Tumors in the Invertebrates: a Review BERTASCHARRER*ANDMARGARETSZABÃ“LOCHHEAD

Tumors in the Invertebrates: A Review BERTASCHARRER*ANDMARGARETSZABÃ“LOCHHEAD

(From the Department of Anatomy, University of Colorado School of Medicine, the Department of ZniHogy, ?'nirer.tity of Vermont, and the Marine Biological Laboratory, Woods Hole, Massachusetts)

INTRODUCTION papers in which invertebrate tumors are reviewed Tumors are the result of abnormal cell prolifera to some extent are two in French (13, 148) and tion. Therefore, the study of tissue growth, normal one in Russian (30). and abnormal, constitutes the central problem of A. critical survey of the present status of the tumor research which thus becomes essentially a problem of invertebrate tumors encounters serious biological problem. When approached from this difficulties. For one thing, the Â«latainthe literature broader point of view, an analysis of tumorous are often controversial, and many of the descrip growth should include representatives from all tions are inadequate or hard to evaluate. Patholo- groups of living organisms. It has been recognized gists specializing in tumor research are not, as a that the study of plant tumors yields significant rule, familiar with invertebrate material. On the results. Within the animal kingdom comparative other hand, zoologists, versed in the intricacies of pathology has concerned itself largely with neo invertebrate anatomy and taxonomy, are usually plasms in various groups of vertebrates (74, 10!), inexperienced in the diagnosis of tumor growth. 112, 124), while invertebrates have been all but Furthermore, the terminology developed almost neglected. As a matter of fact, until fairly recently exclusively for use in mammalian pathology invertebrate tissues were often considered in should not be applied to invertebrate animals, capable of developing tumorous growths. until the analogies between vertebrate and in Teutschlaender (144) believed that tumors can vertebrate tissues are more thoroughly under not occur in animals at a phylogenetic level lower stood. than the fishes. Engel (25) elaborated extensively In spite of such difficulties two facts stand out on the reasons why invertebrates are unable to as the result of this survey: invertebrate tissues are develop cancer. Emphasizing anatomical differ capable of tumorous change, and they offer an op portunity to approach the study of tumors in new- ences between invertebrates and vertebrates he discussed chiefly three points. The first two con ways. cern differences in the nervous and vascular sys TUMORS IN VARIOUS GROUPS tems; the third deals with the embryonal theory of OF INVERTEBRATES tumor growth. Believing that invertebrate cells, on The first question one may ask is :In which types account of their considerable regenerative power, of invertebrates have tumors or cellular reactions are embryonic in character, Engel concluded that comparable to tumorous growth been observed? they cannot revert to the embryonic stage and The information available refers to almost all the produce tumors. In the light of modern biological major invertebrate phyla. Tumors are said to oc concepts these views are obsolete, not only with cur in annelids, sipunculids, arthropods, molluscs, regard to anatomical considerations, but also he- and ascidians. Even among the most primitive cause they are based on inadequate material. metazoansâ€”dicyemids (91)â€”and among the pro Actually, during the past .50 years a consider tozoans (82) nuclear anomalies have been observed able literature on spontaneous and experimentally which are comparable to atypical mitoses as found induced tumors in invertebrates has grown. In in certain mammalian neoplasms. The best known addition, numerous observations exist concerning group and the most interesting from the point of various tissue reactions that may be more or less view of comparative oncology are the insects. closely related to tumorous growth. These data are scattered and often not easily accessible. The only VARIOUS TISSUE REACTIONS AND * Special Research Fellow, I'.S. Public Health Service. Re TUMORLIKE GROWTHS search grantÂ»fromthe American Cancer Society and The Anna Great caution is indicated in an evaluation of Kuller Ktiiul are gratefully acknowledged. the types of tumors occurring in invertebrate ani Received for publication, April 14, 1950. mals. For one thing, the difficulty of arriving at a 40.-5

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1950 American Association for Cancer Research. 404 Cancer Research satisfactory classification, which exists even in tumorous changes is the effect of certain parasites mammalian pathology, is multiplied in inverte on the so-called fat body of insects, a type of con brates. Furthermore, in a number of instances a nective tissue which stores reserve materials and, variety of formations in invertebrates which can in certain species at least, shows no sign of cellu not be considered as true tumors have been desig lar proliferation after metamorphosis. Under the nated as such. Among these are cysts, often the influence of the parasites these adipose cells have result of what is called an "inflammatory process." been observed to hypertrophy and to resume mi- It would be preferable to call such processes "in totic activity in the adult stage. Many of these jury reaction" or "repair hyperplasia," since ac mitotic figures are abnormal (67, 79, 106). The cording to Menkin (78) the term inflammation, result is a hyptrplasia of the fat body of these in which implies vascular response, should be re sects (16, 17, 18, 23, 99). stricted to vertebrates. A frequently observed situ Another instance where caution in the u.se of ation is the following (e.g., 8, 11, 24, 81, 54, 56, 59, terms is indicated is that of the insect "myce- 60, 61, 64, 68, 69, 80, 83, 98): almost any disturb tomes" (structures caused by intracellular sym- ing factor (foreign body, parasite, tissue implant biotes). The practice of Mahdihassan (75, 76) of with or without bacterial contamination, degener considering these biologically useful structures of ating organ, hereditary tissue anomaly, sterile bacterial origin as tumors is not in keeping with agar or celloidin, or irritant, such as croton oil) will commonly accepted views (135, chapters 4 and (i: cause an accumulation of lymphocytes in the af 137, chapter 5). Likewise, parasitic structures such fected area. In many invertebrates certain blood as those described by Mclntosh (77) in the caudal cells may change from free-moving to sessile ele region of Sagitta (Chaetognatha) are not tumors ments and vice versa under various conditions (27, in the strict sense of the word. 28, 73, 163). When they accumulate, often in im Many of these pathological formations are evi pressive numbers in the vicinity of irritants, dently not true tumors but may show certain re phagocytosis and encapsulation of the center of semblances to neoplastic growth. Thus, it is ob disturbance take place. In the cysts thus formed vious that in many instances the decision as to the cells making up the capsule may undergo whether or not a reported structure is to be classi changes, sometimes of a degenerative nature. Such fied as a neoplasm meets with considerable dif- tissue responses resulting in well defined "growths" culty. A great deal of further observation is neces may easily be mistaken for tumorous processes. In sary before an opinion can be formulated. Just as most cases they merely indicate an injury reac certain tumors in vertebrates are considered to be tion, but it is not unlikely that under certain con on the borderline between hyperplasia and benign ditions such cysts may eventually give rise to tumors, some of the formations reported here in tumor-like growths or real tumors. the invertebrates might prove to be borderline Various abnormal growths, with or without ul cases. cÃ©ration, have been observed on the body wall of Nevertheless, so far as can be judged from the molluscs collected in nature or reared in the labora available evidence, cases of true tumors, both be tory. The causes of these growths are unknown. nign and malignant, appear to occur among in In each case the histolÃ³gica! picture showed the vertebrates. These cases are discussed in the fol presence of an injury reaction with repair hyper lowing section, in which the term "tumor" will be plasia, characterized by densely packed nuclei of freely used wherever the balance of evidence seems connective tissue cells, fibroblasta, and numerous to suggest a true neoplastic growth. Also discussed migrating cells. Tissue reactions experimentally in this section will be certain experimental work of produced by burning and by strong acid were es relevant interest, including cases in which no neo sentially the same as these natural growths (139, plastic growth was obtained. 141, 142). Another type of cellular response in inverte CAUSES OF INVERTEBRATE TUMORS AND TUMOR-LIKE STRUCTURES brates which in itself should not be considered as tumorous growth manifests itself in the hypertro Spontaneous occurrence.â€”A number of cases re phy of cells due to the action of parasites. For ex ported in the literature concern incidental obser ample, in the intestinal epithelium of certain vations of so-called spontaneous tumors. It is per marine worms gregarines may cause up to a ten haps more accurate to classify them as tumors fold increase in cellular size accompanied by whose cause is unknown. Among the earliest ob changes in the appearance of nuclei and cytoplasm servations is one on a lobster (Homarus) by Mc lntosh who "many years ago, described a tumour (9, 10, 102, 136, 145). Somewhat more significant in connection with which originated in the wall of the grinding storn-

