Cancer stem cells and signaling pathways in radioresistance

Abstract

Radiation therapy (RT) is one of the most important strategies in cancer treatment. Radioresistance (the failure to RT) results in locoregional recurrence and metastasis. Therefore, it is critically important to investigate the mechanisms leading to cancer radioresistance to overcome this problem and increase patients' survival. Currently, the majority of the radioresistance-associated researches have focused on preclinical studies. Although the exact mechanisms of cancer radioresistance have not been fully uncovered, accumulating evidence supports that cancer stem cells (CSCs) and different signaling pathways play important roles in regulating radiation response and radioresistance. Therefore, targeting CSCs or signaling pathway proteins may hold promise for developing novel combination modalities and overcoming radioresistance. The present review focuses on the key evidence of CSC markers and several important signaling pathways in cancer radioresistance and explores innovative approaches for future radiation treatment.

Keywords: CSC; cancer; radioresistance; radiotherapy; signaling pathway.

Figure 1. A schematic diagram for the putative mechanisms of the acquired cancer radioresistance after RT

This diagram shows that the induced cancer radioresistance is associated with the activation of several pathways (PI3K/Akt/mTOR, ERK, glycolysis, VEGF, autophagy, NHEJ and HR DNA repairs), the induction of cell cycle redistribution and inactivation of apoptosis pathway after exposure to radiation. Notes: ERK: Extracellular signal-regulated kinases, HR: Homologous recombination, NHEJ: Non-homologous end joining, VEGF: Vascular endothelial growth factor.

Figure 2. A schematic diagram for the mechanisms of CSCs in radioresistance

This diagram shows the possible roles of cell cycle (p53, p-Chk1, p-Chk2), DNA repair protein (γH2AX), ROS, apoptosis (Bcl-2 and survivin) and autophagy (Becline-1 and LC3A/B) in CSC-associated radioresistance. Notes: RR: radioresistant; ROS: reactive oxygen species.

Figure 3. The roles of different signaling pathways associated with CSCs in radioresistance

This diagram shows that cancer radioresistance is associated with several different pathways (PI3K/Akt/mTOR, ERK, glycolysis, VEGF, Notch and WNT/β-catenin pathway) as well as CSCs. We have recently demonstrated that the PI3K/Akt/mTOR signaling pathway is associated with the regulation of CSC phenotypes (CD44, CD44v6, CD326, ALDH1, Nanog and Snail) in CaP radioresistance [8]. Notes: FzR: Frizzled receptor.

Figure 4. Overexpression of key proteins from ERK, Glycolysis, VEGF pathways observed in PC-3RR cell line and PC-3RR s.c xenograft tumors

A. The representative images showing increased expression of p-ERK, MCT1, MCT4, CD147, VEGF VG-1 and VEGF R-2 (pathway associated proteins) in PC-3RR CaP cells compared with PC-3 cells by Western blotting. β-tubulin was used as a loading control. B. Representative images showing increased expression of p-ERK, MCT1, MCT4, CD147, VEGF VG-1 and VEGF R-2 in PC-3RR s.c. xenografts compared to parental PC-3 xenografts using immunohistochemistry. Brown indicates positive staining while blue indicates nuclear staining. Magnification in all images x 40. All data were from three independent experiments (n=3).

Figure 5. The top five potential pathways associated with prostate cancer radioresistance identified by label-free LC-MS/MS approach

The p value and ratio of the identified top five potential pathways are displayed by Ingenuity pathway analysis between PC-3 and PC-3RR cells. The identified top five signaling pathways are PI3K/Akt, VEGF, glycolysis, cell cycle and ERK.