Research over the past 25 years has produced a deeper understanding of the molecular, biochemical, and cellular changes that occur as cells are transformed from normal cells to malignant cancers. The multiple genetic defects leading to cancer cell production can result from exposure to environmental, dietary, and lifestyle factors, as well as infectious agents. The multistep, multistage process of gradual carcinogenetic changes in the biological behavior of a clonogenic population of cells is illustrated schematically in Figure 2.1.20As indicated, this progression of cellular changes may span years or decades.21 Among the epithelial cancers, such as colorectal, breast, prostate, lung, pancreas, and others, a diffuse genomic instability after exposure to damaging agents (inflammation, toxins, etc.), and increased epithelial hyperplasia is the initiating act. A single basal cell may develop one or more mutations of a number of critical oncogenic or tumor suppressor genes, allowing escape from regulatory controls on position, differentiation, and growth.22 Oncogenes are genes that as proto-oncogenes are involved in signal transduction and execution of mitogenic signals. However, when their expression or protein function is altered, they demonstrate uncontrolled activity leading to unrestrained cellular growth. The normal function of tumor suppressor genes is in negative control of cell cycling; however, this control is released when the genes are mutated.23 Specific genetic alterations involved with the transformation process have been defined for many cell types. For example, in colorectal cancer, particular events that are associated with initiation and progression include mutation or loss of the Apc gene (adenomatous polyposis coli, a tumor suppressor gene), mutation of K-ras (a proto-oncogene), and generalized disorganization of DNA methylation. Later events associated with malignant transformation include loss of tumor suppressor genes p53, SMAD4, and SMAD2 functions.24 These four sequential genetic changes are necessary to ensure colorectal cancer evolution, and it appears that the temporal sequence, rather than accumulation of alterations, is most important in determining the neoplastic phenotype. However, the fact that K-ras mutations are found in only about 50% of colorectal cancers indicates that other unknown oncogenes, as well as epigenetic events such as alteration in DNA methylation patterns, may be involved (described further below).24 Overall, loss-of-function mutations in tumor suppressor and DNA repair genes, as well as gain-of-function mutations in proto-oncogenes, result in transformed cells, which acquire selective advantage over normal cells.25
Neoplastic clonal expansion of transformed cells starts at one or more sites in an epithelium and progresses independently at different sites. This leads to the development of preinvasive intraepithelial neoplasia, or a multicellular mass that tends to distort surrounding normal cells. The onset of intraepithelial neoplasia is initiated by a monoclonal expansion, which progresses via clonal evolution; that is, the different mutated cell types with the fastest growth rate will overtake all others as they expand. This neoplastic promotion leads to increases in both total mass and extent of dissemination (known clinically as increase in stage and grade of the neoplasm with time).22 The host tissue environment, particularly through the action of hormones and cytokines emanating from the stroma around the developing epithelial tumor, influences the tumor's development. Eventually the mass progresses to an invasive neoplasia defined by the presence of stromal invasion, and subsequent metastasis to distant sites is possible.20 Again using colorectal cancer as an example, the histopathology of this process is seen as a progression from normal intestinal epithelial crypts to aberrant crypt foci, to adenomas or polyps (hyperplastic [nondysplastic] or adenomatous [dysplastic]), and to carcinoma.24 Prevention models target the development of intraepithelial neoplasia due to the high likelihood of progression from dysplasia to invasive cancer, and because evidence indicates that reduction in the precancerous burden reduces cancer risk and/or the need for invasive interventions.21
Thus, tumorigenesis is a multistep process, and these steps reflect a succession of genetic changes, each of which confer a growth advantage that drives the progressive transformation of normal human cells into highly malignant cells. Hanahan and Weinberg26 have postulated that the vast array of cancer cell genotypes can be defined as a manifestation of six essential alterations in cell physiology that cumulatively lead to malignant growth. These six changes are (1) self-sufficiency in growth signals; (2) insensitivity to growth-inhibitory
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