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1950 American Association for Cancer Research. SCHARRERAND LOCHHEADâ€”Tumors in Invertebrate* 405 ach and pushed its way through the carapace be cur which are derived from several smaller hind the eyes. The tumour enlarged and finally re cells by cytoplasmic, and subsequently nuclear, sulted in the death of the lobster, which was a very fusion (20). In the case reported such a round, large and old specimen."1 giant cell, which was clearly separated from the KolosvÃ¡ry (65) found a tumor on the prosoma surrounding tissue, showed distinct signs of kary- of an arachnid, Phalangium opilio L. The chitinous orrhexis. The nuclear membrane had disappeared, body wall produced an overlapping fold over the and numerous chromatin granules and nucleolar tumor; the latter was so large that it pushed the remnants were freely distributed in the cytoplasm. internal organs to one side. The author suggested The cytoplasm appeared dense and homogeneous, that this tumor might have started during em exhibit ing signs of hyaline degeneration. No visible bryonic development. No histolÃ³gica!study of the influence of this condition on the health of the host tumor was made. could be detected. Although this pathological Additional chance observations among arthro structure, whose diameter was 65 p, took up about pods concern insects. The earliest reference to in one-third of the total longitudinal diameter of the sect "tumors" seems to be in a treatise on insect corpus allatum, it seems debatable whether or not diseases by Kirby and Spence in 1826 (quoted it should be classified as a tumor. from 137). Figure 1, taken from a monograph by Another case reported by Palm (!)7) concerns Ilalazuc (4), shows a large tumor in the prothorax the pharyngeal glands of the bumble-bee, Bombos. of a beetle (Phytodecta variabilis) of which no his- One of the male specimens examined showed "tu tological analysis is available. White (152) found mor formation" in the gland of one side. Normally a fibroma-like structure in the thorax of one honey consisting of unicellular units equipped with sepa bee among a large number of dissected specimens. rate canals leading to a common duct, the diseased The tumor appeared as a mulberry-like mass which gland appeared as a displaced, rather large, com displaced adjacent structures and seemed con pact structure containing an abundance of connec nected with the mesothoracic ganglion. However, tive tissue. There was no connection to the com the microscopic picture indicated that the tumor mon duct; numerous aberrant small secretion was derived from connective tissue rather than canals ended blindly. The abnormally large glan from ganglionic elements. dular elements showed signs of hypersÃ©crÃ©tionand Likewise unknown was the cause of tumor-like degeneration. Karyorrhexis occurred among the structures which Ã–rÃ¶si-Pal(92) described in the nuclei. hindgut of old winter bees. They consisted of cysts Among molluscs, several tumors have been re formed by fusion of vacuolated giant cells whose ported. Williams (155) and Collinge (14) found, nuclei did not seem diffÃ©rentfromthose of normal among about one thousand examined specimens of hindgut epithelium. the freshwater mussel (Anodonta cygnaea, var. A rather unique finding of a brain tumor in an zellensis), three with tumors. These growths were ant (Formica pratensi*) was described by Brun (6). apparently derived from the tissues of the mantle The specimen, a worker, showed motor disturb and, in their microscopic structure, resembled ances (continuous circular movements to the right ) adenomyomas. There was evidence that these tu which suggested a cerebral lesion. On microscopic mors had seriously interfered with the physiology examination a compact tumor was found on the of the afflicted animals. upper left side of the protocerebrum, taking the In the oyster (O.ttrea rirginica) G. M. Smith place of the corpora peduncolata. It consisted of (127) observed, as had Ryder (118) before him, a very small, densely arranged cells, presumably benign tumor of mesenchymal character which proliferated glia elements. A differential diagnosis had its origin in the pericardium. The pediculated between tumor and brain abscess was, however, structure, whose largest diameter was 14 inches, not possible on the basis of the available material. A "unicellular tumor" was described by Palm showed a nodular, polypoid appearance (Fig. 2). A single layer of ciliated columnar cells surrounded (IMS)in one corpus allatum of a male nymph of the mass. The tumor cells were large and oval- (Â¡ryllotalpa (Orthoptera). Among the small cell shaped with relatively small nuclei. Finely dis elements of this endocrine organ giant cells oc- persed lipoid granules and probably also glycogen ' The quotation is from Prince (108). In spite of considerable were present in the cytoplasm. Figures 3 and 4 effort, in which the assistance of Dr. S. VV.Smith (I'niversity show the vacuolated appearance of this tumor. of Colorado School of Medicine) and of Dr. J. M. Dodd ((Ã¬atty Marine Laboratory, St. Andrews I'niversity, Scotland) was ob A benign tumor of epithelial origin was de tained and greatly appreciated, the original source of this infor scribed in the slug, Limaxftavus L., by SzabÃ³and mation could not lie located. Dr. Dodd kindly supplied us with SzabÃ³ (140). In an almost 4-year-old laboratory reference (77). specimen this whitish, lobated tumor, connected

