Abstracts Experimental Studies; Animal Tumors

ABSTRACTS EXPERIMENTAL STUDIES; ANIMAL TUMORS of ’ Discussion on Experimental Production Malignant Turnours, J. A. MURRAY et al. Proc. Roy. SOC.,London, Series B 113: 268-292, 1933. In opening this discussion Dr. Murray pointed out that many of the ideas and conclusions resulting from pathologic study of malignant tumors have obtained precision and validity from the Atudy of the transplantable and experimental tumors of animals during the past thirty years. We can now with some confidence define malignant tumors as tissue proliferations arising in a localized area, growing from their own resources in an uncontrolled manner, and showing a continuous graded series in those arising from any one tissue. We are still without a satis- factory explanation of the process which embraces all the characters of neoplasia, and it is impossible to accept any hypothesis of its nature and origin which omits any of these characters. Theories of carcinogenesis may be divided into three groups. (I) The first of these is the genetic or mutation hypothesis, originating yith Boveri. (2) The virus hypothesis is at present inadmissible because cell-free transmission of mammalian tumors has not yet been demonstrated. Until this is accomplished it is dangerous to transfer conceptions arising from the study of filtrable avian neo- plasms to the elucidation of the nature and causation of tumors in other animals and in man. (3) The experimental confirmation of Virchow’s chronic irritation theory has established its validity as a concise description of the emergence of cancer after prolonged, localized, slight irritation of tissue by a variety of agents, and nothing more. The experimental induction of malignant tumors reproduces perfectly the phenomena which occur in the development of occupationd cancer from exposure to tar, x-rays, etc. Wide differences of opinion still find expression as to how this result is brought about. It is possible that the chemical and physicaI carcinogenic agents act indirectly by setting up conditions in the tissues such that here and there cancerous foci are started, but the properties of these agents are so varied as to give no indication of how the uncontrolled type of pro- liferation is induced, or of the nature of the cellular mechanism involved. Until this difficulty is at least partially overcome, it seems useless to indulge in the further speculation that the less precisely known carcinogenic agents (application of cold, x-rays, etc.) produce this effect by liberating in the tissues subshnces more or less closely related chemically to one or other of the pure substances with carcinogenic action. Dr. W. J. Cook, confining his remarks to the experimental production of cancer by pure chemical compounds, pointed out that chronic irritation ” is a misleading term. There are many examples of industrial skin diseases brought about by chemical irritation, but few of these lead to malignant tumor formation. There are many constituents of coal tar which are powerful irritants and yet are not carcinogenic. On the other hand, not one of the carcinogenic hydrocarbons has any apparent irritating effect on the skin. No view of the origin of malignant disease can lie comprehensive if it fails to take into account the cancer-producing properties of all the known carcinogenic agents. Experimental investigation of the effect of these agents on tissue metabolism is of importance. Boyland, for instance, has found that carcinogenic hydrocarbons influence enzyme systems in a manner similar to arsenious acid, which is undoubtedly responsible for cases of 141 142 ABSTRACTS human cancer. A factor common to all the carcinogenic hydrocarbons is the presence of the phenanthrene ring system, which is also contained in a number of naturally occurring compounds of biologic interest, such as the sterols, the ovarian hormone, possibly the male hormone, vitamin D, etc. Dr. W. Cramer remarked that the close chemical relationship between certain carcinogenic substances and the sterols, which are constituents of every animal cell, suggests that normal cells, if placed under abnormal conditions, can themselves produce carcinogenic substances as abnormal metabolites. The conditions vaguely called chronic irritation may act in this manner. Another and quite different method of inducing carcinogenesis is the trans-, mission of tumors by cell-free filtrates containing an agent which is thermolabile and can give rise to antibodies. This immediate and specific type of carcinogenesis has so far been observed only in birds, and produces only tumors of mesoblastic origin. Spontaneous tumors in fowls, as in mammals, appear in middle-aged or old individuals, and do not spread among healthy birds by contagion; experimental transmission by filtrates is effected more easily in young than in old birds. Work on mammalian tumors has led to the conclusion that the change which constitutes malignancy is a purely cellular one, not due to an extraneous agent, and that it probably resides in the nucleus. Bauer’s suggestion that this change affects the genes, so that the cancer cell