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Review
. 2016 Jan 5;8(1):8.
doi: 10.3390/cancers8010008.

Cancer Stem Cell Plasticity Drives Therapeutic Resistance

Mary R Doherty  1 , Jacob M Smigiel  2 , Damian J Junk  3 , Mark W Jackson  4   5
Affiliations
Review

Cancer Stem Cell Plasticity Drives Therapeutic Resistance

Mary R Doherty et al. Cancers (Basel). .

Abstract

The connection between epithelial-mesenchymal (E-M) plasticity and cancer stem cell (CSC) properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence.

Keywords: cancer stem cells; cellular plasticity; cytokines; epithelial-mesenchymal; therapeutic resistance; tumor microenvironment.

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Figures

Figure 1
Figure 1
The importance of E-M and CSC plasticity in tumor recurrence and metastatic progression. Following cancer therapy, many non-CSCs are eliminated while select non-CSCs acquire mesenchymal/CSC properties. Together with surviving CSCs, the induced mesenchymal/CSCs grow to establish a recurrent tumor (upper). Similarly, upon metastatic dissemination, CSCs acquire proliferative capacity and differentiate to establish a metastatic tumor (lower).
Figure 2
Figure 2
Potential therapeutic targets of CSC plasticity. Cancer therapy induces cell death in many non-CSCs. In select non-CSCs retaining the ability to acquire mesenchymal/CSC properties, autocrine or paracrine (from tumor-associated stromal cells) TME cytokines induce EMT and acquisition of a CSC phenotype. Potential therapeutic strategies to suppress the de novo generation of CSCs and prevent therapeutic resistance include (1) the use of neutralizing antibodies (IL-17 Ab); (93), (IL-8 Ab); (94) or decoy receptors to prevent signal initiation in the non-CSCs; (2) blockade of receptor function on the non-CSCs or CSCs (TGFβR inhibitor; LY2157299); (94), SB431542; (17), (OSMR inhibitor); (96); (3) blockade of intracellular signaling emanating from TME cytokine and growth factor receptor activation on the non-CSCs or CSCs (STAT3 inhibitor; BBI608); (96), (IGFR-1 inhibitor); (51), (Src kinase inhibitor; Dasatinib); (47). Targeting the induced CSCs that emerge following cancer therapy would provide a unique approach to limiting tumor recurrence compared to targeting stable CSCs.
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