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1950 American Association for Cancer Research. Fio. 1.â€”Largetumor in prothorax of a beetle FIG. 5.â€”Slug (Limax) showing location of a (Phytodecta). X12.5. From Balazuc (4). large spontaneous tumor (T). About life size. Re Fio. 2.â€”Oyster (Ostrea) with benign tumor. drawn from SzabÃ³and SzabÃ³(140). (a) Location of tumor (A) in pericardia! region. FIG.6.â€”Crosssection of two lobes which fell off (6) Tumor (A) lifted up, showing pedicle (P) and from the tumor shown in Figure 5. Note atypical adductor muscle (M). (c) Cross section through arrangement of epithelial cells with connective turnor (A), showing underlying pericardium (X) tissue filling each lobe of the tumor. Redrawn from and heart (H). From G. M. Smith (127). SzabÃ³and SzabÃ³(140). Fio. 3.â€”Sectionthrough oyster tumor showing FIG. 7.â€”Highpower photomicrograph of same mesenchymal cells and blood vessels (A). From tumor as shown in Figure 6. Cuboidal epithelial G. M. Smith (127). cells forming alveolar tumor tissue; spaces contain FIG. 4.â€”Sametumor as in Figure 3 at higher ing some mucus and necrotic cell particles. From magnification. Note large, vacuolated tumor cells SzabÃ³and SzabÃ³(140). with small nuclei. X75. From G. M. Smith (127).

with the border of the iimntle by a pedicle (Fig. 5), bring about lethal tumors (Figs. 8and!)) which occur periodically fell off and grew again. Its maximum only in males, and which are comparable to certain size was 1Ã“X8X3 mm. Histologically, the epithe vertebrate tumors (melanoepithelioma, lymphosar- lial tissue constituting the tumor (Figs. 6, 7) dif coma). These sex-linked tumors arise for the most fered from the tissue in normal specimens in that part in groups of embryonic cells (imaginai discs) its arrangement was similar to that in alveolar or which normally give rise to adult organs, but which tubular glands. The center of the tumor mass was in this strain become prematurely active (cf. em filled with dense, richly nucleated connective tis bryonal theory of the origin of tumors). They may sue, whose presence was considered secondary by also originate in the epithelium of the integument the authors. The interpretation of this structure as or gut and in "sites of blood formation." As many a true tumor is supported by the abnormal his- as fifteen tumors may be observed in one larva; tological appearance which set it off from sur some may grow to one-fourth the size of the host. rounding normal tissues, the tendency for unlim Excessive amounts of melanin are deposited in the ited growth, and the absence of signs of an injury tumors (for chemical tests see 53). They are said to reaction. proliferate rapidly, to infiltrate surrounding tis Ladreyt (71, 72) found what he considered a sues, to metastasize, and to show mitotic ab malignant growth in a Sipunculus. This abnormal normalities. Extirpation of the tumors from larvae structure had developed in one of the two vascular prolongs their life but does not permit pupation tubes ("hearts," canals of Poli) which extend along to occur. Tumor implants in normal larvae cause the esophagus of this annelid. Under normal condi death of the host before pupation. Larval tumor tions the epithelial lining of these tubes gives rise cell suspensions when injected into adult Dro to various types of blood elements. In the diseased sophila give rise to lethal growths in some speci specimen the endo- and perithelium showed exten mens. There is evidence that the tumors are not sive cellular proliferation by means of (frequently due to the presence of a microorganism. multipolar) amitoses and nuclear fragmentation. In addition to this "malignant" type of tumor. The tumor cells had undergone changes in appear Stark described in a mutation of the same strain of ance; they had become fusiform orepithelioid with Drosophila a nonlethal hereditary tumor, implants large, often irregular nuclei. They formed layers of which in normal hosts do not prevent metamor around the lumen of the tube which became ob phosis and are carried over into the adult fly. This structed in places. Some tumor cells degenerated benign tumor is not sex-linked. It develops at a at the original site, others were disseminated in the later larval stage from embryonic cells whose pro- blood stream. Musculature, nervous system, and liferative potency is consequently decreased. These ncphridia showed signs of degeneration. The evi tumors are more limited in growth and become dence for a diagnosis of malignancy in this case necrotic after being encapsulated by connective was not considered sufficient by other authors (13, tissue elements. 148). The lack of illustrations in Ladreyt's report Some authors, such as N'eedham (88), seem sat further adds to the difficulty of arriving at a con isfied that Stark's "lethal strain" tumors were in clusive interpretation. deed malignant. However, many of Stark's inter Hereditary factors.â€”Inview of the fact that cer pretations do not appear to be supported by con tain chromosomal deficiencies are known to cause clusive evidence and have, therefore, met with cytological abnormalities which lead to severe criticism. The criteria for malignancy seem insuf morphogenetic disturbances in Drosophila (107), ficient (13, 84, 115, 116, 148). Furthermore, Rus it is not surprising that hereditary "tumors" have sell (116) claimed that the death of the larvae was been described in this insect. Stark (130), using a caused by an abnormal and extensive disintegra strain discovered by Bridges, was the first to call tion of the midgut cells, permitting the escape of attention to the significance of such tumors in food and thus causing starvation. This abnormal Drosophila. Since then, a number of investigators ity appears a few hours before the first tumors ap have worked on Drosophila tumors occurring in pear. Russell further pointed out that the tumors various strains. Many important questions con do not really seem to arise from or be a part of any cerning the morphology and physiology of these organ. Whether they are free in the hemocoel or pathological formations are still unanswered, and connected with some organ, they look alike and in the fact that not all the investigators were dealing size most closely resemble groups of amebocytes or with identical material increases the difficulty of of imaginai disc cells. Russell also could find no dif evaluating the descriptions. ference between the malignant and the benign According to Stark (130-134) multiple genetic types of tumors. The prolifÃ©rÃ¢tivegrowthof tu factors in Drosophila larvae of the strain "lethal 7" mors and of tumor transplants has not been dem-

