowledge of the biological behavior of transferred or susceptibility conferred through internal chemical embryonic cells. The work of Roux on the cleavage agencies (cytotoxins or anticytotoxins) might also be im process of frog's eggs, the studies of Spemann on the plicated (1902 [141, p. 61]). autonomous growth of cells isolated from the various Jensen concurred with Loeb's conclusion that slight stages in the embryonation of frog eggs, and the experi family variations were responsible for the failure to obtain ments of Hertwig and Morgan on the segmentation proc greater tumor transplant yields. Jensen (122, pp. 30-31) esses of sea urchin's eggs had promoted such knowledge. was the first to implicate serological reactions, such as Research involving the injection or implantation of em those hinted at by Loeb, with active resistance to trans bryonic or adult tissueâ€”here Loeb recapitulates experi planted cancer; he reported the regression and subsequent ments of the type described in the cell transfer workâ€” absorption of a tumor of a mouse which had received injec reinforced this knowledge, although these studies had not tions of serum from a rabbit previously given inoculations conclusively demonstrated that the growth capacities of of mouse cancer cells, and he proposed the exploration of embryonal transplanted tissues were much superior to similar immunological measures on a clinical level. En those of adult tissues. Loeb concluded that the various couraged by Jensen's accomplishment and his own observa data had not substantiated any of the theories accounting tions on the spontaneous regression of transplanted mouse for malignant tumor formation from the standpoint of epitheliomas, Borrel (39, pp. 116-17), in 1904, urged the atypical embryonic development through the separate or extensive application of serological technics in experi joint applications of Cohnheim's views, and related ideas, mental cancer. or from the standpoint of atypical regenerative phenomena. The influences of the genetic soil came under special On the contrary, they lent support to the opinion that the attention when attempts to propagate the Jensen car causative factors of growth remained almost entirely cinoma were made in various European and American unknown. laboratories. Bashford and Murray (16), with the knowl edge that Jensen's tumor had grown best in Danish white RESISTANCEANDIMMUNITYIN mice, found that English white mice were less susceptible EXPERIMENTALCANCER to the tumor. Other English varieties usually proved Transmissible rodent neoplasms.â€”Theorigins of a funda more susceptible. These investigators (13, 20) also dem mental biological approach to experimental cancer are onstrated that transfers of tumors of Danish, French found in Morau's work of 1889-93 (161-163). Morau's (Borrel), and German (Michaelis) mice to English varie study was the first to consider in detail the nature of the ties proved extremely difficult in the case of tame mice, soil; specifically, the influences of age, sex, race, pregnancy, and attempts to transmit tumors from tame to wild mice heredity, and other factors on the development of the generally failed. Subsequently (1908 [26]), they reported transplanted tumor. Similar observations were substan that imported tumor strains grew in a high percentage of tially implemented only after the introduction of Loeb's rat sarcomas and Jensen's mouse carcinoma, and other 9The important distinction between 'resistance,' implying diminished liability to the development of cancer, and 'immunity,' transmissible tumors, into various laboratory programs. implying protection against the inception of cancer, was first Among earlier reports on this subject Loeb (140, p. 36) brought out by Bashford, Murray, and Haaland (27) in 1908. noted that rat sarcoma transplants established themselves Since both terms were used synonymously throughout the period under review they will be treated in the same context on the fol as well in old and young, male and female rats, although lowing pages. No attempt is made to distinguish between 'active' these transplants were commonly found to regress and and 'passive' immunity and resistance, 'acquired' or 'induced' disappear. On the basis of his preliminary observations immunity and resistance, etc., since these definitions were created Loeb (141, p. 60) suggested that there existed an 'indi for the most part at a later time.

