Abstract
Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance culminating in relapse continues to be associated with fatal disease. The cancer stem cell theory posits that tumors are driven by specialized cancer cells called cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterized in many cancers with data illustrating that CSCs display great abilities to self-renew, resist therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of several survival signaling pathways and increased immune evasion as well as DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we revisit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.
Highlights
Cancer remains one of the major causes of mortality globally, with many recent studies showing significant increases in its incidence [1,2]
Senthebane and colleagues revealed that tumor microenvironment (TME) components including cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM) are major contributors to chemoresistance [3]
Recent data points to cancer stem cells (CSCs) as responsible for therapy resistance and metastasis [5,6,7]
Summary
Cancer remains one of the major causes of mortality globally, with many recent studies showing significant increases in its incidence [1,2]. This review is an updated critical analysis and distillation of available information on CSCs and to target CSCs largely depends on new evidence and in-depth characterization of these cells It is their involvement in cancer therapy resistance and metastasis. By targeting inherent CSCs properties plausible to postulate that long-lasting cancer treatment efficacy can only come from both shrinkage of that allow CSCs to be tumorigenic, resistant and metastatic, new drugs being developed offer a the primary tumor as well as the prevention of cells such as CSCs from metastasizing to new sites better promise at curing cancer. By targeting inherent CSCs properties that allow CSCs to beMarkers tumorigenic, resistant and metastatic, new drugs being developed offer a
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