Mechanisms of chemoresistance in cancer stem cells

Abstract

Chemotherapy is one of the standard methods of treatment in many cancers. While chemotherapy is often capable of inducing cell death in tumors and reducing the tumor bulk, many cancer patients experience recurrence and ultimately death because of treatment failure. In recent years, cancer stem cells (CSCs) have gained intense interest as key tumor-initiating cells that may also play an integral role in recurrence following chemotherapy. As such, a number of mechanisms of chemoresistance have been identified in CSCs. In this review, we describe a number of these mechanisms of chemoresistance including ABC transporter expression, aldehyde dehydrogenase (ALDH) activity, B-cell lymphoma-2 (BCL2) related chemoresistance, enhanced DNA damage response and activation of key signaling pathways. Furthermore, we evaluate studies that demonstrate potential methods for overcoming chemoresistance and treating chemoresistant cancers that are driven by CSCs. By understanding how tumor-initiating cells such as CSCs escape chemotherapy, more informed approaches to treating cancer will develop and may improve clinical outcomes for cancer patients.

Figure 1

Molecular Mechanisms of CSC Chemoresistance (A). ABC transporters can efflux a wide variety of chemotherapeutics out of cancer cells. The specific ABC transporter pump expressed in the CSCs determines the specificity of chemoresistance. (B). ALDH1 is a cytosolic enzyme, whereas other isoforms can localize to the mitochondria as well as the cytosol. The efficacy of chemotherapeutic drugs such as cyclophosphamide is reduced in ALDH expressing CSCs, as these drugs are substrates for these enzymes. (C). Pro-survival protein BCL-2 binds to pro-apoptotic proteins BAX and BAK, preventing the release of the apoptogenic factor cytochrome c from the mitochondria. Aberrant activity of BCL-2 and other pro-survival BCL-2 family members utilize this mechanism to prevent chemotherapy-mediated apoptosis. (D). Following DNA damage, ATM and ATR recognize breaks in DNA and activate CHK2 and CHK1, respectively. CHK2 and CHK1 can impair cell cycle and promote DNA repair. Activation of these DNA repair proteins in CSCs can impair the efficacy of ICL agents.