the recipients of transplants. Michaelis (153, 154), work against both the sarcoma and carcinoma. Ehrlich sug ing with Jensen's carcinoma, obtained less satisfactory gested that such 'acquired' resistance established by one results in 'Berlin' mice than in 'Copenhagen' mice, and tumor strain might extend through several strains. He Haaland (110, p. 187), at the Pasteur Institute, had diffi proposed that this phenomenon constituted a state of culty propagating the same tumor in French and Russian 'pan-immunity.' This concept was challenged from many stocks. quarters, especially by the English workers, and it evoked Gaylord's group had less difficulty in transferring tumor considerable controversy by 1910.10 specimens supplied by Jensen to white 'Buffalo' mice. Transmissible canine neoplasms.â€”Strong supporting evi Shortly after the start of their experiments (September- dence for the existence of immunity to cancer was achieved October, 1904) the Buffalo workers (105) noted the spon through research on the canine venereal sarcoma. Wehr taneous regression and disappearance of tumors in a (1888-89 [253, 254]) is credited with the first observations number of mice which hitherto had borne active growths. on the characteristics of a transferred 'medullary car Recurrences of the tumor were not obtained in these ani cinoma' (lymphosarcoma) of dogs, but Sticker's descrip mals. Controlled experiments were undertaken to deter tion of this class of tumors largely opens the modern mine whether the blood serum of mice in which tumors had experimental literature of the subject. A 1904 report by regressed possessed an immunizing property which could Sticker (236; see also 237, pp. 443-44), showing results ob (a) inhibit the growth of large tumors or (6) cause the total tained from the transplantation of sixteen canine tumors, regression of smaller tumors and thereby confer the host most of which were of the venereal type, indicated that the with a permanent immunity to cancer. A few regressions virulence of transplanted lymphosarcoma did not diminish were noted. These investigators (105, p. 92) simultane through successive passages. Sticker found that the de ously reported that preliminary biochemical studies on velopment of the transplanted lymphosarcoma was not the carcinostatic property of immunized mouse serum significantly influenced by the age, relationship, or race of pointed to the presence of a cytolysin. the animals, and that dogs in which the lymphosarcoma In a subsequent report (November, 1905 [57]) Clowes had become successfully established and then subsequently and Baeslack reinforced the conclusion that mice in which was absorbed proved to be immune to further implantation tumors had regressed were endowed with an active im attempts. Sticker indicated that he would present a suc munity against reinoculation. Cancer inocula previously ceeding paper on the preparation of an 'immune' serum combined with the serum of mice in which tumors had from dogs in which a total regression of the tumor had regressed gave rise to a smaller production of tumors than occurred.11 inocula of the same materials combined with the serum of The problem was taken up by Beebe and Ewing who uninoculated animals. It was also found (57, p. 971) that began a series of dog lymphosarcoma transfers in 1905. the percentage of tumor mice surviving a specified time By 1906 these authors, who had propagated the tumor after inoculation was larger in the 'immune' than in the through five generations, concluded (33, p. 217) that: (a) 'normal' series. By 1906 (103) the Buffalo group estab the tumor grew better in old dogs; young and vigorous lished that the spontaneous cure of cancer, under limited animals showed the greater capacity for spontaneous re experimental circumstances, in mice given inoculations covery; (6) rapid growth occurred under poor nutritive occurred in about 23 per cent of the animals and that the conditions, but improvement of health following operative chances of spontaneous cure were inversely proportional removal of a portion of the tumors was often accompanied to the size of the tumor. This outlook was strengthened by a regression of the remainder ; and (c) it was possible to by other reports of acquired immunity to transplanted produce growth of a second implant in animals in which cancer, such as those by Flexner and Jobling (rat sarcoma, tumors regressed. However, multiple tumors grown in the 1907 [92]), Lewin (rat carcinoma, 1907-8 [136, 137]), and same host always regressed simultaneously, although in by collateral evidence on mouse cancer accrued by Mi any susceptible animal only a portion of the implants chaelis (153, 154). might grow. Bashford, Murray, and Cramer in 1905 advanced the These results supported the conclusion of Sticker that opinion that re-inoculation with the same tumor into ani 10Ehrlich's approach toward propagable new growths in mice mals which had resisted the initial implantation resulted in appears to be correlative to general problems in immunology nearly the same percentage as the number of first 'takes' (118). Apolant (8) found that pre-inoculation with certain of the (24); later (1906 [14]) Bashford asserted that, by repeat low-virulence tumors resulted in a greater measure of resistance to subsequent inoculation with a highly virulent one. Further ing the procedure on animals remaining unaffected and more, if mice were preinoculated with a carcinoma they appeared discarding those in which tumors developed, mice ul to be protected against subsequent inoculation with an otherwise timately could be obtained which exhibited a more pro highly virulent sarcoma. Ehrlich compared these types of 'ac nounced power of resistance. In 1908 [26]) these investi quired' immunity to types which he had investigated in other gators, by standardizing the dose requirement, were able to problems, and he concluded that only a superficial resemblance existed. He was thus led to assume that the state of acquired bring their data into approximate agreement with the immunity in mice represented a condition of 'athrepsia' resulting findings of other researchers. through a depletion of the nutrients necessary for tumor growth. A 1906 report by Ehrlich (71, pp. 72, 92) reported that This conception was tested through series of 'zig-zag' tumor propagations (mice to rats to mice). (For a summary of these mice given inoculations of a hemorrhagic tumor of low studies consult Ehrlich's article, Ueber den jetzigen Stand der virulence were protected against more vigorous growths Karzinomforschung, 1909 [118, pp. 550-562].) and that repeated unsuccessful inoculations either of the 11I have been unable to locate a later paper by Sticker devoted mouse sarcoma or the mouse carcinoma gave protection specifically to this topic.

