Mechanisms of radiotherapy resistance and radiosensitization strategies for esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-related mortality worldwide, with more than half of them occurred in China. Radiotherapy (RT) has been widely used for treating ESCC. However, radiation-induced DNA damage response (DDR) can promote the release of cytokines and chemokines, and triggers inflammatory reactions and changes in the tumor microenvironment (TME), thereby inhibiting the immune function and causing the invasion and metastasis of ESCC. Radioresistance is the major cause of disease progression and mortality in cancer, and it is associated with heterogeneity. Therefore, a better understanding of the radioresistance mechanisms may generate more reversal strategies to improve the cure rates and survival periods of ESCC patients. We mainly summarized the possible mechanisms of radioresistance in order to reveal new targets for ESCC therapy. Then we summarized and compared the current strategies to reverse radioresistance.

Keywords: Cancer stem cells; ESCC; Molecular targets; Radioresistance; Reversal strategies.

Fig. 1

Cellular regulation mechanisms of radioresistance. (A) Normal stem cells are transformed into cancer stem cells through gene mutation or abnormal expression, and different ESCC cell subsets are separated according to the specific markers on them. (B) In the cell cycle, the G1 checkpoint is responsible for the cell size, nutrients, growth factors and DNA damage; the G2 checkpoint is responsible for the cell size and DNA replication; the M checkpoint is responsible for the chromosome attachment to spindle. DNA-PK regulates the response of G1/S checkpoint to DNA double strand breaks (DSB); ATR activates downstream Chk1 or ATM activates downstream Chk2, p53 and other protein, which starts the arrest in S-phase cell cycle; ATM and ATR induced G2/M phase arrest. (C) Mitochondrial hypoxia leads to the increase of ROS release, which promotes the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) to combine with the antioxidant response element (ARE) in the promoter region of the target gene, and activates related antioxidant molecules, such as NADPH, heme oxygenase-1(HO1), and NADPH:quinone oxidoreductase-1(NQO1) driven by Nrf2. So as to reduce or eliminate the generation of ROS, prevent cancer cell damage caused by redox, and enhance the radioresistance of tumors. (D) Hypoxia or tumor-related fibroblasts promote the expression of EMT markers such as slug, snail and Zeb1 by inducing TGF-β activation and paracrine, and mediate the radioresistance mechanism of ESCC. (E) Autophagy-mediated tumor survival is mainly attributed to: (i) clearing dysfunction through mitochondrial autophagy and regulating oxidative stress to promote EMT’s response to GSK-β. (ii) Genomic instability caused subsequently. AMP-activated protein kinase (AMPK) activates autophagy, while mammalian target of rapamycin complex 1 (mTORC1) does the opposite

Fig. 2

Tumor microenvironment (TME) and radioresistance. (A) CAF induces monocyte MDSC production through STAT3 signaling activated by IL-6/exosomal miR-21. (B) CAF crosstalk with TAM through the inflammatory CXCL12-CXCR4 axis. (C) CAF provides cancer cells with amino acids, fatty acids, glucose, phospholipids and glycerides that are essential for ESCC growth; and enhances escape through E-cadherin/N cadherin linkage enhances escape. (D) Cancer cells secrete hydrogen peroxide, which increases oxidative stress in CAF and induces a shift in the metabolic environment of CAF from oxidative phosphorylation to aerobic glycosylation, further providing cancer cells with lactate and pyruvate. (E) CAF secretions, including pro-tumor factors, proteins, inflammatory factors, growth factors, and non-coding RNAs induce migration and invasion of ESCC cells. (F) TAM provides ESCC cells with a variety of amino acids through AKT/mTOR, AKT/ERK and AKT/p38 MAPK induce ESCC cell growth, migration and invasion. (G,H) Regulatory T cell (Treg) mediate ESCC evasion of immune responses through expression of the immunosuppressive factor COX-2, whose interaction with TAM via ligand-receptor interactions may contribute to the immunosuppressed state and disease progression

Fig. 3

Potential therapeutic targets and agents to reverse ESCC radioresistance. (A) Potential therapeutic agents targeting key pathways. (B) Potential agents for epigenetic therapy. DNMT: DNA methyltransferase; KDM: Histone lysine demethylase; HDAC: Histone deacetylase; VPA: Valproic acid