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10.1 TUMOR PROGRESSION

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10.1.1 Cellular Aspects of Tumor Progression

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Cancer is not a static disease. In many tumors (eg, colon, breast, cervical, pancreatic, melanoma), there appears to be an orderly progression from benign tissue to premalignant lesion to frank malignancy. In other tumors, premalignant lesions may not have been identified, but it is likely the tumor has passed through less-malignant stages before detection. The pathological and clinical criteria for tumor progression are often specific to a given type of tumor, but include local spread along tissue planes and into various tissue spaces and cavities. Tumors also have the capacity to invade and spread from their origins to other organs in the body; This process is referred to as metastasis. Increasing numbers and types of genetic abnormalities accompany tumor progression and metastasis.

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More than 50 years ago, Foulds defined tumor progression as "the acquisition of permanent, irreversible qualitative changes in one or more characteristics of a neoplasm" that cause the tumor to become more autonomous and malignant. In 1986, Nowell proposed that such changes arise because cancer cells tend to be genetically unstable and described a conceptual model to explain the process of tumor progression (Fig. 10–1). The key features of this model are the generation of mutant cells within a tumor and the selection and outgrowth of more autonomous cells to become dominant subclones in the population, leading to progression of the tumor and increasing malignancy. Many studies have confirmed the genetic instability of malignant cells (see Chap. 5, Sec. 5.2 and Chap. 7, Sec. 7.4), and have identified somatic DNA copy number changes and mutations using genome-wide analyses (see Chap. 2, Sec. 2.7) that are becoming routine in cancer research and in the clinic. Consistent with this model, recent studies have identified different clonal populations within tumors, raising the possibility for a minor (resistant) subpopulation to cause tumor recurrence following therapy (Navin et al, 2011). The growth and development of various cells within a tumor is largely subject to constraints associated with interactions among the tumor cells, the stromal cells, and the extracellular environment. Thus the normal homeostatic mechanisms that control cell proliferation in the body (see Chap. 9, Sec. 9.2) are not completely lost in tumor cells, but rather the cells may become increasingly less responsive to them. In addition, tumor cells acquire autonomous means to grow, becoming less dependent on extraneous growth factors (Kopfstein and Christofori, 2006). These findings are consistent with the original concepts of Foulds that there are many different paths to malignancy. Tumors are thus evolving cell communities with properties that continue to change as they grow. The role of the stromal cell populations and the extracellular microenvironment is increasingly recognized as a critical element in tumor development and progression (Hanahan and Weinberg, 2011).

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FIGURE 10–1

Schematic showing the clonal evolution of tumors. New subclones arise by mutation. ...

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