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1964 American Association for Cancer Research. TRIÃ“LOâ€”Foundationsof Cancer Research 17 the transmissible lymphosarcoma of dogs was a neoplasm Jensen mouse carcinoma transplants against exposures to and not merely an infectious granuloma, as Bashford main liquid air and chloroform, and Clowes (1906 [56]) charted tained (21). The fact that an acquired immunity to the the inhibitory effects of various concentrations of disin disease could be induced under experimental conditions fectants upon the Jensen and highly virulent 'Brooklyn' appeared to be well established, and this development in (carcinoma) mouse tumor. dicated significant consequences for research on human Radiations.â€”Jensen (122, pp. 136-37) first noted that cancer. Although there were no apparent similarities intense light decreased the viability of mouse tumor between the canine type and types found in humans, it slices. In the first of two papers issued in 1904 Apolant was the judgment of Beebe and Ewing (33, p. 223) that (4) reported the regression and disappearance of numerous the spontaneous disappearance of the dog lymphosarcoma transplanted mouse carcinomas repeatedly exposed to was analogous to the occasional disappearance of sarcoma radium. Apolant (5) postulated that radium exerted a and even carcinoma in man, according to the review of specific action upon malignant cells, since it appeared to Orth (1904 [178]). (The same conclusion was drawn by cause the total absorption of cells or, in partly regressed the Buffalo workers [103] from their work on immunity to tumors, the conversion of cells into necrotic masses. He cancer in mice.) did not elaborate upon the nature of this selective effect, Further studies on immunologie protection. By 1905 a but Neuberg (1904 [165]), working with human cancer number of investigators were passing from the question of tissue, suggested that radium irradiation suppressed cellu whether active resistance could be induced experimentally lar catalysts ('ferments'), except those involved in 'auto- to the question of the nature of this resistance. Loeb (142, lytic' activity. This view was supported by Wohlgemuth pp. 176-88) as early as 1902 had reported the cessation of (1904 [261]), but Schwarz (1903 [224]) proposed that ra growth and regression of transplanted rat sarcomas, and dium treatment disrupted lecithin metabolism. Schwarz's he also succeeded in showing that, when a regressing tumor conclusion was not borne out by Obersteiner and Okada was subdivided and replanted in the same host, it would in (1904 [176]), who found no pronounced cellular impair many rases undergo rapid proliferation (140). This sup ment of the lecithin-rich nerve tissues of mice exposed to ported the assumption that local, growth-limiting factors radium. were at work, and Loeb argued for the 'blocking' action of Bashford, Murray, and Cramer (1905 [25]), who em the connective tissue capsule which invaded the cellular ployed radium as well as radioactive lead, confirmed the edges, thereby interrupting the vascular supply. occasional curative effect of radium upon the Jensen mouse Indications of other complex factors in the resistance to carcinomaâ€”a finding Jensen had communicated to themâ€” experimental cancer began to appear by 1905. Bash- but they were unable to establish whether a selective ford's group reported (1905-06 [14]) that injections of action upon the cell was responsible for this phenomenon. normal mouse blood, prior to inoculations of the Jensen They were able to corroborate Apolant's data, and that carcinoma, secured protection against the tumor. In obtained for human materials by Exner (81, 82, 83), on Ehrlich's Institute, SchÃ¶nediscovered (1905-6 [221]) that the histological appearances of irradiated cancer tissue. preliminary injections of mouse embryo and normal adult However, in spite of histologically evident damage, cell tissues induced resistance in mice to the virulent 'Stamm division continued, and tumor tissue could be trans 5' alveolar carcinoma. Similar reports of induced resist planted successfully after long exposures to radium. This ance to experimental cancer in mice following the infection indicated to Bashford that absorption resulted from of normal tissues were issued by Borrel (1907 [41]), BridrÃ© factors other than directly impaired cellular metabolism. (1907 [43]), and by Michaelis, Fleischmann, and Pincus- Radium applications were followed by extravasation of sohn (1907 [159]). Lewin in 1907 (136) augmented these blood into the tumor tissues, and this led Bashford to the findings by producing resistance against his rat carcinoma supposition that cell absorption might occur through an and Jensen's rat sarcoma by a single injection of normal obstructed vascular (nutritional) supply (a) as a result of rat blood. scar tissue formation in healing, (b) partly through the effects of pressure exerted by the contracting cicatricial PHYSICALANDCHEMICALRESEARCHON tissue (or by a combination of both), and (c) partly through TUMORCELLS phagocytosis (25, p. 59). To test this hypothesis the Temperature and chemicals.â€”With experimental tumor English workers (25, pp. 60-61) treated tumor-bearing strains available cancer investigators were able to explore mice with adrenalin to promote elevated blood pressures the problems of neoplastic growth on the fundamental and capillary hemorrhages into the tumor tissues, and this cellular levels. Loeb found that he could substantially procedure allegedly caused functional disturbances similar lower the virulence of rat sarcoma transplants by exposing to those found in radium-damaged tissues. the tumor cells prior to inoculation to temperatures beyond Loeb (141, p. 70) subjected rat sarcoma tissues to x-rays an optimum (43Â°C.),and to various chemical solutions. and found that the cells survived short exposures and were These facts suggested that the proliferative 'energy' was able to maintain their virulence in subsequent transfers, directly proportional to cell vitality (145, p. 269). Jensen although centralized degenerative softening of the tumors (122, p. 141) presented more exhaustive data on the effects frequently occurred. Herzog (117, p. 79 [and n. 1]) re of heat, cold, desiccation and the action of antiseptics on peated this experiment, but he was unable to affirm any mouse tumor tissue, and corresponding data were fur thing more than a 'temporary improvement" in rapidly nished by Sticker (236, p. 444) for the canine lympho growing sarcomas submitted to x-ray treatment. sarcoma. Similarly, Michaelis (1905 [156, p. 204]) tested Biologic implications.â€”The therapeutic implications of

research on the destruction of tumor tissues through (See Wolff [263], 2: 445-63). In an 1899 study of the physical and chemical agents was apparent to the early water-soluble proteins extracted from cancer and normal cancer investigator, but this research was also largely human tissues, Petry (181) suggested that autolysis pro prompted by his desire to gain a fundamental insight into ceeded at a greater rate in malignant tissues. Autolytic the physical and chemical nature of neoplastic growth. degradation in cancer appeared to result in a build-up of (See G. H. A. Clowes' discussion of 'vital' and 'toxic' noncoagulable protein substances at the expense of heat- theories of cancer (1903-4 [54])). Utilization of the labile proteins, corresponding to the reactions which had propagable animal tumors created an awareness that cell been previously reported by Salkowski for the autolysis of activity was delicately adjusted to various metabolic and normal liver and muscle. Subsequently, Petry (1902 environmental factors. For example, research on the cytol- [182]) suggested that autolysis in cancer resulted in the ysins and cytotoxins proved the futility of transmitting release of several amino acids and purines in amounts cor cancer of human origin to animals and of transplantations responding to those found in autolyzed normal tissues (see within different species (16, p. 12). Investigations on the Table 3, .4). Autolysis thus appeared to be responsible immunological reactions in cancer were supplemented by for approximately the same qualitative transformations in an intensive exploration of tumor chemistry. This work proteins of both normal and neoplastic tissues, a conclu is part of a greater search for biochemical distinctions sion supported by protein analyses of fresh tumor prepara between normal and malignant tissues, an endeavor tions. Petry (182, pp. 98-99) also demonstrated that considered, by 1905, necessary for an improved knowledge injections of fresh or autolyzed tumor products did not of neoplastic processes. alter normal nitrogen balance in dogs, a fact which indi cated that cancer extracts did not affect endogenous meta BIOCHEMICALCHARACTERISTICSOFTUMORCELLS bolic processes. Protein constituents.â€”Petry is responsible for one of the H. Wolff (1905 [262]) was unable to detect any qualita first studies on the biochemistry of tumors, although there tive difference between the protein composition of various are many prior reports on chemical constituents through malignant and normal tissues from humans, except for routine analyses of urine and blood from cancer patients ostensibly higher proportions of euglobulins to pseudo-

