Targeting cancer stem cells and the tumor microenvironment

Compelling evidence indicates that the survival and behavior of cancer stem cells (CSCs) are positively regulated by specific stimuli received from the tumor microenvironment, which dictates the maintenance of stemness, invasiveness, and protection against drug-induced apoptotic signals. CSCs are per se endowed with multiple treatment resistance capabilities, thus the eradication of CSC pools offers a precious strategy in achieving a long-term cancer remission. Numerous therapies, aimed at eradicating CSCs, have been elaborated such as: (i) selective targeting of CSCs, (ii) modulating their stemness and (iii) influencing the microenvironment. In this context, markers commonly exploited to isolate and identify CSCs are optimal targets for monoclonal antibody-based drugs. Furthermore, the molecules that inhibit detoxifying enzymes and drug-efflux pumps, are able to selectively suppress CSCs. Auspicious outcomes have also been reported either by targeting pathways selectively operating in CSCs (e.g. Hedgehog, Wnt, Notch and FAK) or by using specific CSC cytotoxic agents. Other compounds are able to attenuate the unique stemness properties of CSCs by forcing cell differentiation, and this being the case in ATRA, HDACi, BMPs and Cyclopamine, among others. Targeting the interplay between paracrine signals arising in the tumor stroma and the nearby cancerous cells via the inhibition of VEGF, HIF, CD44v and CXCR4, is increasingly recognized as a significant factor in cancer treatment response and holds alluring prospects for a successful elimination of CSCs. In the present chapter, we discuss the latest findings in the optimization and tailoring of novel strategies that target both CSCs and tumor bulk for the eradication of malignancies.