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Every patient's cancer is different. Cancers arising from the same organ have different histology and metastatic proclivity, are more or less aggressive, and have different responses to therapy. There are many interdependent mechanisms and dimensions of heterogeneity that account for this variability between cancers. There is also heterogeneity within individual cancers, between stromal cells with a normal genome and mutated malignant cells, between differently mutated malignant clones, between epigenetically different subpopulations within clonal populations, and between cells within different microenvironments within the tumor (Fig. 13–1; see Chap. 12, Sec. 12.2). Recognition of this heterogeneity gives rise to the intriguing possibility that a subset of cancer cells are resistant to treatment, may cause primary tumor recurrence or seed distant metastasis, and may be identifiable a priori. A surgeon's concern in ensuring complete resection of primary tumors ("negative margins") where more invasive cancer cells may reside, the prognostic relevance of circulating tumor cells (see Chap. 10, Sec. 10.3.4), and the resistance of disseminated micrometastases to adjuvant chemotherapy are phenomena that might be explained by "special" cells within a cancer, so-called cancer stem cells, cells that must be targeted to achieve long-term remission or cure. The cancer stem cell (CSC) hypothesis states that only a minority of cancer cells has the potential to (a) self-renew, (b) proliferate indefinitely, and (c) differentiate to give rise to more differentiated tumor cells (Reya et al, 2001). This chapter addresses the competing models that attempt to account for this epigenetic heterogeneity, led by the CSC hypothesis, but first describes the stromal and genetic heterogeneity of human cancers.


Cancers are heterogeneous. This heterogeneity must be represented and considered in many interdependent dimensions. For example, (A) cancers show stromal heterogeneity as many cells within cancers are nonmalignant (left, CD31+ endothelial cells (brown) in renal carcinoma; right, collagen-positive fibroblasts (brown) in ovarian carcinoma), (B) epigenetic heterogeneity, where malignant cells have different phenotypes that can be associated with different functional behaviors (left, CD44+ cells (brown) in head and neck carcinoma; right, N-cadherin–positive cells (brown) in colorectal carcinoma), and (C) genetic heterogeneity, where different clonal populations within cancer have different genomic mutations (left, distribution of cells with different DNA content analyzed by flow cytometry (Pacific blue-A staining is proportional to DNA content); right, DNA microarray showing gains (blue, green) and losses (orange, red) of DNA across different chromosomes (X-axis), which shows the "copy-number variation" against the normal human genome (background white).


13.2.1 Stromal Heterogeneity in Cancer

Every seed needs appropriate soil to germinate and grow, and all cancers have a stromal component that supports, and often protects, malignant cells. Cancer ...

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