TUMOR .. ..â€ž. EXOSKELETON

TISSUE OF FOOT

FIG. 8.â€”Portions of Drosophila larvae with lepidopterous larva (Pygaera). From Fedorley lethal tumors. Dorsal (1 and 6), ventral (2, 3, and (29). 4) and lateral (5) views. From Stark (130). Fio. 11.â€”Insecthost (ephemerid nymph) with ectoparasitic insect larva (chironornid) causing ir FIG. 9.â€”High power photomicrograph of a ritation and subsequent tumor formation; bt. = longitudinal section of a portion of a Drosophila Region of mesothoracic blood sinus pierced by larva showing tumor (T) attached to the wall of sucking parasite. From Codreanu (13). the stomach (S). The tumor consists of uniform FIG. 12.â€”Syncytialtumor of ephemerid nymph polygonal cells and contains pigment. From Stark derived from macronucleocytes, developing during (132). "local phase" of proliferative process. Xote nu Flu. 10.â€”Tumor in the abdominal foot of a merous mitotic figures (nit). From Codreanu (13).

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1950 American Association for Cancer Research. SCHARRERAND LOCHHEADâ€”Tumors in Inrertehnite.f 40!) oust rated beyond doubt either by Stark or by ner and Woolf (41) found a rise in incidence from Russell. about 76 per cent at 22Â°('. to about 93 per cent at I. T. Wilson (156) studied two Drosophila tu 30Â°C. in the growth abnormality "tnmorous- mors, similarly melanotic and dependent on mul head." The first 24 hours of development were de tiple hereditary factors as were those of Stark. In termined as a temperature-effective period modi one of the two strains as many as a hundred small fying only one of the two chromosomal factors tumors were scattered throughout the body, dis involved. placing normal tissues. Pigmentation increased Prolongation of the larval period by 2,4-dinitro- with the age of the tumor. In the few survivors the phenol, or inhibition of larval growth by certain tumor cells disappeared during pupation. The tu amino acids in high concentration, delay tumor ap mors of the second strain were small in number and pearance (157; see also 149). 0.1 M arginine added far less destructive. Histologically, these struc to the basal diet containing sterile brewer's yeast tures consisted of a center of polygonal cells sur significantly increases the tumor incidence; orni- rounded by spindle-shaped cells and fibrous non- thine does not show this effect (158). cellular elements which may have originated from In experiments by Zivin (164) the feeding of blood cells. thymonucleic acid failed to inhibit the develop In regard to these growths described by Wilson ment of Drosophila tumors; the substance had no and also those originally described by Stark, the mutagenic effect in Drosophila melanogaster. possibility exists that they arc encapsulations by The genetic background for the manifestation of blood cells of small tissue fragments, cell agglutina these tumors was further discussed by Jones (58) tions, or foreign bodies. Such an interpretation is and Russell (117). The tumor incidence may be supported by a close study of the published figures 100 per cent or less depending on the genetic con (peripheral melanization of the nodules; see 27). stitution. The growths described by W7ilson were possibly Extensive work is being conducted in the genet the result of parasitic intrusion from infected ics laboratory of the University of Utah (see food, since tumor incidence was highest in bottles Gardner, Newby, Dearden, Ratty, and Woolf)2 on containing relatively few larvae, in which was seen a growth abnormality ("tumorous-head") in Dro the greatest contamination of the medium by bac sophila melanogaster. These growths appear on any teria and fungi. part of the head derived from the head primordia Morgan, Schultz, and Curry (85, 86) inter and are usually external, less frequently internal, preted as "melanotic necrosis" tumor-like abnor and associated with the hypodermis. They are ir malities in the fat body of hybrids of Drosophila regular in shape and size, and they seem to be dif melanogaster with Drosophila simulons, which they ferent from the tumors described by Stark. This attributed to imbalance of heterochromatin be trait is inherited through the action of a recessive tween the two species. (or slightly dominant) sex-linked gene which pro The melanotic lesions observed by Gowen (44) duces a maternal effect in the egg and of a semi- in adult Drosophila are different from but show dominant third chromosome gene. certain parallelisms with the structures reported The effect of x-ray treatment on the growth of by Stark. Drosophila tumors has been studied by several au Tumors of the type originally described by thors with varying results. While Stark (130) no Stark have been studied in regard to relationships ticed no effect, Enzmann and Haskins (26) ob between environmental conditions and tumor inci served a decrease in the percentage of developing dence. Ardashnikov (1) and Russell (117) found tumors when larvae 18 24 hours of age were ex the appearance of tumors in Drosophila cultures posed to x-rays. Finally, HÃ¤rtung (49) pointed out inversely proportional to the degree of crowding. that the result depends on the dosage. In a certain Temperature is a factor which may modify tumor strain the hereditary incidence of 15 per cent could incidence. According to HÃ¤rtung (50-52) its effect be stepped up to 48.3 percent with 1,500 r. On tIn- may be direct (acting on the ontogenetic process) other hand, the incidence fell below the control or indirect (affecting other environmental condi value when 5,000 r were administered. In this con tions). In general, high temperatures tend to de nection it is of interest that Pogossiants (105) pro crease tumor incidence, while lower ones increase duced pigmented "tumors" in Drosophila by it in the three Drosophila strains tested. However, means of x-rays (4,000 r) which, with respect to this general statement does not seem to hold for all morphology and location, resembled the known tumor strains investigated so far. HÃ¤rtung himself 1We are grateful to Drs. E. J. Gardner and W. W. Newby, (51) reported an increase in incidence with rising University of Ctah, for permitting us to reportthese data while temperature in one of his strains. Similarly, Gard some of the papers were in press.

