Therapeutic Targeting of Cancer Stem Cells: Integrating and Exploiting the Acidic Niche

Cancer stem cells (CSC) or tumor-initiating cells represent a small subpopulation of cells within the tumor bulk that share features with somatic stem cells, such as self-renewal and pluripotency. From a clinical point of view, CSC are thought to be the main drivers of tumor relapse in patients by supporting treatment resistance and dissemination to distant organs. Both genome instability and microenvironment-driven selection support tumor heterogeneity and enable the emergence of resistant cells with stem-like properties, when therapy is applied. Besides hypoxia and nutrient deprivation, acidosis is another selection barrier in the tumor microenvironment (TME) which provides a permissive niche to shape more aggressive and fitter cancer cell phenotypes. This review describes our current knowledge about the influence of the “acidic niche” on the stem-like phenotypic features of cancer cells. In addition, we briefly survey new therapeutic options that may help eradicate CSC by integrating and/or exploiting the acidic niche, and thereby contribute to prevent the occurrence of therapy resistance as well as metastatic dissemination.