In the last several years, our appreciation of intra-tumoral heterogeneity has greatly increased due to accumulating evidence for the co-existence of genetically and epigenetically divergent cancer cells residing in different microenvironments within a tumor. Herein, we review recent literature discussing intra-tumoral heterogeneity in the context of therapy resistance mechanisms at the genetic, epigenetic and microenvironmental levels. We illustrate the influence of tumor microenvironment on therapy resistance and epigenetic states of cancer cells by highlighting the role of cancer stem cells in therapy resistance. We also summarize different strategies that have been employed to address various resistance mechanisms at genetic, epigenetic, and microenvironmental levels in preclinical and clinical studies. We propose that future personalized cancer therapy design needs to incorporate dynamic and comprehensive analyses of tumor heterogeneity landscape and multi-dimensional mechanisms of therapy resistance.
Keywords: cancer stem cells; epigenetic; heterogeneity; microenvironment; therapy resistance.