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1950 American Association for Cancer Research. 410 Cancer Research hereditary types. His results, which he interpreted pose tissue, "lymphocytic tissue," imaginai discs, as "melanotic necrosis (86) give no evidence of and free blood cells have been only insufficiently malignancy. The structures were not transmitted studied (114). In the metamorphosing insect these to later generations (see also 63; for further in tissues undergo radical changes which are ade formation on Drosophila tumors see 7, 42). quately understood in relatively few species. In The hereditary tumors just described are not view of all these facts it would seem evident that restricted to Drosophila. In a lepidopterous larva further work must be done before the real nature of (Pygaera pigra, Notodontidae; Fig. 10) similar these hereditary "tumors" can be clearly estab sex-linked tumors, affecting only the males in the lished. colony while the females are carriers, were ob Parasitic origin.â€”Viruses, fungi, microsporidi- served by Federley (29). To account for this type ans, and insects parasitizing certain invertebrates of inheritance, Federley advanced the interesting have been made responsible for "tumorous hypothesis that the tumors develop from the three growths" observed in their hosts. polar bodies, which in the male would contain sex In a recent study Bird (5) observed insect tu chromosomes X, Y, and Y, respectively; in this mors associated with a virus infection. The ab combination the expression of a recessive gene re normal growths occur in the midgut of the Euro peated on each of the Y chromosomes would not be pean spruce sawfly, Gilpinia hercyniae (Htg.), after suppressed by the single homologous gene on the X infection of the epithelium by the virus. As a result chromosome. Continued division of polar body nu of the infection, polyhedral bodies are formed in clei is a phenomenon well known in insects. the nuclei of the digestive cells of the midgut. In The tumors which Federley described were of the vicinity of the regenerative nidi abnormal cell several types. Large numbers of one type floated proliferations occur which project into the body freely in the hemocoel. Other types were located in cavity or, less frequently, infiltrate the cytoplasm various organs, such as hindgut, testes, ganglia, of the digestive cells. If larvae become infected just hypodermis, glands, tracheae, and musculature. before the last larval molt, i.e., at a time when cel Vacuolated and giant cells with multipolar divi lular activity in connection with metamorphosis is sions, flattened elements, and necrotic structures at a peak, large tumors develop. Such tumors con occurred in some of these tumors. As in the case of tain a necrotic, pigmented center, a layer of great the Drosophila tumors, it is uncertain whether ly enlarged infected cells, and an outer region of these growths in Lepidoptera are true tumors. proliferating cells. During metamorphosis some of Since giant cells and multipolar divisions are these tumors disappear from the gut, either by known to occur normally in the intestinal cells of being pushed into the body cavity or possibly by certain insect larvae (45, 153), and in wound heal coming under the influence of digestive juices. The ing (154), more cytological and histological cri tumor cells do not invade other organs of the in teria would be necessary for a definite diagnosis of fected insects. All available evidence seems to indi neoplasia in these insects. cate a nonmalignant character of these tumors. In summary, there exist in insects pathological As pointed out earlier, not all abnormal ac formations which have certain characteristics of cumulations of cells are tumors. Thus, the prolifer- hereditary tumors. But despite the relatively large ative tissue reactions in the fat body of certain in amount of study these growths have received, sects (Lepidoptera) caused by virus infections (94, there is considerable doubt as to their correct in 95) probably were the result of an injury reaction terpretation. Various factors contribute to the dif (13). Similarly, the "tumeur mycÃ©lienne"found ficulty. Pigment deposition in the growths pro by de Boissezon (19) in the abdomen of an adult ceeds so rapidly that only in the earliest stages can female of Culex may have been merely a 2-mm. the cells be examined in detail; even there difficul cyst formed of dense fibrous tissue to isolate the ties are encountered in securing adequate fixation fungus present; however, the author stated that (HÃ¤rtung, personal communication). Therefore, the intestinal epithelium in its proximity had un no satisfactory figures or descriptions of the his dergone morphological changes as a consequence tology of these tumors have been published. No of the presence of the fungus. direct evidence has been presented of cell prolifera Cellular reactions of interest in connection with tion in the "tumorous" tissue. Comparison with certain features of tumorous growth have been re normal or injured tissues is hampered by inade ported in an ascidian, Ciona, parasitized by the quate knowledge concerning the normal histo- gregarine Monocystis (125, 126). As a rule, almost physiology of the insect organism. Even in a genus the entire development of the parasite is intracel- which has received as wide attention as Drosoph lular, causing the intestinal cells of the host to re ila, the normal functional relationships of adi act conspicuously. They become enlarged up to 20

