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closely knit structure of the chromosome. A plasmagene usually multiplies at about the same rate as the cell but, in certain circumstances, may multiply either more rapidly or more slowly. In the former case, its concentration in the cells will increase in succeeding generations and the character of the strain may become progressively modified. When the multiplication rate is reduced below that of the cell the plasmagene is gradually diluted out and the trait which it controls is ultimately lost.
The interesting observation has been made that plasmagenes may compete with one another for survival. When conditions favorable for the initiation of 2 different plasmagenes are imposed on a cell the result may be that only 1 of the potentialities develops. It is as though the more aggressive factor multiplied at the expense of the other. This competition for survival is of particular interest because, as we shall see, it is a characteristic also of some mixed virus infections.
Plasmagenes are more subject to environmental influence than are genes. Their multiplication may be modified by such factors as the temperature and the food supply of the cells. A special case that is under intensive investigation at the present time is that of the production of adaptive enzymes by yeast cells. It has long been known that yeasts that have the power to metabolize only a few of the simple sugars can be taught to metabolize a foreign sugar by incorporating the latter in the food supply. The new metabolic capacity takes time to develop but when established it is passed on to succeeding generations as long as the foreign sugar is present in the environment. The cells have acquired the capacity to synthesize a new enzyme to deal with the alien nutrient. When the latter is withdrawn from the nutrient medium the capacity to metabolize it is lost because the essential enzyme is no longer synthesized and disappears from the yeast cells in a few generations. Quantitative analyses of these phenomena are best explained by the assumption that a plasmagene is responsible for the synthesis of the enzyme and that the plasmagene only multiplies when the foreign sugar is present. This is one more example of the way in which genetics is currently spilling over into biochemistry.
The cancer cell has been described as mutant cell. It is a difficult matter to decide whether a mutation in a body cell is the result of a change in the nucleus or in the cytoplasm. Genes and plasmagenes probably interact so intimately with one another that the decision which of them suffered a mutation may not be of the first importance. The purpose of this discussion is to emphasize two other aspects of these hereditary units. The first is that both genes and plasmagenes are nucleoprotein structures. Their multiplication, therefore, is a problem in nucleoprotein metabolism. The second point is also biochemical. It is that genes and plasmagenes, alone or in cooperation, are closely linked up with specific metabolic reactions through their control over the synthesis of specific enzymes. A mutation in a gene or a plasmagene may, therefore, be expected to be associated with the appearance of a specific metabolic anomaly in the mutant cells.
That susceptibility to a particular type of cancer is dependent on genetic factors is a conclusion that has derived from studies of pure strains of animals. The mating habits of man are so haphazard that the possibility of the existence of human strains with different sensitivities to cancer is inconceivable. Indeed the evidence that susceptibility to cancer is inherited in man is almost entirely lacking. This does not mean that studies of the genetics of cancer can contribute little to the problem of human cancer. Actually genetic studies probably have done more than any other field of work to illuminate the paths which are currently being followed in the chemotherapy of cancer in man.
VIRUSES AND CANCER
About 40 years ago it was reported that a sarcoma growing in a Plymouth Rock hen had been transmitted to other chickens by the injection of a cell-free extract of the tumor. When, moreover, extracts of the induced tumors were prepared it was found that these would infect other birds and that serial transmission of the disease could be continued indefinitely. The extracts could be dried and preserved without loss of infectivity and the potencies of extracts from successive generations of tumors remained about the same. These observations obviously pointed to the presence of an agent which was able to multiply in the tumor cells, could survive when separated from the cells and could induce sarcomatous growth in normal chicken tissue. That is to say, this tumor appeared to be associated with a viruslike body although it must be recorded that the spon
taneous transmission of the tumor from one bird to another by contagion has never been observed.
This work was soon confirmed and stimulated a diligent search in all manner of tumors for evidence of virus origin. In spite of widespread and persistent effort the results were meager. Apart from a few other avian tumors, certain skin growths in rabbits, a maligrant growth in frogs, and 1 or 2 curious tumors in plants the results were essentially negative. The thesis that cancer was a disease caused by viruslike agents was not sustained by the evidence.
