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Every patient’s cancer is different. Cancers arising from the same organ may have different histology and metastatic potential, may be indolent or aggressive, and may have different response to therapy. Cells within a cancer are also different. Within individual tumors, some cells are genetically normal stromal cells and some are somatically-mutated malignant cells. And within the malignant cell pool, related but differently evolved malignant clones vie for survival, exploiting different epigenetic strategies, within different microenvironments within each tumor (Fig. 13–1; see Chap. 12, Sec. 12.2).


Cancers are heterogeneous. This heterogeneity can be considered in many interdependent dimensions. For example, A) cancers from the same organ vary markedly in histology and genetic driver mutations between different individuals. B) Within a primary cancer, there can be widespread clonal genetic diversity as the primary cancer evolves from a normal (N) cell. C) Cancer cells that metastasize distant to the primary lesion often have a different genomic sequence to primary cancers and may show different epigenetic phenotypes, sometimes as a result of being in different microenvironments. D) Finally, cancers show stromal heterogeneity as many cells within cancers are nonmalignant (eg, endothelial cells, leucocytes, and fibroblasts).

Understanding this complexity and heterogeneity is daunting, but has been appreciated pragmatically for decades, with clinicians combining different chemotherapy agents or different treatment modalities (eg, chemotherapy with radiation) in an effort to overcome treatment failure and improve patient survival. Modern scientific technologies are expanding our knowledge of heterogeneity, and this rapidly unfolding area offers opportunities to better understand the mechanisms of tumor recurrence, distant metastasis, and resistance to cancer treatment.

Paget’s recognition that metastases “seed” into organs that provide a fertile “soil” provided the conceptual framework that tumor cells must interact with their microenvironment, and that some tumor cells may be more fit than others for this process (Paget, 1889). Pierce and colleagues demonstrated that teratocarcinomas and mouse squamous cell carcinomas contained highly tumorigenic cells that could differentiate into morphologically differentiated cell types that were unable to form tumors when transplanted in mice (Pierce and Wallace, 1971). They described cancers as a “caricature” of normal tissue renewal, whereby tumor stem cells divide and differentiate giving rise to terminal postmitotic differentiated cells.

Till and McCulloch (1961) provided the first experimental evidence of normal tissue stem cells by injecting tiny numbers of bone marrow cells into lethally irradiated mice (Till and McCulloch, 1961). They observed the formation of colonies of cells from all 3 blood lineages. When transplanted into secondary recipient mice, some clones could again give rise to blood cells from multiple lineages. Pierce and Speers demonstrated in clonogenic assays that only a fraction of cells from freshly excised human tumors could form colonies in tissue culture (including myeloma, lymphoma, neuroblastoma, ovarian carcinoma, chronic ...

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