The mechanisms of radioresistance in esophageal squamous cell carcinoma and current strategies in radiosensitivity

Abstract

Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer-related death worldwide. Surgery is the primary form of treatment, but the survival is poor, especially for patients with locally advanced esophageal cancer. Radiotherapy has been a critical treatment option that may be combined with chemotherapy in patients with unresectable esophageal cancer. However, resistance to chemoradiotherapy might result in treatment failures and cancer relapse. This review will mainly focus on the possible cellular mechanisms and tumor-associated microenvironmental (TAM) factors that result in radioresistance in patients with esophageal cancer. In addition, current strategies to increase radiosensitivity, including targeted therapy and the use of radiosensitive biomarkers in clinical treatment, are discussed in this review.

Keywords: Esophageal cancer; radioresistance; radiosensitive biomarker; targeted therapy; tumor-associated microenvironment (TAM).

Figure 1

Cellular mechanisms of radioresistance: (I) the cell cycle checkpoint signaling pathway is a critical progress that allowing times for cells to response to repair DNA damage. Cell cycle often arrests in G1/S or G2/M period. The primary mechanism of reparation of DNA double-strand breaks (DSBs) is Nonhomologous end joining (NHEJ); (II) the surface biomarkers of cancer stem cells (CSCs) consist of CD44, CD71, CD90, CD133, CD271, ALDH, and ABCG2; (III) the balance of autophagy and apoptosis is another mechanism of radioresistance. Autophagy, as a conserved process that mediate the degradation, dysfunctional organelles and turnover of long-lived proteins, can limit the effect of radiotherapy through supporting metabolic mechanism in cellular stress times; (IV) epithelial-mesenchymal transition (EMT) is common in cancer progression and related to radioresistance.

Figure 2

Tumor associated microenvironment (TAM) and radioresistance. Hypoxia can improve the expression of VEGF and HIF-1 and induce radioresistance. Cancer-associated fibroblasts (CAF) play a critical role in the development and progression of esophageal cancer, promoting cancer proliferation, invasion, metastasis, angiogenesis. Tumor-associated macrophages are divided into M1 subpopulation that is activated by Toll-like receptor ligands and interferon-γ, which plays a role in antitumor immunity and M2 subpopulations that is activated by interleukin 4 (IL-4) or interleukin 13 (IL-13), which suppresses antitumor immunity. Tregs, divided into nature Tregs (nTregs) and inducible Tregs (iTregs), play a critical role in protecting itself against autoimmunity and tissue damage through their suppressive function. Dendritic cells play a dual role in tumor-associated microenvironment such as mediating potential anti-tumor immune responses and activate the cytotoxic T lymphocytes (CTLs) or blockade anti-tumor immune responses. Exosomes secreted by stromal cells and esophageal cancer cells mediate radioresistant through paracrine and juxtacrine signaling.