About 12 years ago interest in the problem was revived by an arresting report from one of the best known laboratories of genetics in this country. The report was concerned with the results of crossbreeding two pure strains of mice. One was subject to a high incidence of breast cancer while the other showed little susceptibility to this type of tumor. The incidence of mammary tumors in the offspring was found dependent on whether the mother or the father belonged to the cancer-susceptible strain. Following up this unexpected observation it was soon found that it was not the strain of the mother that gave birth to the young that determined susceptibility but the strain of the female that suckled them. The female offspring of a mother of the cancerous strain did not develop breast cancer in later life if fed by a foster mother from the noncancerous strain. Conversely, the female young of a mother of the latter strain became susceptible when suckled by a female from the strain with a high incidence of cancer. A single feeding would suffice. Once susceptibility was estab lished in a female it was passed on from generation to generation by the milk. Susceptibility to this type of cancer was, therefore, a heritable characteristic which was transmitted through the milk rather than through the germ cells.
From the milk and tissues of susceptible mice a cell-free material was obtained which was infective when injected into very young mice. This milk factor has the general characteristics of a virus, notably the capacity to multiply in the cells of the host. It shows a curious latency in action inasmuch as injection or feeding the virus is effective only for a short period after birth yet the cancers do not develop until late in adult life. The milk factor is related to mammary cancers only. It does not influence the incidence of other types of tumors. It is not even essential for the production of breast cancer since some strains of mice that do not carry the agent are susceptible to this type of tumor. On the other hand, wild mice have been shown to transmit the agent without developing the disease. It would appear that the cancerous effect of the virus requires a favorable genetic constitution in the host.
The discovery of the milk factor has done much to reawaken interest in the relation of viruslike agents to cancer. Brief consideration of the general characteristics of viruses is, therefore, appropriate. A virus may be described as an infective agent with an affinity for certain specific cells in certain limited species and with the capacity to multiply in these cells with the production of a characteristic diseased state. All manner of living things—the higher and the lower animals, plants and micro-organisms—are prey to attack by their own particular groups of viruses. Because of favorable experimental conditions much of what we know about viruses is derived from those that induce diseases unrelated to cancer. Indeed, much of what we know comes from studies of the viruses of plants and bacteria. This information, though it does not relate to cancer directly is of the greatest significance to the interpretation of studies on the transmission of cancer.
Viruses are particulate bodies. They can be visualized in the electron microscope. They vary considerably in size. The smaller ones show little evidence of structural organization but the larger ones exhibit a variety of differentiated structures. Chemists have succeded in purifying some of the simpler viruses. A few of the plant viruses have actually been crystallized testifying to a high degree of chemical homogeneity. The simpler viruses have been found to be composed chiefly of nucleoprotein. Other more complex viruses have been shown to contain fat and carbohydrate in addition to nucleoprotein.
The question whether viruses are substances or organisms has often aroused vehement debate. The issue itself is probably debatable and current thought is content to conceive viruses as bodies lying in that twilight zone between the giant molecules of some proteins and the most minute of organisms. The biologist concedes that they are living organisms in respect of their ability to reproduce themselves but he emphasizes the extreme parasitic character of their life. They exhibit few, if any enzyme activities of their own. They cannot be grown on artificial media because they do not have the machinery with which to
metabolize nutrients. They are able to multiply within host cells because they are able to exploit to their own ends the labor of the cells in which they live. They rely upon the cells to manufacture protein and nucleic acid and they then pervert these products to the synthesis of viral substance. Like a barbarian army of occupation the viruses live off the land that they have captured.
In this competition with the needs of the cell the virus may be so successful that the cell starves and dies. The virus is thereby released and is free to invade and destroy other cells. If, however, the growth of the virus is restrained, the host cell may survive but must be regarded as a modified cell in that it harbors an alien component and has suffered a perversion of its metabolism. When the cell divides the virus will be carried into the daughter cells as a heritable component which will be transmitted as long as it multiplies at a rate comparable with that of the host cells.
Viruses will also compete with one another. When two viruses invade a single cell the more aggressive one may inhibit the multiplication of the other. Alternatively, both may survive but each may modify the characteristics of the other. The chemist would say that they have interacted with each other. The biologist might prefer to say that each had suffered a mutation. Certainly viruses are prone to mutate when subjected to modified environments. Their virulence, for example, may often be increased or diminished by passage through types of host cells that are not their usual habitat. This capacity to change in virulence has been effectively exploited in the preparation of attenuated viruses for use as vaccines.
An interesting characteristic of certain tumor viruses, such as the milk factor, is that they may lie dormant in the host for a long period and then rather suddenly begin to multiply actively and to induce malignant growth. In other cases the virus seems to disappear from the cells after malignancy has de veloped. It may be that it has become so intimately incorporated into the organization of the host that it has lost its identity as an alien body.
