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10.1 TUMOR PROGRESSION

10.1.1 Cellular Aspects of Tumor Progression

Cancer is not a static disease. In many tumors, 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 pathologic 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.

More than 60 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 (Foulds, 1954). 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) (Nowell, 1986).

FIGURE 10–1

Schematic showing the clonal evolution of tumors. New subclones arise by mutation and/or epigenetic modifications. Many of these may become extinct (indicated by dark shading) but others may have a growth advantage and become dominant. All of the subclones (indicated by T2 to T6) may share common clonal markers, but many of them have new properties leading to heterogeneity. (Nowell, 1986).

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. 7, Sec. 7.2 and Chap. 9, Sec. 9.2) and have identified both genetic and epigenetic alterations using genome-wide analyses (see Chap. 2, Sec. 2.2). Consistent with this model, multiple studies have identified different clonal populations within tumors (see Chap. 13, Sec. 13.2), raising the possibility for a minor (resistant) subpopulation to cause tumor recurrence following therapy (McGranahan and Swanton, 2017). The growth and development of various cells within a tumor are 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. 6 and Chap. 8, Sec. 8.2) are not lost completely in tumor cells, but rather the cells may become less responsive to them. In addition, tumor cells acquire autonomous means to grow, ...

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