Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review

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.

Keywords: ABC transporters; cancer stem cells; clinical trials; drug resistance; epithelial to mesenchymal transition; hypoxia; metastasis; tumor microenvironment.

Figure 1

Cancer stem cells are able to resist conventional therapies and form new tumors, unless targeted by cancer stem cell (CSC)-specific therapy. Adapted from Dzobo et al. [30].

Figure 2

Cancer stem cell markers expressed in some human cancers are shown in the figure. Figure adapted from Dzobo et al. [34]. See Table 1 for references. The list of CSC markers is not exhaustive. The CSC markers continue to be refined based on new data.

Figure 3

Hallmarks of cancer stem cells include increased expression of ATP-binding cassette (ABC) membrane transporters, enhanced survival signaling, increased drug in activation as well as increased DNA repair processes compared to cancer cells. This allows CSCs to survive conventional therapy and thus contribute to chemoresistance for example. Adapted from Senthebane et al. [3].

Figure 4

Cancer stem cells are able to reside deep within the tumor in hypoxic regions that are normally toxic to normal cells, whilst CSCs are able to release factors such as hypoxia-inducible factor 1 which induces the release of proangiogenic factors, this position means CSCs are inaccessible to drugs or are exposed to reduced drug doses. Adapted from Senthebane et al. [3].