Some viruses are highly specific. The virus of mumps attacks only man and a few species of monkeys. The virus of influenze is less discriminating. It will infect many species as widely distinct as man, monkey, swine, mouse, guineapig, and hedgehog. Cancer viruses appear to be highly specific in respect to the species they will invade and the type of tumors that they will induce. Specificity in the relation between virus and host indicates that the genetic constitution of the host determines whether a virus will invade and multiply. Since, however, viruses also show specificity for particular tissues of a single host one must assume that cytoplasmic and genic factors are both involved.
The reader will have noted the similarities in nature and in behavior of genes, plasmagenes and viruses. Viruses are conventionally distinguished by the criterion that they invade the cell from without. The question may well be asked—though it cannot be answered—where did they come from origin lly? One prominent genticist has suggested that viruses are plasmagenes in the wrong host. Remembering the capacity of viruses to undergo mutation one need only conceive a plasmagene acquiring the ability to survive after detachment from the cell in which it originated and the ability to invade another cell of similar type to reduce the virus to the status of a special type of cell particulate. From what has been said of the ability of genes, plasmagenes and viruses to compete and interact with one another in the struggle for nucleoprotein it is not difficult to conceive of heritable mutations occurring in host cells as a result of invasion by a virus.
A series of experiments that is being watched with great interest at the present time is concerned with the transmission of leukemia in a sensitive strain of mice. The results suggest that the malignancy is induced by an agent that is transmitted from generation to generation by the embryo. Such an agent can scarcely be classed as an invasive agent since it passes directly from mother to young presumably as a normal component of the cytoplasm. Should these results be confirmed they will represent a contribution to the problem of cancer at least as significant as was the discovery of the milk factor.
The genetic factors, be they genes or plasmagenes, that determine the susceptibility of a cell to cancer are intrinsic to the cell itself. The tumor-inducing viruses, on the other hand, if they are true viruses, are agents that invade the cell from without. Reference has already been made to other environmental
factors that are cancerogenic in action. These include certain types of radiations and a variety of chemical substances such as arsenic components of coal tar, products of the dye industry, and a variety of synthetic hydrocarbons. The hydrocarbons are of particular interest since a number of them bear some chemical resemblance to a group of hydrocarbon derivatives that are actually produced in the human body and circulate in the blood. These are the steroid hormones. They are manufactured by the sex glands or by the cortex of the adrenal gland.
In comparison with the complex proteins which have been the subjects of discussion up to this point, the steroids are simple chemical substances. They can be prepared in the pure state, their reactions and molecular structures are known and many of them can be synthesized in the laboratory. From the chemical point of view the steroids are closely related to one another, yet, they have very different physiological activities. Only one of them—the female sex hormone, known as estrone--has been shown to have significant cancerogenic potency. A number of others, however, have been found to exert profound effects on both normal and malignant growths in organs other than those in which they are produced. Thus, although they are growth factors indigenous to the organism, they are extrinsic to the cells whose growth they control.
The sex of an animal is primarily determined by the chromosomes carried by its cells. The extent to which its sexual potentialities are realized and become functional is, however, determined to a considerable degree by the hormones secreted by its sex glands. This is well illustrated by the familiar effects of castrating an animal before puberty. Not only is there a stunting of the sex organs but there is also failure to develop those secondary characters which are typical of the sex to which the animal genetically belongs. On the other hand, overproduction of sex hormones leads to precocious puberty and to an accentuation of sex characters. Moreover, the administration to an animal of one sex of the hormone of the opposite sex results in a partial reversal of the secondary ex characters. These and a great body of related observations lead to the conclusions that the male and female hormones are essentially antagonistic in their physiological actions.
The male sex hormone, testosterone, is secreted by the testes. It shares its masculinizing properties with a number of other steroids that are usually considered together and called androgens. The ovary of the female secretes several steroids. These, together with others which exhibit feminizing actions are known as estrogens. It is a matter of common knowledge that both estrogens and androgens are secreted by animals of either sex. In the female the estrogens predominate, in the male the androgens are in excess. It is customary, therefore, to speak of the estrogen-androgen balance of an individual and to infer that it is this balance that determines the extent to which the innate sexual potentialities of the individual are realized.
The effects of the sex hormones on normal growth are highly specific. The estrogens stimulate the growth of the female genitalia, the uterus, the mammary glands, and bone. The androgens promote the growth of the male genitalia and the prostate and affect the distribution of the growth of hair on the face and body. During the past 40 years a great deal of information has accumilated to show that both types of hormones influence the tumors of certain organs and that, in general, the effects of androgens and of estrogens are antagonistic. Estrone will induce tumors in the breast, ovary, uterus, pituitary, and tests of susceptible mice. It will even lead to breast cancers in male mice of strains that carry the milk factor although these mice do not develop tumors unless estrogen is administered. Estrogens also increase the susceptibility of animals to other cancerogenic agents including radiations.