TABLE 3 ANALYSESOPCHEMICALCONSTITUENTSOFTUMORS The data presented in this table are epitomized to show the trends in early biochemical research on cancer in terms of chemical identifications and are valid only in this restricted sense. The reader is referred to the original articles for the full details of these experiments and for discussions of the significance attached to them in the research of an earlier period.

FREE PROTEINCONSTITUENTSIDENTIFIEDIN AUTOI.YZEDANDFRESHTUMORTISSUEEXTRACT(HUMAN) AUTHOR REF. Aspartic Glutamic TpSÃ•T Alanine acid acid Glycocol Leucine Lycine Se

A. Petry 181, 182 B. Wolff 262 C. Bergell and Dorpinghaus 36 D. Beebe 29

FREE INTRACELLULARENZYMESIDENTIFIEDIN TUIIOKTISSUEEXTRACTS(HUMAN) AUTHOR REF. Amylase Catalase Invertase Lipase Mal tase Oxidase (Peroxidase) Proteolytic

E. Buxton 46 F. Harden and MacFadyen 116

NUCLEICACIDCONSTITUENTSIDENTIFIEDIN TUMORTISSUEEXTRACTS(HUMAN) AUTHOR RET. Nucleoprotcin (Nuclcohistone) Free pentose Nucleophosphorus

G. Bang 11 H. Beebe 31 I. Beebe and Shaffer 34

INORGANICCONSTITUENTSIDENTIFIEDIN TUMORTISSUEEXTRACTS(HUMAN) AUTHOR REF. Fe Ca' Na

J. Beebe 30 * The significance of the calcium potassium balance with respect to tumor growth activity was suggested by Beebe and substan tiated experimentally by Clowes and Frisbie (58) in the Jensen mouse adenocarcinoma.

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1964 American Association for Cancer Research. TRIÃ“LOâ€”Foundations of Cancer Research 19 globulins. Wolff (see Table 3, B) did not isolate amino postulated that cachexia in cancer was merely the exten acids from cancer extracts, but in several cases the propor sion of this impaired metabolism to generalized functions. tion of albumins to globulins appeared to be higher than This hypothesis, endorsed by Neuberg (1905 [167]), did in normal cell extracts. He concluded that the latter not gain wide acceptance because it patently disregarded result was more apparent than real, since it could be largely many previously reported results and rested upon several traced to artifacts resulting from the isolation technic. misinterpretations. For example, Petry's work did not More specific data, reported by Bergell and DÃ¶rpinghaus suggest that tumors possessed 'heterolytic' activity. (1905 [36]), suggested high proportions of amino and di- Nucleic acid constituents.â€”-Amore telling contemporary amino acids in various cancer tissues from humans, but the criticism (79, p. 79) of BlumenthaPs hypothesis was that relative amounts of leucine in these tissues appeared to be it failed to account adequately for nucleic acid-bound pro smaller than those found in normal tissues (see Table 3, C). teins or 'nucleoproteids' (nucleoproteins). A representa Beebe (1904 [29]) indicated that leucine, tyrosine, and tive of this category, 'nucleohiston' (nucleohistone), had tryptophan appeared to be the most prevalent amino come under intensive investigation after Kossel and his acids in human neoplasms under autolytic conditions (see students in the 1880's and 1890's identified it as a promi Table 3, D). nent constituent of blood cells, thymic and lymphatic tis Enzymes.â€”The nature of cellular 'ferments' in cancer sue. A running controversy after 1900 centered on the was first taken into consideration by two American investi question of whether nucleohistone precipitated from brei gators, B. H. Buxton and Philip Shaffer (at the Loomis could be considered material present in the cell nucleus or Laboratory for Experimental Pathology, Cornell Univer whether it merely represented a mixture of nucleic acid sity). These workers (1903 [46]), utilizing the contem and protein which combined as a result of the precipita porary technics of microbial enzymology, presented data on tion reaction (31). 'intracellular' enzymes occurring in 30 malignant tumors Bang (1903 [11]) reported that he was unable to detect (see Table 3, E). Amylase and various proteolytic nucleohistone in various human neoplasms, except in one enzymes, as well as catalase and peroxidase, were com case in which a 'nucleoprotein-like' substance was de monly found. In a second paper (1904-05 [47]) these posited. However, extracted materials from a growth in workers carried out the same procedures on a variety of the inguinal lymph gland metastatic from a round-cell sar embryonal and normal adult tissues. This study indi coma of the testes gave a typical nucleohistone reaction. cated that there were no significant differences in the On this evidence Bang proposed that the sarcoma resem enzyme composition of normal tissues and of tumor tissues bled normal lymphatic tissues; the fact that histone was except for relative amounts of enzymes which appeared to not usually found in human testicular tissue led him to be higher in normal adult tissues and lower in embryonic assume that the primary growth stemmed from an em tissues; this suggested to Buxton (46, p. 370) that cancer bryonic, lymphatic cell group, an argument which he ad apparently did not represent misplaced embryonal ele vanced as proof for Cohnheim's theory. ments. These investigations failed to establish a hypothe Beebe (1905 [31, pp. 344-45]) presented results of a sis that 'suboxidation' (selective oxidation) played a role nucleohistone analysis of neoplastic growths from humans. in tumor formation. The substance was identified with certainty only in cases A less detailed study of tumor enzymes was undertaken involving lymphatic tissues (see Table 3, H). Although by Harden and MacFayden (1903 [116]) who analyzed, by this finding corroborated Bang's, Beebe gave it an alto unspecified methods, the enzymes in broken cell extracts of gether different interpretation. The abundance of nucleo normal and cancerous tissues, duplicating Buxton and histone in the secondary growths in the lymph glands and Shaffer's results. However, this study established the its regular absence from the primary growths signified occurrence in cancer extracts of proteolytic enzymes active that, chemically, mÃ©tastaseswere not similar in all re in both acid and alkaline solutions (see Table 3, F). spects to the primary growth. Beebe concluded that Harden and MacFayden did not venture an interpretation mÃ©tastasesin some degree were capable of receiving a of their results. chemical 'impress' from their environment, although they Although these investigations revealed no enzymatic could be considered histologically identical to the primary reactions exclusively attributable to tumor metabolism, growth. special significance was attached by a number of investi After 1900 a cleavage product of the nucleoproteins, a gators to the proteolytic activity in cancer. On the as 'reducing pentose,' a product first reported by Hammar- sumption that Petry's data showed a greater autolytic sten in 1894 for pancreatic nucleoprotein and then by activity for tumors, several efforts to localize this effect Blumenthal in 1897 for nucleoproteins of other mammal were attemptedâ€”i.e., by Blumenthal and H. Wolff (1905 ian tissues, attracted the interest of cancer biochemists. [38]), who presented data which appeared to establish the In 1904 Neuberg and Milchner (168) obtained a free existence in neoplastic tissues of a 'selective' enzyme. pentose from autolyzed liver carcinoma nucleoprotein, Largely on the basis of this claim, Blumenthal proposed but they were unable to duplicate this result with nucleo- (1905 [37]) that malignant growth could be differentiated from normal growth on the basis of protein metabolism; zymatic degradation of cancer tissues by enzymes present in according to this author cancer tissues showed not only them, as distinguished from 'heterolysis' or the capacity of tumor 'autolytic' but also 'heterolytic' activity.12 Moreover, he extracts to accelerate the enzymatic degradation of nonmalignant tissues. This distinction, recognized by Blumenthal but denied 12The term 'autolysis' is not strictly comparable to the term by other workers, presupposed that cancer tissues possessed used in modern biochemistry. Here 'autolysis' refers to the en- unique types of enzymes.

