The Importance of Differential Consideration of the Stages of Carcinogenesis in the Evaluation of Cocarcinogenic and Anticarcinogenic Effects Albert Tannenbaum, M.D

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The Importance of Differential Consideration of the Stages of Carcinogenesis in the Evaluation of Cocarcinogenic and Anticarcinogenic Effects Albert Tannenbaum, M.D.

(From the Department o[ Cancer Research, Michael Reese Hospital, Chicago 16, Illinois) (Received for publication June 28, 1944)

This communication is an attempt to clarify and studies many workers have demonstrated that when a extend the concepts dealing with certain extrinsic or chemical carcinogen is applied repeatedly, or even once, intrinsic factors that augment or retard .darcinogenesis. to the skin of a susceptible animal a series of changes Before discussing carcinogenesis it may be helpful to antecedent to tumor formation takes place. In the differentiate again between carcinogenesis and the main these include epithelial hyperplasia and increase subsequent growth of a tumor. 1 Carcinogenesis im- in nuclear and nucleolar size; dermal alterations in- plies the initiation of a neoplasm by a tumor-producing volving the hair follicles, sebaceous glands, collagen agent acting on normal tissue. Once the tumor is of and elastic fibres, and inflammatory cells; and definite microscopic size, even before it is perceptible on gross chemical changes in the epidermis (13-15, 18, 32; 34, examination, carcinogenesis can be assumed to have 35, 39, 41, 49). These nmy be only coincident with, been completed; the multiplication of the new tumor or may themselves actually be, the lesions that have cells represents growth. The differentiation between been referred to as initiation or pre-neoplasm. For genesis and growth is based both on morphological even though the application of carcinogen is discon- considerations and on the experimental observation of tinued before tumors are expected, papillomas may factors that encourage or inhibit carcinogenesis, while develop in the pre-neoplastic site. It is therefore be- they have little or no influence on the growth of the lieved that the first stage, either gradually or abruptly, tumor. Thus it is of experimental and possibly of clini- goes over into the second stage of tumor /ormation cal importance to distinguish between the genesis of a or neoplasm. neoplasm from normal tissue, and the growth of such In a previous communication (44) it was pointed a tumor, or of tumor implants. Nevertheless one still out that biological experiments of diverse nature sup- finds references in the literature to the effects of a port this view: That carcinogenesis may be divided into particular agent or procedure, without regard to the at least two distinct stages: (a) a stage of preparation, difference between genesis and growth. latency, initiation, or pre-neoplasm, in which the nor- A parallel situation, dependent on the recognition mal cells become biased toward forming a tumor; and of distinct stages in carcinogenesis itself, has devel- (b) a stage of development, formation, or neoplasm, oped more recently. On the basis of experimental data which eventuates in a perceptible tumor. In this res- and suggestions by Rous and his associates (30, 36), pect our conclusions agree with those of Rous and his Berenblum (10), Tannenbaum (44), and the earlier associates, Berenblum, and others. work of others (19-21), and for experimental and Berenblum (10), in discussing the genesis of skin tu- possibly clinical purposes, it appears desirable to con- mors, also includes the concept of metacarcinogenesis sider differentially the recognizable stages of carcino- (the conversion of a benign into a malignant tumor). genesis. We prefer to omit discussion of this concept, since the Stages of carcinogenesis.--In extensive morphological relationships of benign to malignant neoplasms are not clear. In the case of the skin, does the malignant The distinction between genesis and growth of a tumor may be likened, in a broad sense, to the distinction between concep- cell develop from a papilloma cell or from a normal tion and growth of a fetus. In both phenomena there may be cell that is converted directly into a malignant cell? no general agreement regarding the exact limits of component Is the carcinogenic agent responsible for this conversion, parts of the complete processes, or even whether such exact or is the change produced by the growing papilloma? limits exist. Nevertheless, for the discussion of clinical and experimental observations, such separations have validity and Often the malignant tumor seems to be formed directly, usefulness. and not from a benign papilloma. Moreover, other 678

