Resistance to Cell Death and Its Modulation in Cancer Stem Cells

Abstract

Accumulating evidence has demonstrated that human cancers arise from various tissues of origin that initiate from cancer stem cells (CSCs) or cancer-initiating cells. The extrinsic and intrinsic apoptotic pathways are dysregulated in CSCs, and these cells play crucial roles in tumor initiation, progression, cell death resistance, chemo- and radiotherapy resistance, and tumor recurrence. Understanding CSC-specific signaling proteins and pathways is necessary to identify specific therapeutic targets that may lead to the development of more efficient therapies selectively targeting CSCs. Several signaling pathways-including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), maternal embryonic leucine zipper kinase (MELK), NOTCH1, and Wnt/Β-catenin&and expression of the CSC markers CD133, CD24, CD44, Oct4, Sox2, Nanog, and ALDH1A1 maintain CSC properties. Studying such pathways may help to understand CSC biology and lead to the development of potential therapeutic interventions to render CSCs more sensitive to cell death triggered by chemotherapy and radiation therapy. Moreover, recent demonstrations of dedifferentiation of differentiated cancer cells into CSC-like cells have created significant complexity in the CSCs hypothesis. Therefore, any successful therapeutic agent or combination of drugs for cancer therapy must eliminate not only CSCs but differentiated cancer cells and the entire bulk of tumor cells. This review article expands on the CSC hypothesis and paradigm with respect to major signaling pathways and effectors that regulate CSC apoptosis resistance. Moreover, selective CSC apoptotic modulators and their therapeutic potential for making tumors more responsive to therapy are discussed. The use of novel therapies, including small-molecule inhibitors of specific proteins in signaling pathways that regulate stemness, proliferation and migration of CSCs, immunotherapy, and noncoding microRNAs may provide better means of treating CSCs.

FIG. 1

Cancer stem cells (CSCs) and their implications for the development and progression of tumors. CSCs are generated from normal stem cells (NSCs) through tumorigenic transformation of several potential pathways, including Hh: hedgehog (Hh); epithelial–mesenchymal transition (EMT); and mesenchymal–epithelial transition (MET). CSC and drug-induced CSCs (Di-CSCs) are enriched following conventional chemotherapy treatment.

FIG. 2

Overview of the intrinsic and extrinsic apoptotic pathways, the TRADD/NF-κB survival pathway, and the growth factor (GF) receptors PI3K/AKT pro-survival signaling axis in CSCs. A logical strategy to target CSCs is to use inhibitors of the antiapoptotic and prosurvival proteins in these interconnected pathways as shown in this figure.

FIG. 3

Antiapoptotic drugs and miRNAs for targeting CSCs. Some of the drugs and miRNAs known to decrease c-FLIP variants, increase DR5, and target Bcl-2 family members are shown.