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.
ABC transporters, ALDH, cancer stem cells, DNA damage response, differentiation therapy, epigenetics, resistance
Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology; 02-093 Warsaw, Pasteur 3 str., Poland.