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1944 American Association for Cancer Research. Tannenbaum--Differential Consideration of Carcinogenic Stages 679 malignant neoplasms in animals, such as the spon- tion of suboptimal doses of carcinogen for a limited taneous breast adenocarcinoma and induced sarcoma period, evidence that the augmenting effect evokes of the mouse, seem to develop directly and not through and/or maintains the neoplastic stage. It is likely that an intermediary benign tumor. Consequently, meta- the same agents have little or no effect upon the de- carcinogenesis will be omitted from this discussion and velopment of the pre-neoplastic stage; thus these means carcinogenesis will be regarded as consisting essentially of promoting carcinogenesis can be considered cocar- of the two stages: (a) pre-neoplasm (initiation), and cinogenic actions that affect principally the develop- (b) neoplasm (development). ment of the second or neoplastic stage of carcino- ,4nticarcinogenesis and cocarcinogenesis.--In recent genesis. years substances have been found that either promote On the other hand, certain substances exert their or inhibit the development of skin tumors when they principal influence when applied during the period of are applied concurrently with a carcinogen. Beren- limited carcinogen application, tt is well known that blum (4) applied the term "anticarcinogen" to di- the potency of a carcinogen is dependent on the nature chlorodiethylsulfide (mustard gas), which inhibits the of the solvent used and the condition of the skin, as well formation of tumors when applied concurrently with as on other experimental factors. For example, when the carcinogen, and Shear (38) suggested the term 0.5 per cent strength of 1,2,5,6-dibenzanthracene was "cocarcinogen" to describe the augmenting effect of the applied in various solvents it was found that tumor basic fraction of creosote oil. Both stressed the fact production was highest with chloroform, lower with that these substances, by themselves, do not initiate oleic acid, and lowest with liquid paraffin (46). Again, tumors, 2 but under optimal conditions either inhibit ether or acetone, for a specific concentration of car- or promote their induction by carcinogens. Later these cinogen, effects a much higher production of tumors two investigators reported further experimental work than benzene (16, 42), and the addition of as small an along these lines (6, 7, 9, 12, 37) and Berenblum amount of paraffin as 2 per cent increases the effective- adopted Shear's term "cocarcinogen" to describe the ness of both ether and benzene (16). On the other augmenting effect of croton resin. hand, dissolving the carcinogen in mouse fat or lanolin One gets the impression from Berenblum's paper rather than in benzene results in a considerable (10) that he considers that anticarcinogenic and co reduction of tumor formation (31, 40). There are carcinogenic actions influence the conversion of the pre- many more examples of the now established fact that neoplastic stage to the neoplastic stage (epicarcinogenic the physical and chemical nature of the solvent can action--Berenblum), though his definition and discus- greatly influence the response to a given concentration sion of cocarcinogenesis also imply that it may exert of a carcinogen. its effect at other times. However, our experimental In addition, there is much experimental evidence results, as given both in the preceding and succeeding that application to the treated area of various sol- communications (44, 45), coupled with a critical evalu- vents and agents before or between applications of car- ation of the literature, indicate that it may be possible cinogen may considerably affect tumor formation. Wat- to differentiate between the effects of a cocarcinogen son and Mellanby (47) review the early work on this (or anticarcinogen) in each of the two distinguishable subject, and in their own experimental data clearly stages of carcinogenesis. establish the accelerating effect of mouse fat and olive In brief, it is our thesis that cocarcinogenic and anti- oil under these conditions, and an increased tumor carcinogenic agents may involve either the pre-neoplas- incidence due to preliminary application of mouse fat tic or neoplastic stage separately, and that the mechan- has been confirmed (31). Baumann and his associates ism and nature of the effect may be entirely different have also contributed valuable data (26-28). during these two stages. It is possible that a particular The same wide variation occurs in sarcoma pro- means or substance may have one effect, cocarcino- duction when different solvents are used in the sub- genic, anticarcinogenic, or none, on the develop- cutaneous, intramuscular, or intraperitoneat injection ment of the pre-neoplastic stage; and another effect, of carcinogens. Early reports by Peacock (33), Wat- cocarcinogenic, anticarcinogenic, or none, on the con- son (48), and Berenblum and Kendal (8) emphasize version to the neoplastic stage. this. For example, a carcinogen in homologous fat It has been demonstrated that wound healing (30, produces fewer tumors than when dissolved in Iard 36), croton resin (10), and free caloric intake (44) or sesame oil. There is considerable literature on this will all promote the production of skin tumors at sites subject, which has been adequately surveyed by Bur- already rendered pre-neoplastic by the previous applica- dette and Strong (11) and by Dickens and Weil- Malherbe (22). More recently Leiter and Shear (29) 2 An agent, administered alone, may have a slight carcinogenic effect, but this does not preclude the ~ossibility that it have reviewed certain aspects of this subject, and in may possess a strong cocarcinogenic or anticarcinogenic action. extensive experimentation have compared tricaprylin

