The epigenetic instruction manual for the operation of the genome.

The factors composing the instruction manual for the operation of the genome are, at least initially, of maternal origin and supplied in the egg; they are postulated to be reproduced only slowly, if at all, during growth. This would insure that, as the size of the animal increases, the concentrations of these factors would decline. The progressive decline is postulated to sequentially trigger appropriate master genes, each of which is turned on or off by precise concentrations of these regulatory factors; each master gene in turn specifies a specific pattern of subsidiary gene expression. This formulation can explain how a divided early embryo can grow into two nearly perfect but miniature larvae. The concentration of the regulatory factors would reach a nadir when growth stops and then gradually recover. The increasing concentration after puberty might tend to activate the genome in reverse order and thus contribute to senescence.

On the prevention and therapy of prostate cancer by androgen administration.

It has been widely suggested that elevated androgen levels may be critically involved in the genesis of prostate cancer. Despite the dependency of the normal prostate and of most prostatic cancers upon androgens and the fact that tumors can be produced in some rodent models by androgen administration, I will argue that, contrary to prevalent opinion, declining rather than high levels of androgens probably contribute more to human prostate carcinogenesis and that androgen supplementation would probably lower the incidence of the disease. I will also consider the possibility that the growth of androgen-independent prostate cancers might be reduced by the administration of androgens.

Regeneration versus neoplastic growth.

Amphibian tissues seem to resist oncogenesis in proportion to their regenerative capacity, a phenomenon most easily seen in relation to limb regeneration. There is evidence that mammalian tissues also possess, in addition to and distinct from the capacity for physiological renewal, a limited and not always overtly evident degree of amphibian-like capacity for regeneration (epimorphic regeneration). It is the thesis of this paper that cancer in mammals would seldom occur were it not for a local destruction or exhaustion, secondary to injury or aging, of this normal amphibian-like regenerative capacity.

The paradoxical association of regression with a poor prognosis in melanoma contrasted with a good prognosis in keratoacanthoma.

Partial regression in cutaneous malignant melanoma has been reported by a number of observers, albeit not all, to be associated with a relatively poor prognosis; in contrast, a keratoacanthoma, which eventually regresses, does not metastasize. The Hammond effect could explain the possibly poor prognosis of the thin regressing melanoma. Hammond(W.G. Hammond et al., Cancer J., 8: 130-138, 1995) showed that the speed of biological progression to less differentiated phenotypes is directly related to the immunocompetences of the tumor hosts. If partial regression is a sign of an unusually strong immune reaction, then the melanoma that partially regresses might have a relatively poor prognosis because of the greater risk of biological progression among the surviving tumor clones. A Hammond effect is not associated with regression of a keratoacanthoma. I postulate that the growth of this tumor is accelerated, rather than restrained, by the immune reaction and that the ultimate regression of the tumor is the result, not of immune cytotoxicity, but of a rapid terminal differentiation (a reverse Hammond effect); alternatively, very rapid growth might lead to an exhaustion of growth potential before progression to clonal immortality could occur.

Immunostimulation of cancer versus immunosurveillance.

A moderate antitumor immune reaction is optimal for tumor growth and most (perhaps all) untransplanted tumors, rather than being inhibited, are probably dependent, at least early in their progression, upon the immune reaction. Some tumors, as for example most human skin tumors, have a higher incidence in immunodepressed patients than they do in the general population. This could mean that the normal immune reaction usually inhibits the growth of these tumors. More probably, the increased incidence in immuno-depressed heart and kidney transplant patients is caused by a lowering of a tumor-stimulatory immune reaction to a level that is even more stimulatory. Other tumors, such as human mammary tumors, have, in contrast to the skin tumors, a lower than expected incidence in immunodepressed patients. Mammary tumors are postulated to possess, on average, a low immunogenicity that arouses an immune reaction that is usually equal to or less than that required for optimal tumor growth; a further lowering of the reaction, as occurs in heart or kidney transplant patients, thus results in a lowered tumor incidence. In such patients, an immunostimulating adjuvant or vaccine might, we predict, sometimes accelerate rather than inhibit tumor growth.

Cancers beget mutations versus mutations beget cancers.

Despite the plethora of "oncogenes" and "tumor suppressor genes," the hypothesis that cancer is usually the result of genomic mutations may be wrong. We should at least examine the alternative hypothesis, for which there is considerable evidence, that mutations do not commonly beget cancer, but rather that cancer phenotypes result from confused or aberrant patterns of normal-gene expression; the abnormal patterns are postulated to result from epigenetic mechanisms rather than from mutations. The epigenetic hypothesis that I am proposing suggests that cancers may exhibit mutations primarily because replicative errors at inactive sites in the cancer genome may be repaired slowly or not at all, but the mutations so produced, occurring at already inactivated sites in the genome, may have limited biological significance. Thus, it may be more correct to say that cancers beget mutations than it is to say that mutations beget cancers.

Stimulatory effects of immune reactions upon the growths of untransplanted tumors.

