Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment

Despite the recent advances in cancer patient management and in the development oftargeted therapies, systemic chemotherapy is currently used as a first-line treatment formany cancer types. After an initial partial response, patients become refractory tostandard therapy fostering rapid tumor progression. Compelling evidence highlightsthat the resistance to chemotherapeutic regimens is a peculiarity of a subpopulation ofcancer cells within tumor mass, known as cancer stem cells (CSCs). This cellularcompartment is endowed with tumor-initiating and metastasis formation capabilities.CSC chemoresistance is sustained by a plethora of grow factors and cytokines releasedby neighboring tumor microenvironment (TME), which is mainly composed by adipocytes,cancer-associated fibroblasts (CAFs), immune and endothelial cells. TME strengthensCSC refractoriness to standard and targeted therapies by enhancing survival signalingpathways, DNA repair machinery, expression of drug efflux transporters and antiapoptotic proteins. In the last years many efforts have been made to understand CSCTME crosstalk and develop therapeutic strategy halting this interplay. Here, we report thecombinatorial approaches, which perturb the interaction network between CSCs and thedifferent component of TME.