SOMATIC MUTATIONS AS a FACTOR in the PRODUC- TION of CANCER for Nearly Thirty Years the Phenomenon Known by Von Hanse- Mann's

SOMATIC MUTATIONS AS A FACTOR IN THE PRODUC- TION OF CANCER A CRITICAL REVIEW OF v. HANSEMANN’S THEORY OF ANAPLASIA IN THE LIGHT OF MODERN KNOWLEDGE OF GENETICS R. C. WHITMAN From the Henry S. Denison Research Laboratories of the University of Colorado, Received for publication, March 4, 1918 For nearly thirty years the phenomenon known by von Hanse- mann’s term, anaplasia, has been widely used among patholog- ists to describe and exphin the origin of cancer cells. Any well established facts, therefore, which throw added light upon the nature of the process of anaplasia itself and any possible relation it may have to cancer genesis must be important and significant. The term anaplasia has been, however, so loosely used that it will be worth while to review at length von Hansemann’s theory in order that we may start with a clear conception of what the word really means. The pleomorphism of cancer cells and the irregular, atypical mitoses so characteristic of their nuclei had been observed and carefully studied since the middle of the nine- teenth century. Arnold (Virch. Arch., vol. 79, cited by von Hansemann (l)),observing irregularities in the mitotic process itself, had inferred that thesemight be of fundamental significance. A voluminous literature dealing with the mitoses in cancer cells and other forms of rapidly proliferating tissues had already ac- cumulated when von Hansemann (1) undertook a further inves- tigation in the same field. In a carcinoma of the larynx he found besides a great abundance of normal mitotic figures, large numbers of tripolar and multipolar divisions and other departures from the normal type already observed and described by earlier writers; and in addition many hyperchromatic and hypochromatic mitoses, the hypochromatism consisting not merely in a reduction of the amount of chromatin in the chromosoines but rather in an 181 182 R. C. WHITMAN actual reduction of the total number of the chromosomes. He reproduces a monaster with only nine chromosomes. Further search led to the finding of a hypochromatic diaster one member of which contained five chromosomes, the other eight, or possibly nine. This asymmetry of division, which he regarded as anal- ogous to the process by which he believes that differentiation, or specialization of the cells occurs during normal embryonic development, might, he thought, take place either as the result of delay, or of complete failure of the chromosomes to split longitudinally during the mitotic process; or else through failure of the two longitudinal halves of the chromosomes to separate and pass to the opposite ends of the spindle. In one of his cases he found numerous instances in which, in the monaster stage, late in the metaphase, (or telophase), the chromosomes were found lying in pairs close to and parallel with one another, indicating that splitting had occurred shortly before. Since splitting normally occurs early in the anaphase, he inclines to the view that the asymmetry in question is due to delayed splitting, at least in some instances. In the search for further unequal mitoses von Hansemann found, in a rodent ulcer, a diaster one member of which contained eleven chromosomes, the other sixteen. The fact that here, as also probably in the first case, the number of chromosomes in one or both members of the diaster is odd, constitutes further evi- dence that the asymmetry is due to the failure of splitting to occur at all in certain chromosomes, so that parts (of the chromo- some) properly belonging in one-half are retained in the other. No further mitoses were found in which inequality could be determined by actual count, but he was able with some patience to find, in every case, mitotic figures, both diaster and pluripolar forms, in which asymmetry was obviously present although the actual count could not be made. In a later paper (2), additional instances of this type are described and figured. The occurrence of asymmetrical mitoses is then taken as established. I may add parenthetically that no one (so far as I can learn) who has concerned himself with this matter since has denied their occurrence. Strobe (4), (cited by Hansemann SOMATIC MUTATIONS IN PRODUCTION OF CANCER 183 (3)), indeed, claims to have observed such mitoses in a great variety of inflammatory and regenerative conditions, in sarco- mata and benign tumors, and denies that they possess any biologic significance; but v. Hansemann contends that these assertions are based on inaccurate observations. Now, since the cells with a reauced number of chromosomes can have no other possible origin than the tumor cells, it follows that the production of such hypochromatic cells (von Hanse- mann, as already mentioned, applied the term hypochromatism only to cells with a reduced number of chromosomes-not to cells with merely a reduced amount of chromatin) must be accompanied