As noted in the last chapter, neoplastic growth significantly alters the homeostasis of the host. The presence of the neoplasm may alter the host’s nutritional status to the point of starvation, termed cachexia in the tumor-bearing host. The complexity of the mechanisms of tumor cachexia was emphasized, but clearly the effects of the neoplasm on the host and the relatively autonomous growth of the neoplasms are the key factors in the development of the cachexia of cancer.
Normal homeostasis is controlled in the organism by a delicate balance of multiple inter- cellular regulatory molecules generally known as hormones. This is not to say that small mole- cules such as glucose, nonesterified fatty acids, amino acids, and other small molecule substrates are not important in the homeostasis of the organism. However, generally speaking, the func- tional, trophic (replicative), and tissue-specific controlling factors that maintain organismal ho- meostasis are hormones. Hormones may be polypeptide in character, such as growth hormone and insulin, or of low molecular weight, such as prostaglandins and steroid hormones. Some groups of hormones have distinctive designations dependent on their function, such as cytokines (Chapter 19), interleukins (Chapter 19), growth factors (Chapter 16), and others. Still, in the general sense, these chemicals produced by specific cells and acting in an autocrine, paracrine, or endocrine manner may be considered as hormones. In previous chapters we have discussed a number of such hormones, including growth factors (Chapter 16), tumor necrosis factor alpha (Chapter 17), and the parathyroid hormone-related protein (PTHRP) (Chapter 17). Many of these and other components designated, in the general sense, as hormones are produced by a variety of cell types, whereas other polypeptides, steroids, and small molecules are produced primarily by specific cell types and have largely an endocrine function, such as growth hormone, steroid hormones, and insulin. This chapter considers the latter class both from the standpoint of the effect of such hormone production by the host on the neoplasm and the effect of the produc- tion of such hormones by neoplasms on the host.
Effects of the Endocrinology of the Host on the Neoplasm
As emphasized at the beginning of the last chapter, neoplasia must always be taken in the con- text of the neoplasm and the host. Since neoplastic cells must exist within the environment of the host, factors produced by the host that directly affect the neoplastic cell will obviously alter the neoplasm’s growth and function. In Chapter 3 (Figure 3.19), the cybernetic relationship of endo- crine glands within the mammalian organism was depicted in relation to the demonstration of the carcinogenicity of endogenous hormones (Figure 3.20). Earlier studies by Furth and associ- ates (cf. Furth, 1961) demonstrated the inhibition of the development of mammary neoplasms in
rats induced with 3-methylcholanthrene by ovariectomy and hypophysectomy shortly after ad- ministration of the carcinogen. These authors demonstrated that administration of mam- motrophic pituitary polypeptide hormones for several months after surgery would allow the development of mammary neoplasms, indicating their growth responsiveness to the effects of these pituitary trophic hormones. Briand et al. (1982) carried out similar experiments but in- duced mammary adenocarcinomas by treatment of ovariectomized mice with progesterone or estrone. Continued treatment with the hormone resulted in mammary neoplasms, but absence of such treatment resulted in the development of very few neoplasms. However, if the animals were kept for extended periods of time (a year or more), then some neoplasms developed. Similar findings have been demonstrated experimentally with other types of neoplasms that grow only in animals possessing very high levels of circulating hormones of the type to which the cell of ori- gin is normally responsive (cf. Clifton and Sridharan, 1975).
In a more detailed experiment, Furth and colleagues (cf. Furth, 1961) performed a varia- tion of the experiment depicted in Figure 3.20, utilizing, as a source of hormone, functional pitu- itary neoplasms that could be transplanted into the host. In this instance, as outlined in Figure 18.1, a functional pituitary thyrotropin-producing neoplasm was transplanted into a rat, and the thyroid gland was sampled at various periods. Initially lesions histologically indistinguishable from neoplasms of the thyroid developed in the gland, but—as noted in the figure—surgical re- moval of the functional pituitary transplant resulted in complete regression of these “neo- plasms.” Furthermore, transplantation of these lesions into animals of the same inbred strain but with no functional pituitary thyrotropic neoplasm transplant (FPTNT) allowed for no growth. However, if the FPTNT was maintained in the host for longer periods, some neoplasms devel- oped which on removal of the transplant did not entirely regress, although substantial regression occurred (Figure 18.1). Finally, if the thyrotropin-producing transplant was maintained suffi- ciently long in the host, neoplasms would develop which even in the absence of the transplant and the thyrotropic stimulus grew, could be transplanted into other animals, and metastasized. Furth termed these three “stages” in the development of completely autonomous neoplasms as dependent, responsive, and autonomous (Figure 18.1). The reader will immediately see the com- plete analogy to the stages of promotion and progression in neoplastic development. The fully dependent neoplasm is a preneoplastic lesion arising from a spontaneously initiated cell but still completely dependent on the promoter (thyrotropin). The responsive neoplasm is one with a cel-
Figure 18.1 Diagram of the development of dependent, responsive, and autonomous neoplasia follow- ing chronic exposure of the thyroid in vivo to thyrotropin from a functional pituitary thyrotropic neoplasm transplant.
lular population that can survive and exist in the absence of the hormone but grows relatively slowly in the stage of progression. The completely autonomous lesion is that of the usual malig- nant neoplasm in the stage of progression. Theoretically, a neoplasm of any of the tissues de- picted in Figure 3.19 may undergo a similar series of “stages” in the development to neoplasia. In the human there are no unequivocal examples of dependent neoplasms, although in one re- spect the placenta may be considered a dependent tumor, its maintenance dependent entirely on the “abnormal” hormonal environment of the pregnant female.
Continued proliferation of such “dependent” cells can lead to a gradual progression in pro- liferative vigor as a result either of environmental stimuli, of host-induced modification of cells, or of a natural selection of a more aggressive cell type, in a manner analogous to tumor progres- sion (Chapter 9). Such neoplasms may exist in the host even in the absence of the trophic hor- mone or environmental stimulus, although at relatively low growth rates in many instances. Such neoplasms are termed hormonally responsive tumors and are exemplified by such neoplasms as carcinoma of the prostate or of the breast in the human, since castration or treatment with hor- mones substantially reduces the growth rate of many of these neoplasms. Less often, hormone- responsive neoplasms give rise to nonresponsive or reversely responsive variants—the original inhibitor becoming a stimulant of the tumor cell in the latter case (Clifton and Sridharan, 1975). Although the latter situation is rare, it may be brought about by therapy in humans and has also been shown to develop in experimental situations. This may be related to the demonstration of the development of mutations or variants in the steroid hormone receptors present within the neoplastic cell (cf. Sluyser, 1994; see below). Finally, responsive tumors may progress to an au- tonomous neoplasm, in which hormones have little if any effect on its growth rate. The natural history in humans of neoplasms of endocrine tissue is a progression from responsive to the au- tonomous stage.