Normal PrecancerCancer Sequence

Insight into tumor development first came from epidemiological studies that examined the relationship between age and cancer incidence that showed that cancer incidence increases with roughly the fifth power of elapsed age (2). Hence, it was predicted that at least five rate-limiting steps must be overcome before a clinically observable tumor could arise. It is now known that these rate-limiting steps are genetic mutations that dysregulate the activities of genes that control cell growth, regulate sensitivity to programmed cell death, and maintain genetic stability. Hence, tumor-igenesis is a multistep process.

Although the processes that occur during tumorigenesis are only incompletely understood, it is clear that the successive accumulation of mutations in key genes is the force that drives tumorigenesis. Each successive mutation is thought to provide the developing tumor cell with important growth advantages that allow cell clones to outgrow their more normal neighboring cells. Hence, tumor development can be thought of as Darwinian evolution on a microscopic scale with each successive generation of tumor cell more adapted to overcoming the social rules that regulate the growth of normal cells. This is called clonal evolution (3).

Given that tumorigenesis is the result of mutations in a select set of genes, much effort by cancer biologists has been focused on identifying these genes and understanding how they function to alter cell growth. Early efforts in this area were lead by virologists studying retrovirus-induced tumors in animal models. These studies led to cloning of the first onco-genes and the realization that oncogenes, indeed all cancer-related genes, are aberrant forms of genes that have important functions in regulating normal cell growth (4). In subsequent studies, these newly identified onco-genes were introduced into normal cells in an effort to reproduce tumorigenesis in vitro. Importantly, it was found that no single oncogene could confer all of the physiological traits of a transformed cell to a normal cell. Rather this required that at least two oncogenes acting cooperatively to give rise to cells with the fully transformed phenotype (5). This observation provides important insights into tu-morigenesis. First, the multistep nature of tu-morigenesis can be rationalized as mutations in different genes with each event providing a selective growth advantage. Second, oncogene cooperativity is likely to be cause by the requirement for dysregulation of cell growth at multiple levels.

Fearon and Vogelstein (6) have proposed a linear progression model (Fig. 1.1) to describe tumorigenesis using colon carcinogenesis in humans as the paradigm. They suggest that malignant colorectal tumors (carcinomas) evolve from preexisting benign tumors (adenomas) in a stepwise fashion with benign, less aggressive lesions giving rise to more lethal neoplasms. In their model, both genetic [e.g., adenomatous polyposis coli (APC) mutations] and epigenetic changes (e.g., DNA methyl-ation affecting gene expression) accumulate over time, and it is the progressive accumulation of these changes that occur in a preferred, but not invariable, order that are associated with the evolution of colonic neoplasms. Other important features of this model are that at least four to five mutations are required for the formation of a malignant tumor, in agreement with the epidemiological data, with fewer changes giving rise to intermediate benign lesions, that tumors arise through the mutational activation of oncogenes and inac-tivation of tumor suppressor genes, and that it is the sum total of the effect of these mutations on tumor cell physiology that is important rather than the order in which they occur.

An important implication of the multistep model of tumorigenesis is that lethal neoplasms are preceded by less aggressive intermediate steps with predictable genetic alterations. This suggests that if the genetic defects which occur early in the process can be identified, a strategy that interferes with their function might prevent development of more advanced tumors. Moreover, preventive screening methods that can detect cells with the early genetic mutations may help to identify these lesions in their earliest and most curable stages. Consequently, identification of the genes that are mutated in cancers and elucidation of their mechanism of action is important not only to explain the characteristic phe-notypes exhibited by tumor cells, but also to provide targets for development of therapeutic agents.

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