by the production of cells hyperchromatic to whatever extent the former are deficient in chromosomes. The tumor thus contains cells of three sorts, viz., cells containing an ’excess, a normal number,’ and a reduced number of chromosomes, between which there is no sharp dividing line. Only the extreme cases are recognizable. The last mentioned are capable of further mitoses, but sooner or later undergo a process of necrobiosis, as is evidenced by the occurrence of certain abortive forms of mitosis (2) which we need not discuss here. The first type, on the other hand, may be assumed to convert itself into the resting forms of the tumor cell. Such cells may continue thereafter to divide symmetrically, or may undergo further asymmetrical divisions from time to time. Hansemann (3) states explicitly that asymmetrical mitoses may possibly, even probably, occur in other than tumor tissues, and cites cases from the literature. But he inaintains that no epithelial cancer occurs without asymmetrical mitosis. In order tb make clear 6Hansem4m’s idea of the significance of this departure from the normal type of mitosis it will be neces- sary to follow him in a digression. The biologic properties of cells are inherent in certain definite, formed chstituents of the cells, larger than a molecule, which by growth and division transmit those properties to the descendants of the cells. Hansemann believed, in 1890, with de Vries, that these constituents, then called idioplasmae or pangenes, now called genes or simply factors, are seated partly in the chromosomes, partly in the cytoplasm. 184 R. C. WHITMAN They are now known to lie exclusively in the chromosomes (vide infra). The change in views on this point does not affect the validity of what follows. During embryonic development each new stage is marked by the appearance of cells not identical with the cells from which they arise. The production of such cells is identical with the process of differentiat4on of the several organs, and is accompanied by a division of labor among the several kinds of cells whereby each becomes more and more de- pendent on the cooperation of all the rest for its own continued existence, and becomes therefore less and less capable of inde- pendent existence. This division of labor, or altruism as he calls it, he regards as brought about (see especially his monograph (5) ), by a process of unequal, (i.e., asymmetrical) division, so that one set of functions passes into one daughter cell, and another set into the other. But the separation of functions is not absolute and complete, as otherwise even the known limited powers of meta- plasia, whereby cells of one type may be converted into other but closely related types, would be incomprehensible. Those idioplasmae, or factors, which dominate the chlahcter of the fully differentiated cell, he calls (5) chief plamae (Hauptplamen) and those factors which become latent, so as to exercise no visible effect on the functional activity of the cell under normal. cir- cumstances, he calls secondary plamue (Nebenplasmen). The whole process by which the embryonic cell develops into the fully differentiated cell, he calls prosoplasiu. The reverse process, by which a cell loses more or less completely its specialized functions, and its altruistic relation to the rest of the organism, i.e., gains in its capacity to live independently, he calls anaplasia. It is at this point that von Hansemann’s argument becomes a bit involved. Anaplasia is defined as a process of undifferentiation. Ribbert (6, p. 451 ff.), who comments on the frequent misunderstanding of von Hansemann’s theory, himself falls into obvious error. von Hansemann thinks, he says, that “through the loss in differentiation, changes arise in the cells which he in- cludes under the designation ‘anaplasia.’ ” That is incorrect. Anaplasia means, not changes due to undifferentiation but the undifferentiation itself. Furthermore, von Hansemann is ex- S~MATICMUTATIONS IN PRODUCTION OF CANCER 185 plicit (5) in his statement that the anaplastic cell is not an embryonic cell in the sense that it is identical with any cell at any time present in the normal embryo. Anaplasia is not a reversal of the normal direction of ontogenesis. The embryonic cell is a prosoplastic cell, and anaplasia begins where the embryonic cell leaves off. Anaplasia produces a cell different from any cell at any time normally present in the body. The difficulty in understanding just what is meant by anaplasia arises primarily from hasty reading, but in large part also, it seems to me, from an unfortunate selection of descriptive terms on v. Hansemann’s part. For, after all, one can hardly be blamed for visualizing undiflerentiation as precisely that reversal of the normal course and direction of ontogenesis which anaplasia is not. If he had spoken of anaplasia as a process of re-diferentiation much of the misunderstanding would have been avoided.

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