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1944 American Association for Cancer Research. 680 Cancer Research and various lard fractions. They report: "In communication (44), which introduces experimental evi- parison with tricaprylin as the control vehicle, lard dence suggesting that caloric restriction definitely in- residue produced a striking retardation of tumor pro- hibits carcinogenesis in the developmental (neoplastic) duction whereas lard filtrate promoted it. Further phase and has little effect, if any, on the initiation fractionation indicated which components may be re- (pre-neoplastic) phase. It is even conceivable that a sponsible for the promoting action and demonstrated particular substance :~ may have an inhibiting effect in that the retarding influence resides in the glyceride one stage, and a promoting action in the other. The fraction richest in saturated fatty acids of high mo- results of Berenblum's experiments with carbon dioxide lecular weight." snow (3, 5) and of Crabtree's with monochloracetone The effectiveness of a carcinogen is therefore depen- (17) suggest this latter possibility, but it would be dent, among other factors, on the nature of the solvent, premature to say more until this point is carefully and, with regard to skin tumors, can be modified by the tested. addition of certain agents to the skin before or between The factual and theoretical considerations discussed applications of the carcinogen. In other words, solvents in this communication indicate the desirability of and other agents may exert a profound cocarcinogenic testing, when feasible, the effect of a particular agent or anticarcinogenic influence during the in.itiation or or procedure (solvent, chemical agent, hormone, physi- pre-neoplastic stage. In contrast, these same solvents cal agent, inflammation, trauma, wound healing, or and agents may have little or no effect when applied dietary change) during each stage of carcinogenesis after a limited application of carcinogen, i.e., during as well as during the whole experimental period. It is the developmental or neoplastic stage. likely that such practice will improve our concepts of Little is known about the fundamental cellular carcinogenesis and our understanding of the mode of changes of carcinogenesis, in either its pre-neoplastic or action of the experimental agent or procedure. It may neoplastic stages. However, it is obvious that solvents be worth while to repeat that the effects of these agents or agents that augment or inhibit in the pre-neoplas- and procedures may be different for the two stages of tic stage must do so in the presence of the carcinogen carcinogenesis, and entirely unrelated to their effects on (or its conversion products). On the other hand, cocar- the subsequent growth of the tumor. cinogenic and anticarcinogenic actions in the neoplastic From comparisons of experimental carcinogenesis stage may occur principally in the absence of carci- in animals and occupational tumors in man it may be nogen, since it has been shown that this disappears assumed that the latent period may be as long as 20 from the skin within a few weeks after the last ap- years in the latter. Therefore, from a prophylactic plication (2, 23-25, 39, 43 page 474). viewpoint, there are practical possibilities of thinking It is likely that a solvent or agent applied during the in terms of cocarcinogenic and anticarcinogenic effects pre-neoplastic stage exerts its main effect on the on the separate stages of tumor genesis. It would be ad- rate and amount of carcinogen absorbed into the skin; vantageous to find means and methods that (a) pre- or, in the case of sarcoma production, the rate of re- vent and retard the initiatory stage of carcinogenesis, moval or diffusion from a subcutaneous site. This and (b) retard or do not accelerate its formative stage. mechanism may be considered a physical or solvent On the basis of this discussion, the author believes that influence on the effective dosage of the carcinogen. these are practical goals. On the other hand, some agents, whether applied after a limited or throughout a prolonged application of a SUMMARY carcinogen may act on the developing tumor cell Promotion and inhibition of carcinogenesis by means itself, during the neoplastic, or developmental, stage, of noncarcinogenic agents and procedures have been thereby imhibi.tingor.enhancing carcinogenesis. described as cocarcinogenesis and anticarcinogenesis Carcinogenesis may thus be augmented or inhibited respectively. In view of certain experimental data and in either the pre-neoplastic or the neoplastic stage. The interpretations from our laboratory, coupled with con- means, mechanisms, and significance of the changes sideration of the pertinent literature, it appears desirable brought about in these two periods are worthy of to emphasize the following: differentiation, for such an analysis should result in 1. The genesis of a tumor proceeds through at least better understanding. Technics for separating car- two stages: cinogenesis into stages may not be possible with all types of tumors, but it is certainly practical for the in- (a) A pre-neoplastic stage (preparation, initia- duced skin tumor and probably for the induced tion, inception), which under proper conditions leads to sarcoma (1). That a particular noncarcinogenic procedure may (b) A neoplastic stage (development, formation). promote or inhibit in one stage of carcinogenesis and not in the other has been shown in the preceding corn- 3 See footnote 2,

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1944 American Association for Cancer Research. The Importance of Differential Consideration of the Stages of Carcinogenesis in the Evaluation of Cocarcinogenic and Anticarcinogenic Effects

Albert Tannenbaum

Cancer Res 1944;4:678-682.

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