proteins from autolyzed normal liver. These investi power of normal tissues to metabolize blood pigments, but gators suggested that the product obtained from the secondary growths adopted the activities of the organ in cancer tissue was analogous to L-xylose described by which they were situated. Wohlgemuth (1902-3 [260]) for a pentose derived from the In 1905-6 Martha Tracy (242), who employed various nucleoprotein of normal liver and the form considered most human cancers for the determination of iron, showed that likely to be present in the nucleoprotein of other tissues.13 inorganic and 'albuminate' iron were localized to hemor Neuberg (1905 [166]) attempted to establish a further rhage areas. Organic iron was found to occur chiefly in argument for chemical distinctions in cancer by suggest the nuclei of epithelial cells in a distinct network (pre ing that the relative amount of autolytically liberated sumably in the chromatin) in leukocytes and connective 'reducing pentose' was significantly higher for a liver car tissue cells. Whether organic iron was in actual combina cinoma than for a primary carcinoma of the stomach. tion with nucleoprotein, whether it was merely attached Pursuing this lead, Neuberg attempted to show that the through an affinity of the protein for metals (ion-protein establishment of mÃ©tastasesinvolved a rearrangement of complex), or whether it was involved in some unknown the enzymatic pattern typical for the primary growth. functional capacity could not be demonstrated. As a This circumstance, in his opinion, pointed to irregularities result, the author questioned the utility of the technic in in the nucleoprotein composition of tumors and argued in elucidating the nature of malignant growth. Beebe favor of Blumenthal's hypothesis. (1904-05 [30]), as a result of a similar study concluded The question was also taken up by Beebe and Shaffer that a part of the iron came from the blood remaining in (1905 [34]), who reported that malignant tissues appeared the tissues, and a part was probably derived from 'nu- to contain average amounts of pentose somewhat higher clein.'14 than those occurring in normal tissues of the corresponding Beebe (30) presented other results on the sulfur, phos organ but falling well within the normal range of values phorus, calcium sodium, and potassium, etc., content of found for normal tissues (see Table 3, /). This result cancer tissues (see Table 3, J). Degeneration of the appeared to be explained partly by the fact that malignant tumors was generally accompanied by an increase in cal tissues contained more nuclear material than normal tis cium or a decrease in potassium, the ratio of which appar sues. The pentose composition of metastatic growths was ently depended upon relative increases in the calcium found to parallel that of primary growths, a finding in levels. Beebe suggested that MacCallum's discovery keeping with the view that cancer cells transferred to a dis (1903 [147]) of a calcium antagonism to potassium ion ac tant site should retain the same chemical composition as tivity in the gland cells of the intestines might have a the parent tissue. This explanation did not invalidate definite bearing on this matter: the assumption that the secondary growth could be influ "The relations between cause and effect are as yet too obscure enced chemically by the tissues which surrounded it. Beebe and Shaffer concluded that Neuberg's claims for to form the basis for any theories, but it would be interesting to Blumenthal's hypothesis remained unproved. know whether, as in the gland cells of the intestine, the continued Inorganic constituents.â€”This era finds the beginnings of exposure of the cells in a rapidly growing tumor to the influence of the calcium ion would be followed by an inhibition of the another area of biochemical research on tumorsâ€”the intense metabolic activity associated with the preponderance of analyses of inorganic constituents and their relationship the potassium ion" (30, p. 172). to metabolic processes. The work of J. Loeb and his Beebe's observations on the potassium-calcium relation associates, between 1900 and 1903, established that bio logical activity was dependent upon the physiological salt ship in human cancer were substantiated through exten balance and that minerals played a decisive role in the sive studies involving the Jensen mouse adenocarcinoma, life of the cell. By 1905 several investigators had already reported by G. H. A. Clowes and W. S. Frisbie (1905 explored this question with reference to the cancer prob [58]). Their results indicated that rapidly growing, large lem, among the earliest of whom was Schwalbe (1901 tumors generally contained a high percentage of potas [223]). Schwalbe assumed that iron localized in primary sium and little or no calcium and that old, slowly growing, and metastatic carcinoma cells (liver) was not derived relatively necrotic tumors usually contained large amounts from extravasated blood ; in one case in which hemorrhage of calcium and little or no potassium. In groups of com had occurred, the iron content of the neighboring car parable mice the potassium and calcium content was cinoma cells was low whereas hemosiderin granules were found to fall into a functional relationship with the age and abundant in the hemorrhage areas and in the leukocytes. rapidity of tumor growth. The ratio of potassium to cal Although he was unable to arrive at any firm conclusions cium in growing tumors averaged from 2:1 to 3:2. The on the functional characteristics of iron in the cancer cells, findings of Clowes and Frisbie afforded a firm experimental Schwalbe believed that the primary growths retained the basis for the assumption that potassium was essential to 13Bang and Raaschou (1904 [12]), through a study of the nucleo- cellular growth. proteina of the pancreas, proposed a formula for nucleic acid based IMMUNOLOGICRELATIONSHIPS upon a guanylic acid (guanine nucleotide) structure. The struc ture was amended by Neuberg and Milchner (1904, 168, p. 1083) Cytolytic and cytotoxic agents.â€”Aspreviously indicated, upon a reinvestigation of the 'xylose' component. This consti by 1905 clear-cut lines of research on the activity of 'im- tuent was identified in yeast nucleic acid as o-ribose by Levene and Jacobs in 1909. (For a resumÃ©on the history of nucleic acids 14A decomposition product of nucleoprotein intermediate be see Van R. Potter's, Nucleic Acid Outlines, 1:1-22. Minneapolis: tween native nucleoprotein and nucleic acid, described by Mies- Burgess, 1960). cher in 1874.