Androgens do not appear to be actively cancerogenic but they do definitely influence the growth of existing tumors of certain types. In particular they stimulate tumors of the prostate and cause regressions of breast cancers. Conversely, estrogens inhibit prostate cancers and stimulate many tumors of the breast.
The steroids of the adrenal gland have not, as yet, been shown to have any pronounced effects either on normal or on malignant growth. When the remarkable physiological effects of cortisone were first publicized it was natural to hope that this product of the adrenal cortex would prove to have some value in the control of cancer. The results of many trials on all manner of human cancers have been disappointing. The hormone does cause short-lived regressions in leukemia and so may prove to be a useful palliative in this condition but nothing more.
Quite recently much interest has been evoked in reports of favorable results of the surgical removal of both adrenal glands in patients with prostatic and some other cancers. The treatment is now being tried out by many surgeons so that its long-term efficacy should soon be ready for judicious appraisal. Why the removal of the adrenal secretion should inhibit malignant growths is a matter for speculation. There is evidence that the adrenal cortex manufactures androgens and it may be that the lack of these contributes to the regression of cancers of the prostate. The adrenal cortex, however, secretes a number of steroids each of which seems to have different but, as yet, poorly defined effects on metabolism. It is possible that the value of the operation does not depend on a simple readjustment of the estrogen-androgen balance so much as on some deep-seated change in steroid metabolism or in the general metabolism of the body cells.
In this brief recital of the more striking effects of steroids on normal and malignant growth several points merit emphasis. In the first place, it will be noted that the effects of the sex hormones are confined to tumors of those organs whose normal functions are under their control. Secondly, when a tumor is influenced both by estrogens and by androgens the effects are generally antagonistic. This is consistent with the view that cancer is often associated with an estrogen-androgen imbalance. Further evidence for this may be found in the fact that the incidence of cancers of the organs that are under the control of the sex glands is definitely increased at the menopause when there are known to be major readjustments in the secretion of the sex hormones. On the other hand, it may be that the problem is oversimplified by restricting consideration to the balance of the steroids that are the normal secretions of the sex glands. Steroids undergo many changes in the body. More than 50 different steroids have been identified in normal urine. Were some defect in metabolism to occur that resulted in the production of a steroid that was actively cancerogenic, a plausible explanation of the causes of some types of cancer would be available. In view of the high cancerogenic potencies of some synthetic hydrocarbons and the fact that estrone itself is mildly cancerogenic this view cannot be dismissed as an implausible hypothesis. It is one that is inspiring many investigators to undertake systematic studies on steroid metabolism. The work is difficult. The steroids are unstable substances. The amounts which are present in the body are exasperatingly small so that the isolation and identification of individual substances present formidable technical difficulties.
In this area metabolism, as in so many others, tracer techniques are being exploited to great advantage, and knowledge of the reactions which enter into the synthesis and metabolism of steroids in the body is accumulating rapidly. Some evidence that there are abnormalities in steroid metabolism in patients with cancer has already been disclosed. The significance of the results is uncertain. One must, perforce, hasten slowly in their interpretation. There is always the difficulty of deciding whether an observed abnormality is a cause or is merely an incidental result of the diseased state that one is studying. However this may be, investigations of the metabolism of steroids are of the first importance to the problem of cancer and will continue to occupy a prominent place in the research program of the Cancer Society.
This review of the relation of hormones to cancer has been confined to the steroid hormones because the effects of some of these on certain types of tumors is experimentally demonstrable and, therefore, inescapable. There are, however, many other hormones in the body that cannot be ignored in any comprehensive survey of the intrinsic chemical factors that control growth processes. They are entirely different in nature from the steroids being related chemically to the proteins. All of them in some manner or other influence metabolism. A few of them, notably the growth hormone of the pituitary gland, has pronounced effects upon the growth of the body as a whole. Their relations to malignant growth are obscure but are not to be ignored because they are indirect.
Beyond the immediate effects of individual hormones on growth, is the problem of the control of the secretions of the endocrine glands by the organism as a whole. This is the central problem of endocrinology at the present time. A fascinating story is unfolding of the interplay of individual glands, of cooperating hormones and of antagonistic hormones, of a complex system of mutual self-controls. There emerges a pattern of a closely knit interlocking directorate that controls the overall hormone balance of the organisms and, therefore, the balance of metabolism.
There are still wider ramifications that the future must explore. The balanced growth of the different organs of the body and the regenerative processes that