Drug resistance mechanisms of cancer stem-like cells and their therapeutic potential as drug targets

Abstract

Despite of recent advances in cancer research and development of new anti-cancer drugs, tumor patients' prognoses have not yet been improved well enough. Treatment failure of tumors is highly attributed to the drug resistance of a small population of cancer cell known as cancer stem-like cells (CSCs). CSCs also have the self-renewal activity and differentiation potency, conferring strong tumorigenicity on them. Therefore, development of CSC targeting therapy is urgently needed in order to overcome possible recurrence and metastasis by them after therapy. CSCs show some characteristic features that are not observed in other differentiated cancer cells, which give them higher resistance against conventional chemotherapy or radiotherapy. Targeting such specific features could be useful for CSC eradication. This review will summarize the recent advances in the study of CSC characteristics along with the promising therapeutic strategies targeting them.

Keywords: Cancer stem-like cell; drug resistance; epithelial-to-mesenchymal transition; hypoxia; quiescence.

Figure 1

Schematic model of CSC-derived recurrence and metastasis. CSCs are thought to possess high tumorigenic potential because they have the self-renewing activity and the potency to generate differentiated cell populations. CSCs also survive after treatment with chemotherapy or radiotherapy, which leads to recurrence and metastasis, two major causes of poor patient prognosis. CSCs: cancer stem-like cells

Figure 2

Characteristic of CSCs contributing to higher drug resistance. Higher therapeutic resistance of CSCs is maintained by many features including quiescence, epithelial-to-mesenchymal transition, low ROS level, efficient drug efflux ability and upregulated survival signaling. CSCs: cancer stem-like cells

Figure 3

Stemness related pathways could be useful for targeting CSCs. When Wnt binds to FZD receptor, it downregulates the function of AXIN/GSK-3/APC complex, which leads to stabilization of β-catenin. Stabilized β-catenin moves into nucleus and induces the stemness related gene expressions. When a transmembrane Notch ligand (Delta or Jagged) on one cell binds to a transmembrane receptor (Notches 1-4) on a neighboring cell, the receptor is cleaved and interact with nuclear factors to regulate stemness related gene expressions. Inhibition of these pathways may contribute to CSC eradication. FZD: frizzled; GSK-3: glycogen synthase kinase-3; APC: adenomatous polyposis coli. CSCs: cancer stem-like cells

Figure 4

PI3K/Akt signaling pathway contributes to CSC maintenance and could be a promising target. When CD74-NRG1 fusion protein (in lung cancer) or heregulin (in breast cancer) binds to HER2/HER3 heterodimer receptor, PI3K/Akt/NF-κB signaling is activated. NF-κB induces gene expression of IGF-2 and growth differentiation factor 15 (GDF15), which enhances self-renewal ability of CSCs. Therefore, inhibition of this signaling pathway would be promising to target CSCs. IGF-2: insulin-like growth factor-2; GDF15: growth differentiation factor 15. CSCs: cancer stem-like cells

Figure 5

Semaphorin/MICAL3 signaling induces symmetric division of CSCs. By semaphorin binding to neuropilin 1 (NP1) receptor, MICAL3/collapsin response mediator protein 2 (CRMP2)/Numb axis is activated, leading to symmetric division and expansion of BCSCs. NP1: neuropilin 1; CRMP2: collapsin response mediator protein 2. CSCs: cancer stem-like cells