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1964 American Association for Cancer Research. TRIÃ“LOâ€”Foundationsof Cancer Research 21 muÃ±e'sera centering about the prominent, contemporary logical reactions in experimental cancer, such as those re serological issue of cytotoxins and cytolysins, were on the ported from the New York State Cancer Laboratory.16 scene. This development was foreshadowed as early as 1899, when von Dugern (66) proposed the use of a cyto- THEORIESOF BIOLOGICALORIGINS toxic serum in the destruction of detached cells that The theories of Virchow, Thiersch, Cohnheim, and Rib- remained in the tissues after the surgical excision of a bert appearing from 1865 to 1895 largely formed the core of tumor. A part of the earlier research in immunology experimental lines which sought an explanation for cancer implicated nucleic acids or their protein component (in in terms of organic irregularities. The early laboratory nucleoproteins), under certain conditions, with cytolytic, record did not present a convincing case for this approach, hemolytic, and agglutinative phenomena. For example, but the 'irritation' hypothesis gained material support Beebe (1905 [32]) reported the preparation, through injec from the clinical quarter. A variety of observations such tions of nucleoproteins into dogs, of cytotoxic sera specific as those in the 1870's and 1880's implicating tar and soot for various tissue extracts obtained from these animals. in the etiology of carcinoma in humans16 brought forth Moreover, he is purported (79, p. 80) to have prepared by statistical evidence that injurious environmental in 1907 a similar serum which was specific for leukemic fluences were responsible in some way for the occurrence spleen, lymphosarcoma, and several types of carcinoma of neoplastic processes. Fischer's investigations, begin in humans. ning in 1905, on the carcinogenicity of Scharlach R and The immunity in mice to the adenocarcinoma allegedly other dye-stuffs, which constitute an initial probe into the produced by Jensen through injections of 'immune' serum nature of these interactions, formed the basis from which could not be demonstrated by Michaelis (1905 [156, p. the irritation idea was gradually generated into the modern 205]). The apparent optimism aroused through the field of experimental carcinogenesis. initial findings on immunity in experimental cancer, par ticularly the suspected presence of a cytolytic agent, was CELL AUTONOMYCONCEPT somewhat dimmed by the results of later studies, reviewed The views of Thiersch, Waldeyer, Cohnheim, Ribbert, by Clowes (1906 [56, p. 1550]). These investigations and other proponents of the idea that malignant growth tended to show that immunization was somehow depend represented a variant from the normal pattern furnished ent upon the direct mediation of viable cells, since it could the elements that eventually were to be fused into one of not be achieved in mice through injections of tumor cells the most critical conceptions of cancer researchâ€”the destroyed by heat or through a variety of chemical agents theory of cell autonomy. According to this theory an including nucleoproteins and nucleohistone extracted from aberrant process of the cell endowed it with the powers of tumors. Whether a specific antitumor factor, such as an an independent existence. Exempted from the controlled antibody, was actually present in mice rendered immune functional performances of its normal counterpart, the to cancer continued to be a contested issue and the subject deviant cell diverted its entire resources into an unlimited of various investigations (see 159, pp. 866-68). capacity for growth. The malignant cell, regardless of its A reproduction of selected experimental results referred origins, thus appeared to possess a unique functional to in this section, appended in Table 3, represents a typical status. Although these ideas are found in rudimentary form in several late nineteenth-century sources of cancer sampling of the chemical and biochemical data on cancer pathology, the theory of cell autonomy was given a more accumulated at the turn of the century. or less formal introduction in 1901 by J. George Adami CONCLUSIONS (1), who advanced its claims as a more productive alter native to the infection theory. By 1907 Ewing (79, pp. A summary of the major trends in early experimental 47-48) stated that the prodigious clinical and experimental cancer research, discussed in this review, is as follows : testimony in favor of the theory of cell autonomy de manded its consideration in any approach to the patho PARASITETHEORY logic anatomy of malignant diseases. The first experimental system to achieve a highly organ TUMORGROWTHRESEARCH ized status, since it fell within the existing framework of The discovery of the transmissible rodent tumors per classical microbiology, was founded upon the concept of mitted investigators such as Loeb to explore the various cancer as an infectious disease. As unrewarding as the avenues opened through the cell autonomy concept. Given widespread search for infective particles in human and these new experimental materials it now became possible animal neoplasms proved to be in the emerging years of for the cancer investigator to exercise a greater measure of the infection theory, it provided a definite incentive for 16Gaylord for the first time in 1904 was able to challenge the much of the earlier work on the experimental transmission claims of many pathologistÂ» who denied the infectious character of animal tumors, and principles resembling Koch's Rules of cancer on a priori grounds. 16Actually, this issue had its beginnings a century before in provided the first regular basis for confirming the propa Percivall Pott's description of chimney-sweeps' cancer (1775 gation of specific tumor tissues through successive genera [188]). Rehn's report (1895 [191]) on the frequent appearance of papilloma and carcinoma of the bladder among men employed tions (207, p. 190). After 1900 the infection theory, in the aniline dye industry and Frieben's study (1902 [96]) on the championed by Borrel in the virus concept, was decisively carcinogenic effects of x-rays in man are important contiguous strengthened particularly by the discovery of immuno- developments on the topic of environmental carcinogenesis.

