Cancer stem cells and chemoresistance: Strategies to overcome therapeutic resistance

Cancer stem cells (CSCs) are hypothesized to initiate cancer and give rise to heterogeneous tumors made up of self-renewing CSCs and the differentiated, less tumorigenic non-CSCs, which make up the bulk of the tumor. Importantly, in terms of successful patient treatment, CSCs are also more resistant to commonly used chemotherapeutics. Multiple mechanisms have been identified for CSCassociated chemoresistance. These mechanisms include increased expression of ABC transporter efflux pumps, aldehyde dehydrogenase (ALDH) detoxification enzymes, anti-apoptosis proteins, enhanced DNA repair mechanisms, increased activation of the embryonic signaling pathways (Notch, Wnt and Hedgehog), and quiescence. Identification of these mechanisms has led to development of specific strategies to circumvent CSC-associated chemoresistance (e.g. inhibitors of ABC transporters, ALDH enzymes, and Notch, Wnt, and Hedgehog pathways, and epigenetic modifying drugs). Future clinical evidence will reveal if employing these adjuvant therapies will eradicate CSCs along with the bulk of the tumor, and lead to improved patient outcomes with decreased cancer recurrence.