times their original size and show a vacuolated can be produced experimentally. Various attempts cytoplasm. The nuclei hypertrophy and later have been made to induce tumors in invertebrates break down and disintegrate with the rest of the in which either the customary ways of approach, cell. There is evidence that this influence of a for such as the administration of carcinogenic hydro eign organism on the individual host cell is chemi carbons, or essentially new methods have been cal in nature. Up to this point, the observations used. The effects of chemicals, of bacteria, of en would seem to indicate cellular hypertrophy due docrine and of nervous factors have been studied. to parasitism, as discussed before. In some cases, Hammett and his associates conducted exten however, Siedlecki also noted a reaction in neigh sive investigations in an attempt to elucidate boring cells; the epithelium proliferated, and even growth mechanisms relative to neoplasia. Experi connective tissue elements became involved in the ments with various invertebrates, as well as with resulting abnormal growth. These tumor-like struc plants, mice, and humans led these authors to tures, in which the original cause, i.e. the parasite, postulate that cell proliferation with consequent is often no longer found, were compared by the au growth is stimulated and regulated by certain thor with mammalian liver adenomas. chemical compounds containing the sulfhydryl Papilloma-like structures, of mesoderma] origin, group. In the course of regeneration experiments have been described in the annelid worm Pota milia on tlie hermit crab, Pagurm longicarpus, acciden torelli by Mesnil and Oaullery (81) as caused by tal injuries often occurred at the site of a regener another sporozoan parasite. They grow rather in ating chela and between segments of the new chela tensely, ramify, and protrude into the coelom, where the chitin was thinnest (47). Aberrant which is filled with parasites. In these growths the growths developed from such lesions in controls as nuclei continue to divide amitotically, even after well as in animals treated with Â¿Â»-thiocresol.How the parasites have disappeared. It is difficult to ever, in the experimental group all lesions resulted decide whether or not these structures should be in growths, whereas only 7o per cent of the controls classified as tumors, or whether they are simply produced growths. Furthermore, the growths in hyperplastic formations. the group treated with the chemical were always Several authors have studied the effect of insect considerably larger. In a few instances, and only parasites on insect hosts (98, 99), but the most in after treatment with p-thiocresol, crabs developed formative results are those of Codreanu (12, 13). an aberrant growth on the tip of the regenerating An ectoparasitic larva, the chironomid Symbio- chela in the absence of a lesion. Histologically such cladius, feeds on the blood of certain insect hosts, aberrant growths consisted of normal tissues in a i.e. ephemerid nymphs of the genera Heptagenia, highly unorganized arrangement showing no re Kithrogena, etc. (Fig. 11). When so doing the semblance to any organ. In the opinion of the au parasite causes the following progressive reactions thors, these pathological overgrowths can be com in the host. Aside from an injury reaction due to ir pared with malignant tumors. Figure 21, p. 348, of ritation, a proliferative process takes place which the paper by Hammett and Hammett (47) may consists of two phases. During the "local phase" a serve as an example. It shows a section through a syncytial tumor derived from macronucleocytes growth which had developed "spontaneously," i.e. but gradually changing in its histological appear without injury, after p-thiocresol treatment at a ance (increasing cytoplasm, vacuolization, change site which is normally an intensely proliferating of nuclear and nucleolar size, abnormal mitoses) center. It is described as consisting of epithelial appears near the site of the parasite (Fig. 12). In cells without chitin formation and is interpreted as the "generalized phase" which follows, free macro a wildly disorganized proliferation analogous to nucleocytes accumulate in the circulation (leuke certain types of malignancy. The magnification at mia), infiltrate organs of the host, and form small which the photograph is reproduced does not per nests, for instance in the vicinity of the ovarian mit the distinction of cell types, and further de tubes. The formation of these tumors which tails about the histology of this growth and the Codreanu compares with a leucosarcoma, and ultimate fate of similar structures are not given. which in all probability are malignant, continues From a study of the material presented one gets even when the ectoparasite is removed at an early the impression of an injury reaction at a rather stage. The host invariably dies before the comple early stage. More information would seem neces tion of its development with tissues depleted and sary for an evaluation of the possible malignant prematurely "aged." potencies of this and similar structures. Experimental work.â€”In the investigation of Bacterium tumefaciens, known to cause tumors vertebrate and invertebrate tumors alike the most in plants and in fishes, was inoculated into the useful material is that in which neoplastic growth marine annelid Nereis by Thomas (145-148). The

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1950 American Association for Cancer Research. 412 Cancer Research conditions under which tumorous growth took consisted of the introduction of foreign bodies, ir place in these experiments are of interest because, ritants, etc., into experimental animals (p. 404). in addition to the bacterial action, an ecologie fac Implants of this kind frequently caused injury re tor is involved. The author found that in a given action and cyst formation by fibroblasts. In the ex habitat, characterized by a certain salt content of periments of LabbÃ©(70)who used celloidin soaked the water, the oÃ¶cytesof the worms degenerated in coal tar in the marine snail Doris, tumor-like and gave rise to granulomas (88). Only specimens structures subsequently developed. Their cells, thus affected responded to the stimulus of bacterial being fibroblastic in origin, became giant, pluri nuclear, their growth pattern invasive. While LabbÃ©himselftook these criteria as signs of a can cer-like behavior, Thomas (147, 148) could not produce comparable effects in Nereis, Ascidia, and other forms and, therefore, expressed a certain skepticism with regard to LabbÃ©'sconclusions.

SALIVAR* GLANDS During the last decade, newer methods were adopted in the application of carcinogenic com RECURRENT NERVE pounds. The carcinogens used in invertebrates were the common ones, methyleholanthrene, 1,2,5,6-dibenzanthracene, benzpyrene, etc. They

SALIVARY RESERVOIR were administered by mouth, as implants of crys tals, as aerosols in the surrounding atmosphere, or

FOREGUT dissolved in aqueous media, etc. A. response most closely approaching those ob served in mammals due to the action of carcino genic hydrocarbons was elicited in cephalopods - M1DGUT (Sepia) with 1,2,5,6-dibenzanthracene (57). With in a few days after the subcutaneous administra tion of a pellet of this compound a whitish tumor, several cm. in diameter, could be observed. His- tologically, the epithelium and subcutaneous con nective tissue appeared replaced by numerous dif fusely infiltrating histiocyte-like cells which showed signs of degeneration (autolysis; homoge 13 neous, pyknotic nuclei). There was no indication that the tumor was attacked by the defense mech anisms available to the host. This type of lesion FIG. 13.â€”Diagram of I/eucophaea, showing sites of tumor differs essentially from the injury reaction ob formation, i.e., anterior portion of alimentary canal (foregut served earlier in the same species, as well as in and midgut) and salivary organs (salivary reservoir and Octopus and Eledone, as a consequence of trauma glands), and their innervation by branches of the recurrent or irritants (59 61) or of subcutaneous coal tar nerve, a, l>.c, three locations where nerve has been cut. X2. Orig. injections (62). The tolerance for carcinogenic azo dyes in the infection with abnormal growth of the connective cockroach, Blattella, is much higher than in the tissue, appearance of giant nuclei, atypical mi rat or mouse. After administration of 0.2 per cent toses, whorl formation, etc. The resulting tumors of three of these dyes in the diet nodular forma were characterized by fast growth and invasive- tions were observed in these insects, whose tu ness. They were fatal to the worm and were "sar- morous nature could, however, not be estab comatous" in appearance. Thomas, therefore, con lished (90).3 sidered them as malignant or close to malignant Based on the hypothesis that cancerous growth growths, an interpretation which was subsequent may be correlated with mutations occurring in ly questioned by Codreanu (13). somatic cells, the effect of carcinogens on the mu Earlier attempts to cause tumors in caterpillars tation rate of Drosophila was studied. While of Galleria mellnnella by inoculation of Bacterium 3The effect of benzpyrene on insects is currently being finnefaciens emulsions were unsuccessful (66). studied by M. I'. Boulet, MusÃ©ezoologique, UniversitÃ©de Another approach to induce tumor growth in Strasbourg, France, to whom we are indebted for this informa invertebrates, chosen by several investigators, tion.