control over the growth environment.17 An early recog In spite of this legitimate dissent, the biochemical view nition of this research potential is apparent from (a) the point in cancer research through a few of its implications rapidity with which the animal tumor work was taken up in immunology and therapeutics was favored by several on two continents, (6) the appreciable amount of data recommendations. To a generation of investigators en accumulated within the first two years of its inception on dowed with a greater sensitivity to the shortcomings of the behavior of the transplant under relatively fixed con new fields of research (G. H. A. Clowes is a representative ditions, and (c) the steady advance of operational improve of this type) it was readily apparent that the predominant ments to insure the greater reliability of these results. weakness in the biochemical outlook was its immaturity. The ever widening scope of this research area not only promoted knowledge of neoplastic growth but also laid the RESEARCHPROGRAMSINTHE UNITED STATES basis for new programs of therapeutics through the inves 1. The New York Slate Cancer Laboratory, among the tigation of immunity reactions in experimental cancer, and through information gained on the response of propa first of its kind, came into existence at the very time when research on the parasite question appeared to be the most gated tumors to various external stimuli. promising route to the ultimate solution of the cancer TUMORMETABOLISMRESEARCH problem. It is reasonable that the founders of the Buffalo laboratory proceeded not from the assumption The theory of cell autonomy advanced the concept that whether a cancer parasite existed but when it might be dis the neoplastic process fell into the category of abnormal covered, given the necessary time, money, and equipment. physiology. This assumption raised the distinct possi Although this philosophy subsequently proved unreward bility that cancer represented a species of metabolic disease ing, it promoted fruitful lines of investigation. Several of in which functional peculiarities should exist. By use of the earliest developments in immunology, chemotherapy, newly discovered technics a segment of the research field and metabolism research in experimental cancer are an focused itself upon the special problems of cancer bio outgrowth of the lively interest at this laboratory in vari chemistry. The significance attached to several aspects ous phases of the parasite issue. These activities ulti of this approach, particularly by the German investigators, mately gained their proper due as important research ends. fostered an enthusiasm equivalent to that associated with 2. Entirely different attitudes characterize the work of the earlier parasitological attack on cancer. However, the Caroline Brewer Croft Cancer Commission. The Har the new era, after 1900, introduced a far greater skepticism vard group, from the outset, aimed to discover whether into experimental circles, reflected through a greater the observable processes in cancer were in any way at awareness of imperfect analytical methods and the insuffi tributable to parasitic involvement. Their final verdict ciency of knowledge of the modes of normal metabolism. was that the infection theory remained unproved. More That this area of research, in its rudimentary stages, was over, many foibles of the theory were elucidated by these capable of rendering only limited services to the study of investigators. Moving into more fertile territories the cancer pathology is brought out by Ewing (1907) : Croft Cancer Commission was among the first to grapple "There are chemical problems in tumors, but the problem of with the problem of tumor growth. In later years, with tumors is not chemical. An experiment in antiseptic autolysis the appearance of the propagable rodent tumors, more of comminuted cells, prolonged over several months, may be critical factors, such as the genetic characteristics of the sound for chemistry, but is it fruitful for pathology? In these biological soil, were diligently mapped out by collaborating and other experiments the language employed and the conditions investigators (i.e., E. E. Tyzzer [246]). secured are those of chemistry, but the conclusions are drawn in a physiologic sense. Yet between the two there is a wide gap of 3. The aims of the Huntington Cancer Research Fund are assumption. The help of the chemists is needed, but until their drawn up in a 1905 summary report on the results of the technic approaches more closely to physiologic requirement it first 2 years of research at the Loomis Laboratory of Cor would seem that some of their results need not detain us long. nell University (N.Y.C.) : The present studies do not, as a whole, offer a satisfactory demon "The cancer research work of various institutions has for the stration that tumor cells possess chemical peculiarities sufficient to justify the assumption that they represent a specific biologic most part been devoted to the object of discovering the cause of series" (79, p. 80). cancer, and with this end in view the question of its parasitic nature has been the chief subject for investigation. The work 17Even before most of the propagable animal tumors were done has been of great value, but unfortunately has led to abso available the awareness of a necessity for expanding the range of lutely negative results. experimental manipulations in the study of neoplastic growth "It has therefore seemed advisable, instead of treading the was coming into existence. One of the best examples of this de velopment is Loeb's discovery (1900-1901 [139, 143]) that slices ordinary beaten track, to branch out into new methods, and of guinea pig epithelium, cultivated upon agar or blood serum attempt to investigate, not so much the cause of cancer as the and incubated within the animal, underwent endogenous changes conditions under which it may arise. which resembled changes occurring in carcinomatous epithelium. "Attention, therefore, has been principally directed to the Loeb was fully cognizant of the fact that this technic permitted a chemical constituents of tumors, in the hope that by collecting a more exact identification of 'intrinsic' as well as 'extrinsic' in number of data a deeper insight into the question may ultimately fluences on the growing cell (143, p. 114). Following in the foot be obtained, and a nearer approach be made to a conception of steps of Loeb, Harrison (1907) and Carrel (1910) advanced the the nature of the processes involved" (193). science of tissue culture to the in vitro level. Since in vivo growth systems were limited by irregularities inherent in the soil, the work of Harrison and his successors constitutes the beginning of a new The versatility readily apparent in the programs of the era in growth research. American laboratories and their counterparts throughout

