Stem Cell Theory of Cancer: Implications for Drug Resistance and Chemosensitivity in Cancer Care

SIMPLE SUMMARY: Science and history teach us that stemness properties pave all drug resistance pathways. Evidence and experience inform us that stemness origin and nature etch all cancer hallmarks. A stem cell origin of drug resistance encompasses heterogeneity and dormancy, embraces ABC transporters and DNA repairs, and explicates chemotherapy and chronotherapy. It alludes to a unified theory of cancer and suggests that cancer is a stem cell disease—uniting chemoresistance with chemosensitivity, connecting progenitor cells with progeny cells, and linking multicellularity with the microenvironment. Importantly, it clarifies genetic content vs. cellular context, delineates drug vs. therapy development, and enlightens precision medicine vs. integrated medicine and targeted therapy vs. multimodal therapy in cancer care. ABSTRACT: When it concerns cancer care and cancer therapy, drug resistance is more than an obstacle to successful treatment; it is a major cause of frustration in our attempts to optimize drug development versus therapy development. Importantly, overcoming the challenges of drug resistance may provide invaluable clues about the origin and nature of cancer. From this perspective, we discuss how chemoresistance and chemosensitivity in cancer therapy could be directly linked to the stem cell origin of cancer. A stem cell theory of cancer stipulates that both normal stem cells and cancer stem cells are similarly endowed with robust efflux pumps, potent antiapoptotic mechanisms, redundant DNA repair systems, and abundant antioxidation reserves. Cancer stem cells, like their normal stem cell counterparts, are equipped with the same drug resistance phenotypes (e.g., ABC transporters, anti-apoptotic pathways, and DNA repair mechanisms). Drug resistance, like other cancer hallmarks (e.g., tumor heterogeneity and cancer dormancy), could be intrinsically ingrained and innately embedded within malignancy. We elaborate that cellular context and the microenvironment may attenuate the effects of cancer treatments. We examine the role of circadian rhythms and the value of chronotherapy to maximize efficacy and minimize toxicity. We propose that a stem cell theory of drug resistance and drug sensitivity will ultimately empower us to enhance drug development and enable us to improve therapy development in patient care.