Auerbach (2) had negative results, Demerec (21, with bacteria-free cultures should be extended to 22), using a different technic, was able to produce include other ciliates, especially paramecia. gene mutations (considerable increase in lethal In view of the known connection between en imitations) with four carcinogenic hydrocarbons, docrines and tumor growth in mammals it is sig as well as with a nitrogen mustard (3). The muta- nificant that abnormal tissue reactions similar to genie effect of these compounds, especially of di- certain vertebrate tumors could be elicited in the benzanthracene, on Drosopbila is very similar to that of x-rays, ultraviolet light, and neutronsâ€”all agents whose carcinogenic capacity is well known. Phenol has a positive effect on the mutation rate of Drosophila (46), an observation which is of interest in view of clinical evidence that this x-v,'---;*ifvâ€¢¿sijA compound may produce skin cancer (138, p. 16,5). -.\ /-..*â€¢.*.'â€¢â€¢¿'ut f â€¢¿ . Â«k'.- The early phase of growth, but not cell differen â€¢¿â€¢"â€¢'-y- tiation, was stimulated in the marine hydroid Obelia by 1,2,5,6-diben/aiithracene and by metli- ylcholanthrenc in experiments by Hammett and Reimann (48) and Reimann and Hammett (113). Since cell proliferation is one of the primary manifestations of cancer, these results have some bearing on the problem of neoplastic growth. Regeneration in planaria!) worms was .stimu lated by the presence of carcinogenic compounds without effect on the histolÃ³gica! appearance of the tissues (93). Tchakhotine (143) exposed sea urchin eggs to sodium monobromo- or monoiodoacetate with the result that atypical tissue proliferation took place. The mesenchyme became "wild," filling up the blastulae and thus preventing gastrulation. The \** v, outcome was fatal in the early sea urchin stages. **>\* In a study involving a number of chemical sub stances Rapaport (110) found that arsenic and i* ' Â¿ boron compounds caused melanotic tumors in :Ãir> Drosophila larvae, similar to the hereditary types 15 already discussed. The effect of carcinogenic hydrocarbons on pro FIG. 14.â€”Midgut tumor of Leucoptiaea. The large tumor tozoans has been studied by several authors. Tit- mass, replacing the normally thin gut wall incorporÃ¢tes parts of the intestinal caeca (<â€¢),andthe hindgut (/i), m, lumen of tier (150), using pure cultures of a ciliate (Tetra- inidgut with debris. About X24. Orig. hymena) was unable to detect mutagenic effects FIG. 15.â€”Same tumor as in Figure 14 at higher magnifica wit h l ,2,5,6-diben/ant hracene, 3,4-benzpyrene, tion. The tumor cells differ greatly from the cells normally com and iiK'thylcholanthrene in concentrations rang posing the midgut wall. X.'iliO. Orig. ing from 1:50,000 to 1:200,000. This observation is in contrast to the positive results in Paraniecium insect Carausius (Dixippus, walking stick) by reported in earlier papers (87, 129, 151, 160). The Pflugfelder (100, 103, 104) by means of an experi effects observed in these experiments (polymorph mentally induced disturbance of the hormone bal ism, increased growth rate, enhanced vital func ance in early nymphal stages. This effect, as well tions) may have been indirect, i.e. they may have as degenerative processes, was brought about by been brought about via the bacteria, present in the removal of the corpora aliata. RÃ©implantÃ¢tion the cultures on which Paraniecium feeds. This of these endocrine glands prevented the abnormal interpretation suggested by Tittler would seem tissae reactions. Implants of supernumerary cor plausible, because carcinogenic hydrocarbons are pora aliata also caused abnormal growths. The known to increase the rate of reproduction of bac atypical growths were observed in certain loca teria, such as Escherichia (43,55). However, before tions, especially in mesoderma] structures. A.mitot- a more definii e stai einen t can be made, experiments ic divisions were noted in the proliferating part of

