5.1 MODELS OF CARCINOGENESIS
Cancer is a disease that results from cumulative genetic changes. Sporadic mutations take place in all cells of the body and may lead eventually to a cell that is transformed and whose progeny develop into a cancer. Any agent or process that increases genetic changes will increase the probability of a cancer developing, so that minimizing the incidence of cancer requires identification of and avoidance of exogenous agents (ie, carcinogens) that can cause it (Okey and Harper, 2007; Loeb and Harris, 2008). Carcinogens include chemical agents (Wogan, 2004), many of which are known to be mutagenic (described in Section 5.2), ionizing and ultraviolet radiation (Chap. 9, Sec. 9.2.2 and Chap. 15, Sec. 15.4.1), and some viruses, which can introduce oncogenes into the human genome (Chap. 7, Sec. 7.4.4). Although the mechanisms that lead to cancer differ following exposure to these different types of exposure, there are some common properties.
5.1.1 Tumor Initiation, Promotion, and Progression
Both epidemiologic and experimental studies have confirmed that a latent period (often decades in humans) exists between the exposure to a carcinogenic agent and the appearance of cancer. This knowledge led to the formulation of a sequential model that divided the carcinogenic process into 3 stages, termed tumor initiation, tumor promotion, and tumor progression.
Tumor initiation is the process by which a carcinogenic agent interacts with DNA to produce damage that, if not repaired before the next cell division, could lead to error-prone DNA replication, resulting in fixation of mutations within the genome of individual cells. The efficiency and fidelity of DNA repair (see Chap. 9, Sec. 9.3) and the balance of cell proliferation and cell death are important in determining if this process leads to cancer. If a mutation disrupts the function of a gene whose product plays a role in maintaining the terminally differentiated function of the cell, the cell may acquire an altered (usually less differentiated) phenotype. Although initiation is irreversible, not all initiated cells will go on to establish a tumor, as many of these cells may die by apoptosis (see Chap. 8, Sec. 8.4), and further proliferation-enhancing signals are required for initiated cells to progress along the pathway to autonomous (cancerous) growth.
Tumor promotion involves the clonal expansion of an initiated cell as a consequence of events that alter gene expression, so as to provide the cell with a selective proliferative advantage. Although there is no single unifying mechanistic feature of tumor-promoting agents, they tend to be nongenotoxic and to cause cells to divide but not to differentiate terminally or die, resulting in the survival and proliferation of preneoplastic cells and the formation of benign lesions such as papillomas, nodules, or polyps. Many of these lesions may regress spontaneously, but a few cells may acquire additional mutations ...