In the last chapter, characteristics and mechanisms of the early stages of neoplastic develop- ment—initiation and promotion—were presented as being the result of cellular and molecular changes induced by specific carcinogenic agents. However, one must not forget that a neoplasm, by definition, develops within a complete, viable, multicellular organism. In a later chapter (Chapter 14) the “transformation” of normal cells to cells having distinctive characteristics while cultured in vitro is considered. However, in order to relate such transformation in vitro to the neoplastic process in vivo, the whole animal must be utilized as a testing arena in order to deter- mine the neoplastic potential of cells that have been altered in culture.
The host plays a variety of modifying roles in carcinogenesis as the result of its interac- tion with exogenous modifying factors, factors present within the organism (termed endoge- nous modifiers), or both. For all general categories of carcinogenic agents—chemicals, viruses, radiation, and genetics—the interplay of exogenous and endogenous modifiers with the host as defined both phenotypically and genotypically is a major factor in the development of neoplasia.
The stage of neoplastic development that appears most susceptible to the action of exoge- nous and endogenous modifiers is promotion. On the other hand, genetic factors, which may be less susceptible to modification, may play a role at more than one stage in neoplastic develop- ment. Just as the host-tumor relationship (Chapters 17, 18, and 19) is critical to our ultimate understanding of the control and therapy of established neoplastic disease, a complete compre- hension of host effects during carcinogenesis may be vital for the practical prevention of neo- plasia or termination of its natural history prior to significant clinical effects in the host.
Within the organism, a variety of substances can affect the development of neoplasia. Some of these are products of specific genes within the organism, some of which have already been dis- cussed (Chapter 5). Others are factors inherent in the development of the organism, as well as hormones and related endogenous components that under normal circumstances maintain the “internal milieu” of the organism. As has been pointed out, several of these latter factors are carcinogenic in their own right and thus might be important in the development of spontaneous neoplasia (Pitot, 1993).
Genetic Modifiers in Spontaneous and Chemically Induced Carcinogenesis
The most basic of the endogenous factors that may modify the process of carcinogenesis is the genetic constitution of the host and the resultant gene products produced by the expression of a number of “modifier” genes, many of which were discussed in Chapter 5. However, it is impor- tant to distinguish between such “modifying” genes and those genes, tumor suppressor genes and proto-oncogenes, that are directly involved in the origin of the stages of initiation and pro- gression (see Chapters 5 and 9). Modifying genes, discussed in Chapter 5, can generally be grouped as those involved in xenobiotic metabolism and the major histocompatibility complex (MHC) in both humans and animals. In animals, a number of modifying genes do not appear to be involved in either xenobiotic metabolism or in the MHC system (Drinkwater, 1995; Table
5.16). The functions of the products of several of these genes are known, whereas others are only speculative. A genetic alteration in the MHC in the rat has been associated with a marked in- crease in the development of liver cancer in males and breast cancer in females (Melhem et al.,
1991). Similarly, in several mouse strains differing genetically in the MHC (termed H-2 in the mouse), substantial differences in the incidence of neoplasms of the liver, lung, mammae, ovary, and uterus were seen and correlated with different alleles of the H-2 locus (cf. Smith and Wal- ford, 1978). These situations may be analogous to that seen with the relationship of specific MHC alleles and an enhanced incidence of specific neoplasms in humans (Chapter 5). On the other hand, modifying genes in the development of neoplasia other than genes of xenobiotic me- tabolism and the MHC region in the human have not been extensively characterized. Table 8.1 shows several examples of such modifying genes that fall into a number of categories, including receptors or mutations in the G-CSF receptor gene, that are involved in the pathogenesis of se- vere congenital neutropenia with progression to acute myeloid leukemia in many cases (Dong et al., 1995). Enhanced susceptibility to prostate cancer has been seen with genetic polymorphisms in the vitamin D receptor and the androgen receptor (Ingles et al., 1997), while an increase in pulmonary cancer and a number of other cancers, especially in the black population, appears to be related to a deletion in the poly(ADP-ribose) polymerase gene (Bhatia et al., 1990). Interest- ingly, hereditary pancreatitis resulting from a mutation in the cationic trypsinogen gene in- creases the risk of pancreatic cancer dramatically (Lowenfels et al., 1997). Thus, it is likely from this and animal studies that there are numerous genes whose products exhibit a variety of differ- ent functions that may modify, in a positive or negative manner, the development of neoplasia.
This is not unexpected in view of the discussion presented on polygenic inheritance of neoplasia in Chapter 5.