Tumor heterogeneity is reflected and influenced by genetic, epigenetic, and metabolic differences in cancer cells and their interactions with a complex microenvironment. This heterogeneity has resulted in the stratification of tumors into subtypes, mainly based on cancer-specific genomic or transcriptomic profiles. Subtyping can lead to biomarker identification for personalized diagnosis and therapy, but stratification alone does not explain the origins of tumor heterogeneity. Heterogeneity has traditionally been thought to arise from distinct mutations/aberrations in "driver" oncogenes. However, certain subtypes appear to be the result of adaptation to the disrupted microenvironment caused by abnormal tumor vasculature triggering metabolic switches. Moreover, heterogeneity persists despite the predominance of single oncogenic driver mutations, perhaps due to second metabolic or genetic "hits." In certain cancer types, existing subtypes have metabolic and transcriptomic phenotypes that are reminiscent of normal differentiated cells, whereas others reflect the phenotypes of stem or mesenchymal cells. The cell-of-origin may, therefore, play a role in tumor heterogeneity. In this review, we focus on how cancer cell-specific heterogeneity is driven by different genetic or metabolic factors alone or in combination using specific cancers to illustrate these concepts. Cancer Res; 76(18); 5195-200. ©2016 AACR.
©2016 American Association for Cancer Research.