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1950 American Association for Cancer Research. 414 Cancer Research the gut at the place of origin of the Malpighian niitotic and amitotic nuclear division. The embry vessels. The wall of the oviduct and the corpora onic mesoderm displayed a tendency to invasive cardiaca showed similar changes with occasional growth which affected particularly the muscles of giant nuclei. the host. No pathological growths of this kind Atypical new growths could also be produced were observed in embryonic implants which had when embryonic tissue of the same insect species been transferred to normal hosts serving as con was transplanted into the head capsule of nymphs trols. Spemann (128) has discussed the production or adults whose own corpora aliata had either been of tumors by embryonic tissue implants in verte brate hosts. It is difficult to state at this point to what extent the abnormal growths in Carausius are comparable to true neoplasms, but the fact that they are definitely due to an endocrine im balance should make them interesting objects for further study. An essentially new way of inducing tumors was found in Leucophaea, a large roach which offers many advantages for experimentation (Ili), 120, 122). In this insect the severance of a nerve (recur rent nerve) causes tumors to develop in organs which are innervated by this nerve. The organs concerned are the anterior portion of the alimen tary canal (foregut and anterior midgut) and the salivary organs (salivary reservoir and salivary glands). Figure 13 shows the topography of these organs and their innervation by branches from the recurrent nerve. Three possible locations for nerve transection are indicated; all three types of opera tion were carried out with essentially the same re sults. The tumors developing in a large proportion (75-80 per cent) of the operated adults and nymphs after varying periods of time were, as a rule, conspicuous structures. Histologically, they consist of layers of cells which in the course of de velopment apparently became progressively more 17 abnormal and finally necrotic. Few, if any, mitotic figures were observed, a fact which, in view of the FIG. 16.â€”Tumorin wall of foregut of Leucophaea. To the often rapid growth of the tumors, may be ex left and right of the tumor the wall is normal, consisting of a muscularis and a chitin-covered epithelium facing the lumen plained by assuming that the mitoses are com (above). Note stratification of the tumor. About X24. Orig. pleted within a very short time or that cell division FIG. 17.â€”Tumortissue of Figure 16 at transition of layers is mainly by amitosis. Giant cells, not normally ob at higher magnification. The types of tissue shown do not nor served in the organs in question, are not infrequent mally occur in the foregut wall. X360. Orig. in the tumors. The most commonly affected organ is the an extirpated or which had received supernumerary terior portion of the midgut (stomach). Normally iillatuin implants (101, 103). The abnormal growth consisting of an almost transparent columnar of the embryonic tissue, taking place in part by mi- epithelium and muscularis, the mucosa increases totic division, in part by nuclear fragmentation in width many times after nerve section and be (atypical amitoses), involved all three germ layers. comes opaque or brown (Figs. 14, 15). Severe tu Certain neuroblasts, for example, developed no mors of this kind usually lead to the death of the axons, became giant elements, while their nuclei animal. A foregut tumor, sarcoma-like in its micro divided amitotically. Glia cells surrounded such scopic structure, is shown in Figures 16 and 17. pathological elements and proliferated to form The conspicuous tumors of the salivary reservoir cystlike structures or large cell aggregates. The (Figs. 18, 19), which is normally a thin transparent prospective midgut (entoderm) showed profound membrane, suggest epithelial tumors. Their size abnormalities with cell proliferation by means of may become impressive (diameter up to 10 mm.).

The tumors of a certain number of operated in mal, castrate, and tumor-bearing animals was sects showed signs of malignancy (121). Tissues compared (159). The content in body fat of the near the original tumor site were invaded and tumor-bearing males (with nerve severance only, sometimes incorporated in a large mass of tumor or with nerve severance after castration) was be tissue. In a few cases this process led to the per low normal and close to starvation levels. The cor foration of the chitinous body wall. responding values for females with nerve severance The primary (possibly degenerative) effect of ranged from starvation to normal levels. The severance of the recurrent nerve on the tissues amount of fat in ovariectomiwd females with tu which it innervates, and the early phases of the mors ranged from the low values found in starva- pathological growth process which this operation brings about, are not yet fully understood. The possible role of connective tissue and blood ele ments in this process need further study. Insects ! are capable of producing large masses of connec tive tissue at sites of injury. The tumors in Leuco- phaea, which develop at locations distant from the injury caused by the operation, do not re semble such connective tissue masses. Control operations with equal or greater injury at the same site, but without nerve severance, do not lead to tumors. The tumors due to nerve severance do not show melanization. (Ã¬iantcells occur in certain gÃ¬*M. insects normally, or during wound healing, but the ones mentioned in the Leucophaea tumors are evidently not involved in the healing process, are different from those observed in cases of injury re action, and are normally not found in the corre sponding tissues of nonturnorous specimens. The histolÃ³gica]appearance of the tumors developing in organs whose innervation has been disturbed by severance of the recurrent nerve differs to such an extent from the normal histology of the organs in question that these tumors cannot be looked upon merely as the result of tissue hyperplasia. Against their interpretation as ulcerative processes 19 speak the lack of necrosis and the maintenance of FIG. 18.â€”-Tumor in the wall of the salivary reservoir of surface continuity in the earlier phases of their de Leucophaea, filling part of the lumen. About X24. Orig. velopment. FIG. 19.â€”Salivary reservoir tumor of Leucophaea at higher Following severance of the recurrent nerve in magnification. X.'ÃŽCO.Orig. Leucophaea early death from the resulting tumors is more frequent in females than in males. In ani tion to the above average amounts characteristic mals which have been gonadectomized several of castration. These data seem to indicate essential weeks previous to nerve severance this sex-linked differences between males and females. In at least difference in mortality is no longer observed. The some of the analyzed females death cannot be at survival rates in tumor-bearing castrates of either tributed to starvation in connection with tumorous sex are approximately equal and represent values changes in the alimentary canal, since it occurred intermediate between those of males and females at a time when the fat reserves were not yet in which only the nerve has been cut (123). These diminished. differences may perhaps be based on sex differ SUMMARY ences in metabolism, in that the greater lability in Phenomena related to neoplastic growth have the metabolic pattern of the reproducing females been studied in a number of invertebrate phyla, may account for their lower resistance to tumor and tumors of either epithelial or connective tissue growth. In an attempt to substantiate these pos origin have been reported in annelids, sipunculids, sible correlations, the fat content, in relation to arthropods, molluscs, and ascidians. Evidence of total dry matter and body weight, of whole nor the true neoplastic character of such alleged tu-

mors is often scanty; reasonably convincing signs 18. DEBAISIEUX, P., and GASTALDI, L. I-es microsporidies parasites des larves de Simulimi!. IL Cellule (Ixnivain), of malignancy are found only in a small number of 30:185-214, 1919/20. reported cases. 19. DE BOISSEZON, P. Contribution Ã l'Ã©tudede la biologie et A number of tumors described in representa de l'histophysiologie de l'idei pipienx L. Arch. Zool. tives from various invertebrate groups may be ExpÃ©r.GÃ©n.,70:281-431, 1930. 20. DE LERMA, B. Osservazioni sui corpora aliata del Grillo classified as spontaneous growths, since their cause talpa. Arch. Zool. Ital., 17:417-33, 1932. is unknown. In insects certain of the alleged tu 21. DEMEHEC, M. Mutations in Drosophila Induced by a mors are known to be hereditary. Other factors Carcinogen. Nature, 169:604, 1947. reported to cause tumors or abnormal growths in 22. â€”¿â€”¿.Production of Mutations in Drosophila by Treat ment with some Carcinogens. 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Berta Scharrer and Margaret Szabó Lochhead

Cancer Res 1950;10:403-419.

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