28 May

Figure 10.14 presents a diagram of the natural history of neoplasia as the student may perceive it, beginning with the process of initiation, extending through the reversible promotion of the initiated cell to a visible tumor, followed by the natural progression of this tumor into a benign neoplasm and the ultimate expression of malignancy, that of distant metastases. At the bottom of the figure is the concomitant  relationship  of the cellular karyotype  extending  throughout  this process. Exactly where in this scheme the progeny of initiated cells begin to exhibit the karyo- typic abnormalities characteristic of the stage of progression will depend on the tissue of origin, the dose of the carcinogenic agent, and the rate of cell proliferation in the preneoplastic stages. Furthermore, it is important to remember that, although this diagram indicates the monoclonality of neoplasms, multiclonal  neoplasms may well follow the same natural history, although in a somewhat more complicated manner, such as the coalescence of multiple clones during the stage of progression. The diagram does not show the potential for regression or dormancy during the stage of progression but rather represents the primary pathway of neoplastic development.

It should also be realized that not every neoplastic cell resulting from the transformation of a normal cell must follow this entire series of stages. Thus, complete carcinogens at very high doses may result in aneuploid neoplastic cellular populations on initial administration, such that the stages of initiation and promotion as defined in this text are bypassed. However, the develop- ment of the greater majority of human neoplasms is likely to progress through the natural history depicted in Figure 10.14.

An understanding of the natural history of neoplastic development is essential to our un- derstanding of the mechanisms involved in the induction of neoplasia by chemical, physical, and biological agents as well as genetic factors. Table 9.10 gives a mechanistic classification of car- cinogens as related to their specific actions during the individual stages of carcinogenesis. It is obvious from this classification that some chemicals may possess two of the classifications, such as promotion and progression or initiation and progression. It is, however, important to note that in this classification a complete carcinogen must have exhibited the capability of possessing ini- tiating, promoting, and progressing capabilities by definition. The importance of this classifica- tion should be obvious to the student by now in that promoting agents given chronically over a long period of time, acting on spontaneously  initiated cells, may mimic complete carcinogens and be classified as such in the absence of detailed mechanistic studies. On the other hand, pro- gressor agents that truly do not have initiating capabilities would be dependent on their “com-

Figure 10.14 The natural history of neoplasia, beginning with the initiated cell after application  of an initiating agent (carcinogen)  followed by the potentially  reversible stage of promotion to a visible tumor, with subsequent progression of this tumor to malignancy. The relation to karyotype is presented as a gener- alization on the lower arrows. The reader should again be cautioned that not all neoplastic  cells undergo this entire natural history. It is theoretically possible, although this has not yet been definitively shown, that some neoplasms, such as those induced in animals by radiation or high doses of chemical carcinogens, may enter this sequence in the stage of progression, exhibiting aneuploidy, and thus bypass the early euploid cell stages.

plete carcinogenic”  effects in the presence  of promoted  clones of cells. Since spontaneous promotion clearly occurs but takes considerable time in order to produce significant lesions, en- vironmental progressor agents may be more carcinogenic in older individuals. Thus, an under- standing  of the mechanistic  classification  of carcinogens  will lead  not only  to a better understanding  of the mechanism  of action of specific carcinogenic  agents but also to an im- provement in the modalities of both cancer prevention and cancer therapy.

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