The accumulated literature suggests that altering the immune capacities of animals or humans seldom has detectable effects on tumor incidence nor, it seems, does the growth of an untransplanted tumor, either spontaneous or induced, immunize the host against the growth of a subsequent implant of that tumor. These observations suggest that even clearly immunogenic transplanted tumors may not have had their growths modulated by an immune reaction when they were as yet untransplanted in their primary hosts. Also, there are many data that have been interpreted to show that spontaneous tumors of rodents are, even when transplanted, nonimmunogenic. A reconsideration of the available studies, especially those in which either host immune capacity or tumor immunogenicity was titrated, has led me to different conclusions. I believe that the data suggest that probably all tumors, including spontaneous ones, are immunogenic but that the weak immune response in the primary host to the antigens of even the more immunogenic induced tumors usually produces stimulation of tumor growth rather than growth inhibition. The prevalence of immunogenicity suggests that vaccination or other forms of immunotherapy will eventually succeed; however, the analysis also suggests that, in the case of weakly immunogenic tumors, increasing the immune reaction, unless the increase is massive, may have little effect or may actually stimulate rather than inhibit the growths of these tumors in their primary hosts. Immunosuppression might actually be therapeutic in these cases; this may be an unrecognized benefit of the chemotherapy of many human tumors.

Two competing influences that may explain concomitant tumor resistance.

A second tumor inoculum is often inhibited in its growth by the presence in the recipient animal of an earlier implanted, growing tumor. The tumor resulting from the first inoculum may, paradoxically, continue to grow despite the simultaneous inhibition of the growth of the second inoculum, a phenomenon usually called "concomitant immunity." Evidence now suggests that the phenomenon can be observed in the absence of any recognizable type of immune reaction and might often be named more appropriately "concomitant tumor resistance." Consideration of a variety of probably related observations suggests that concomitant tumor resistance can best be explained by the competitive interaction of two opposing influences: a local diffusible, tumor-facilitating environment, produced by both tumor and normal tissues, that is counteracted by circulating inhibitors that are also produced by both tumor and by normal tissues. In an implanted small tumor, because of geometric considerations and diffusion, the action of the local facilitating environment is weak; in a larger tumor the local facilitating environment has a relatively greater influence and thus the larger tumor can continue to grow despite levels of circulating tumor inhibitors capable of inhibiting the smaller growth.

Many growth factors may not be growth factors.

Both organ growth and tumor growth are dependent upon a biased ratio of cell births to cell deaths; this ratio is independent of the frequency of mitosis. Thus, so-called growth factors that affect only the frequency of mitosis are not really growth factors. I shall advance two hypotheses: that the normal adult ratio of cell births to cell deaths is maintained by the activity of a factor or factors produced by the stem cells; and that the differentiating cells, as well as the stem cells, produce a different factor that limits the frequency of mitosis.

The inhibition of tumor growth by tumor mass.

Evidence suggests that a tumor behaves, in its pattern of growth, like an integrated organ rather than a collection of independently growing cells. Tumor growth tends to slow progressively as size increases and to undergo compensatory growth after partial resection. Consequently, therapies that reduce tumor mass may tend to accelerate the growth of the remaining tumor and tumor metastases. An approach to therapy based upon a simulated increase in tumor mass may be worthy of consideration.

Immunological tolerance to many self epitopes may be unnecessary.

The demonstration of the existence of antigenic mimicry suggests that immunological tolerance to self antigens may be an insufficient basis for distinguishing self from non-self. However, some data suggest that even in the absence of tolerance most self epitopes would not immunize the host and that tolerance to all self epitopes may, therefore, not be necessary for the prevention of autoimmune disease.

Tumor-specific antigens as altered growth factor receptors.

Most induced, as opposed to spontaneous, tumors possess tumor-specific transplantation antigens. Data suggest that the prevalence of these antigens, at least among tumors induced chemically in diffusion chambers, is dependent upon the density of the culture at the time of carcinogen application. Other data show that density inhibition of cell growth is mediated by the interaction of various "growth factors" with their respective cell surface receptors. The juxtaposition of these two observations leads me to hypothesize that the tumor-specific transplantation antigen is an altered growth factor receptor. Development of the hypothesis leads to rational explanations of some paradoxical features of tumor growth in nude mice, to a possible understanding of why spontaneous tumors are nonimmunogenic, and to an explanation of the phenomenon of facilitation of tumor growth by a weak immune reaction.

The flip side of tumor immunity.

A large amount of data suggest that tumors are, to some degree, dependent for their growth on a positive level of immune reaction, a level that is unique for each tumor. Each tumor gradually adjusts its immunogenicity to the level that will, in the immunologic context of its own particular host, maximize its growth. Thus, it follows that immunosuppression may be as likely as immunoaugmentation to have a therapeutic effect.

The autoimmune nature of cancer.

Four different kinds of data from the 3-methylcholanthrene-induced sarcoma system of the mouse show that the immune system stimulates oncogenesis; i.e., the presence of a tumor-specific immune reaction is a positive aid to tumor development. It seems proper, therefore, to consider cancer, at least in part, an autoimmune disease.

Surveillance, latency and the two levels of MCA-induced tumor immunogenicity.

Among 154 different, MCA-induced mouse sarcomas, the immunogenicities of those tumors that had had the shortest original latencies in their autochthonous hosts were of an intermediate level with relatively little scatter. This fact is not predicted by the theory of immunological surveillance, but does fit the predictions of the immunological facilitation theory of oncogenesis. The frequency distribution of the tumor immunogenicities showed 2 peaks; the cluster of higher immunogenicity had a shorter latency than did the cluster of lower immunogenicity. The data for tumors initiated within in vivo diffusion chambers also showed 2 immunogenicity clusters, suggesting that the discrete clusters were not caused by host immunity. However, immunity apparently reduced the mean latency of the more immunogenic cluster and/or lengthened the mean latency of the less immunogenic, a result also inconsistent with the theory of immunological surveillance.