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1964 American Association for Cancer Research. TRIÃ“LOâ€”Foundations of Cancer Research 23 the world is indicative of the pyramidal growth of cancer and Its Relation to the Spontaneous Arrest of their Growth. Ibid., pp. 56-68. research after 1900. 26. . The Natural and Induced Resistance of Mice to the Growth of Cancer. Ibid., 3:331, 1908. ACKNOWLEDGMENTS 27. BASHFOBD,E. F.; MURRAY, J. A.; AND HAALAND,M. Re The author is indebted to Dr. Elizabeth C. Miller and Dr. Use sistance and Susceptibility to Inoculated Cancer. Sci. L. Riegel of the McArdle Memorial Laboratory for their valuable Rep. Imperial Cancer Res. Fund, 3:359, 1908. suggestions on the preparation of the manuscript. Special 28. BAUMGARTEN, P. Ueber Scheurlen's Carcinombacillus. acknowledgement is owed Dr. Harold P. Rusch whose advice, Centralbl. Bakteriol. Parasitenk., 3:397-98, 1888. encouragement, and support made this work possible. 29. BEEBE, S. P. 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Toxic Theories of Cancer and Their Bearing on the Parasite 82. . Ueber die Behandlung von Oesophagus-Karzino- Theory. Buffalo Med. J., 43:14-18, 1903-4. men mit Radiumstrahlen. Wien. Klin. Wochschr., 17:96- 55. . Preliminary Communication Regarding an Im 97, 1904. mune Body Capable of Inhibiting the Development of 83. . Ueber die Art der RÃ¼ckbildung von Karzinomme Cancer in Mice (Adenocarcinoma, Jensen). Johns Hop tastasen unter der Einwirkung der Radiumstrahlen. Wien. kins Hosp. Bull., 16:130-32, 1905. Klin. Wochschr., 17:181-84, 1904. 56. . A Study of the Influence Exerted by a Variety of 84. FEINBERG, L. Ueber der Erreger der krankhaften Aus Physical and Chemical Forces on the Virulence of Carci wÃ¼chsedes Kohls (Plasmodiophora Brassicae, Woronin). noma in Mice. Brit. Med. J., 2:1549, 1906. Deut. Med. Wochschr., 28:43-44, 1902. 57. CLOWES,G. H. A., ANDBAESLACK,F. W. Further Evidence 85. . Zur Lehre des Gewebes und der Ursache der of Immunity against Cancer in Mice after Spontaneous KrebsgeschwÃ¼lste. Ibid., pp. 185-89. Recovery. Medical News, 87:968-71, 1905. *86. FIRKET, C. De la rÃ©ussitede greffes sarcomateuses en sÃ©rie. 58. CLOWES, G. H. A., ANDFRISBIE, W. S. On the Relation Note prÃ©liminaire. Bull. Acad. Royal MÃ©d. Belgique, ship between the Rate of Growth, Age, and Potassium and 6:1147-18, 1892. Calcium Content of Mouse Tumors (Adenocarcinoma, *87. FISCHER, B. Ueber experimentelle Erzeugung von Epi Jensen). Am. J. Physiol., 14:173-92, 1905. thelwucherung und Epithelmetaplasie. Verhandl. Deut. *59. COHNHEIM, J. Congenitales, quergestreiftes Muskelsar Pathol. Gesellsch., lOte Tagung, pp. 20-22, 1906. kom der Nieren. Arch. Pathol. Anat. Physiol., 65:64-69, *88. . Die experimentelle Erzeugung atypischer Epi 1875. thelwucherungen und die Entstehung bÃ¶sartiger Gesch 60. CORNIL, V. Sur les greffes et inoculations de cancer. Bull. wÃ¼lste. MÃ¼nch.Med. 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