Abstract

Cancer stem cells (CSCs) are rare tumor cells that exhibit stem cell properties such as self-renewal capacity and pluripotency. In recent years, cancer stem cells have been recognized as key tumor-initiating cells that are therapyresistant and highly tumorogenic and therefore may play a pivotal role in cancer recurrence following chemotherapy. While chemotherapy is often capable of inducing cell death in tumors and reducing the tumor bulk, remaining cells can re-grow and many cancer patients experience recurrence and ultimately death. Herein, we discuss the mechanisms of chemoresistance identified in CSCs and methods of treating chemoresistant cancers driven by CSCs. These mechanisms include: aberrant ABC transporter expression/activity, aldehyde dehydrogenase (ALDH) activity, B-cell lymphoma-2 (BCL2) related chemoresistance, enhanced DNA damage response, activation of pro-survival signaling pathways and epigenetic deregulations. Developmental pathways, such as the Wnt/β-catenin pathway, direct the differentiation of normal stem cells promoting: proliferation, genomic instability and DNA damage tolerance in CSCs. The Notch/- secretase/Jagged and BMP signaling pathways are important regulators of differentiation. These signaling pathways represent novel attractive targets for drug discovery. CSCs can be forced to differentiate, lose their properties and become more sensitive to chemotherapy. Growing evidence emphasizes the interplay between metabolic disturbances, epigenomic changes and cancer. Epigenetic-based mechanisms are reversible and the possibility of "resetting" the abnormal cancer epigenome by applying pharmacological compounds provides a new and attractive approach. A number of compounds targeting epigenetic enzymes were screened for their ability to induce differentiation or to make CSCs more sensitive to therapy. Despite controversies surrounding the CSC hypothesis, there is substantial evidence for their role in cancer and a number of drugs intended to specifically target CSCs have entered clinical trials. Understanding how tumor-initiating cells escape chemotherapy will help to develop more specific and personalized approaches to treating cancer that may improve clinical outcomes for cancer patients.

Keywords: ABC transporters, ALDH, cancer stem cells, DNA damage response, differentiation therapy, epigenetics, resistance to therapy.