Causes and Consequences of Variable Tumor Cell Metabolism on Heritable Modifications and Tumor Evolution

When cancer research advanced into the post-genomic era, it was widely anticipated that the sought-after cure will be delivered promptly. Instead, it became apparent that an understanding of cancer genomics, alone, is unable to translate the wealth of information into successful cures. While gene sequencing has significantly improved our understanding of the natural history of cancer and identified candidates for therapeutic targets, it cannot predict the impact of the biological response to therapies. Hence, patients with a common mutational profile may respond differently to the same therapy, due in part to different microenvironments impacting on gene regulation. This complexity arises from a feedback circuit involving epigenetic modifications made to genes by the metabolic byproducts of cancer cells. New insights into epigenetic mechanisms, activated early in the process of carcinogenesis, have been able to describe phenotypes which cannot be inferred from mutational analyses per se. Epigenetic changes can propagate throughout a tumor via heritable modifications that have long-lasting consequences on ensuing phenotypes. Such heritable epigenetic changes can be evoked profoundly by cancer cell metabolites, which then exercise a broad remit of actions across all stages of carcinogenesis, culminating with a meaningful impact on the tumor's response to therapy. This review outlines some of the cross-talk between heritable epigenetic changes and tumor cell metabolism, and the consequences of such changes on tumor progression.