The mechanisms and reversal strategies of tumor radioresistance in esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of most lethal malignancies with high aggressive potential in the world. Radiotherapy is used as one curative treatment modality for ESCC patients. Due to radioresistance, the 5-year survival rates of patients after radiotherapy is less than 20%. Tumor radioresistance is very complex and heterogeneous. Cancer-associated fibroblasts (CAFs), as one major component of tumor microenvironment (TME), play critical roles in regulating tumor radioresponse through multiple mechanisms and are increasingly considered as important anti-cancer targets. Cancer stemness, which renders cancer cells to be extremely resistant to conventional therapies, is involved in ESCC radioresistance due to the activation of Wnt/β-catenin, Notch, Hedgehog and Hippo (HH) pathways, or the induction of epithelial-mesenchymal transition (EMT), hypoxia and autophagy. Non-protein-coding RNAs (ncRNAs), which account for more than 90% of the genome, are involved in esophageal cancer initiation and progression through regulating the activation or inactivation of downstream signaling pathways and the expressions of target genes. Herein, we mainly reviewed the role of CAFs, cancer stemness, non-coding RNAs as well as others in the development of radioresistance and clarify the involved mechanisms. Furthermore, we summarized the potential strategies which were reported to reverse radioresistance in ESCC. Together, this review gives a systematic coverage of radioresistance mechanisms and reversal strategies and contributes to better understanding of tumor radioresistance for the exploitation of novel intervention strategies in ESCC.

Keywords: ESCC; Mechanisms; Molecular targets; Radioresistance; Reversal strategies.

Fig. 1

The major components of tumor microenvironment. Tumor-associated macrophages, DCs dendritic cells, CAFs cancer-associated fibroblasts, CSCs cancer stem cells;

Fig. 2

Cancer-associated fibroblasts regulated tumor radioresponse. By secretion of chemokines/cytokines, CAFs initiated the crosstalk with tumor cells and induced the activation of epithelial-to-mesenchymal transition, DNA repair response, anti-apoptotic signaling and migration and invasion of cancer cells, thereby creating a radioresistant tumor niche

Fig. 3

The involvement of cancer-stemness in tumor radioresponse. After exposure to IR, those cancer stem-like cells which were inherently radioresistant survived and were enriched, due to the activation of Wnt/β-catenin pathway, Notch pathway or Hedgehog and Hippo pathway, or epithelial–mesenchymal transition, hypoxia and autophagy