Stem Cell Theory of Cancer: Origin of Tumor Heterogeneity and Plasticity

SIMPLE SUMMARY: Tumor heterogeneity complicates our diagnoses, confounds our prognoses, and challenges our therapies. Unless we understand the origin of tumor heterogeneity, our diagnosis of cancer will be unsatisfactory, our prognosis uncertain, and treatment unreliable. We observe heterogeneity in myriad mixed tumors, including testicular, lung, and breast cancers. We recognize heterogeneity in diverse tumor subtypes, no matter how we subgroup and subdivide them. We postulate that cancer subtypes can be meaningless and useless without a proper theory about cancer’s stem cell versus genetic origins. We propose that tumor heterogeneity alludes to a stem cell theory of cancer and provides clues that cancer is a stem cell disease. A stem cell, as opposed to a genetic, origin of cancer constitutes a unified theory of cancer, which predicates that the same genetic abnormalities and microenvironmental aberrations lead to different biological effects and clinical outcomes in a progenitor stem cell versus a mature progeny cell. ABSTRACT: In many respects, heterogeneity is one of the most striking revelations and common manifestations of a stem cell origin of cancer. We observe heterogeneity in myriad mixed tumors including testicular, lung, and breast cancers. We recognize heterogeneity in diverse tumor subtypes in prostate and kidney cancers. From this perspective, we illustrate that one of the main stem-ness characteristics, i.e., the ability to differentiate into diverse and multiple lineages, is central to tumor heterogeneity. We postulate that cancer subtypes can be meaningless and useless without a proper theory about cancer’s stem cell versus genetic origin and nature. We propose a unified theory of cancer in which the same genetic abnormalities, epigenetic defects, and microenvironmental aberrations cause different effects and lead to different outcomes in a progenitor stem cell versus a mature progeny cell. We need to recognize that an all-encompassing genetic theory of cancer may be incomplete and obsolete. A stem cell theory of cancer provides greater universality, interconnectivity, and utility. Although genetic defects are pivotal, cellular context is paramount. When it concerns tumor heterogeneity, perhaps we need to revisit the conventional wisdom of precision medicine and revise our current practice of targeted therapy in cancer care.