represents a mutation of a normal somatic cell, is merely an interesting guess, which does not enable us to understand the character- istic properties of the malignant cell, such as its infiltrative growth and altered metabolism. Warburg’s work seems to offer a better explanation of malignant cell growth than do the conceptions of a virus or a mutation. The changed metabolism makes the cancer cell more independent of an available oxygen supply than the normal cell from which it is derived. But whatever explanation of the intracellular change we may adopt, we still have to explain why the normal cells of one and the same organism can give rise to such varied manifestations of malignancy, each of which breeds true. The.essentia1 features of cancer have been fixed by experimental study and are not affected, whatever may be found to be the intimat,e cellular change. If cancer is a mutation, we cannot mutate back at will; if it is an intracellular virus we can not kill the virus within the cell; an immune system capable of neutralizing completely an active extract of Rous sarcoma has no effect whatever on the cells of this tumor. The correction of an abnormal type of metabolism offers greater therapeutic possibilities, but so far attempts along this line have not been RUC- cessful. Dr. C. E. Andrewes expressed his opinion that the filtrable fowl tumorR afford an important line of attack on the tumor problem as a whole. It is difficult to believe that the fowl sarcomas are essentially and entirely different in nature from mammalian tumors, and to maintain the attitude that these filtrable tumors form a group of virus diseases quite different from fowl tumors as a whole. Whenever a fowl tumor has been studied over a long period, it has proved to be filtrable. If the virus theory of cancer is worth considering seriously, we should also be pre- pared to accept the principle that the viruses that cause tumors are probably not sharply distinguishable from those causing infections. There are various pathologic conditions which many cancer workers dismiss from consideration as not being true tumors, yet these stand in an intermediate position between the tumors and the infections. Examples are the lymphosarcoma of dogs, the myxoma of rabbits, and Shope’s interesting filtrable fibroma of the rabbit [see Am. J. Cancer 17: 808, 809, 19331, the agent of which apparently behaves at one time like a tumor producer and at another causes an inflammatory reaction bearing no resem- blance to a tumor. EXPERIMENTAL 8TUDIEB ; ANIMAL TUMORS 143 Dr. P. R. Peacock agreed that the filtrable avian tumors and their relationship to mammalian tumors present a probIem which must be solved before generaliza- tions as to the causation of tumor growth can be regarded as more than interesting speculations. An obvious method seems to be the induction of tumors in fowls by agents which produce tumors in mammals, and it is surprising that so far only about a dozen such tumors have been described, only one of which has been carried beyond the second generation. This tumor, produced in Murphy's laboratory, was carried through eleven generations of transplantation, but was never shown to be filtrable. But inability to do something is not. proof that it cannot be done. Peacock had found no real difficulty in producing tumors in fowls by injecting carcinogenic tars intramuscularly, provided the birds could be kept alive for from six months to a year. The tumors thus obtained were not distinguishable clinically or histologically from some of the filtrable tumors, such as the Rous sarcoma. These tumors could be propagated, though with difficulty. [See Abst. in Am. J. Cancer 17: 969, 1933.1 Prof. J. McIntosh prefaced his remarks by saying that we have many theories, but more definite facts are required; " the birth,of a fact is the death of a theory." He had obtained tumors in 12 out of 20 birds treated with tar, and even in this mmall number there was considerable histologic variety. Some were fibrosarco- matous, others mainly fibro-endotheliomatous; in others these types were asso- ciated with leukosarcoma or leukemia. Three of these different types of tar tumors were carried through one or more passages. One, a fibrosarcoma, originally a leukemia with only a fibrous reaction in the breast muscle, has been carried through six passages and now breeds true, having lost the leukemic element, and it is readily fltrabie. That these tumors were of spontaneous origin seems nega- tived by the fact that before these tarring experiments began, during seven years only one spontaneous tumor had been found among more than 5000 birds used. The work of Ellerman, Furth and others on the leukemias of birds hau shown that there is a good deal of pleomorphism in the type of disease produced by inoculation of a leukemic virus; for instance, Furth, in propagating a single strain of leukosis in a large series of birds, found that at one time or another it gave rise to erythroleukosis, lymphoid leukosis, myeloid leukosis, a combination of myeloid leukosis and erythroleukosis, myeloma, and sarcoma.

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