Our research showed that the serum VEGF level of patients with ESCC before and after radiotherapy is related to the curative effect, and knocking down the expression of VEGF in ESCC cells can improve the sensitivity to radiation in vitro, which suggested that VEGF plays an important role in radiation resistance, provided ideas for future clinical radiotherapy sensitization.
In China, esophageal cancer is one of the digestive tract tumors that seriously endanger people's health, of which more than 90% are squamous cell carcinoma, while adenocarcinoma is the main esophageal cancer in occident countries (Huang et al. 2021). At present, the treatment of ESCC is mainly based on a combination of various treatment strategies, including surgery, chemotherapy, radiotherapy and targeted therapy. Radiotherapy combined with anti-angiogenesis therapy has been proved to be a good way to improve the anti-tumor effect in many types of cancer. Liu et al. (Liu et al. 2020) evaluated the therapeutic effect of radiotherapy combined with apatinib (anti-angiogenesis drug) on mouse nasopharyngeal carcinoma xenograft model, and found that the tumor inhibition effect of combined therapy was stronger than that of apatinib alone or radiotherapy alone. This is similar to the research results of Koo et al. (Koo et al. 2016) and Gao et al. (Gao et al. 2015), which all indicate the synergistic effect of anti-angiogenesis therapy on radiotherapy. Moreover, compared with radiotherapy and chemotherapy, the tumor volume of patients with non-small cell lung cancer with multiple brain metastases after whole brain irradiation combined with apatinib is significantly reduced, and patients can get better objective remission rate and longer median progression-free survival time, but there is no significant difference in median overall survival time (Ren et al. 2021). Another study showed that the curative effect of radiotherapy combined with antiangiogenesis for nasopharyngeal carcinoma patients was similar to that after radiotherapy and chemotherapy, but the acute adverse reactions were significantly reduced (Kang et al. 2018). At present, there are few studies on the combination of antiangiogenesis and radiotherapy in esophageal cancer. Hu et al. (Hu et al. 2020) found that the combined use of apatinib in patients with ESCC undergoing radiotherapy and chemotherapy can significantly improve the median survival time of patients, but not the total survival rate. Shi et al. (Shi et al. 2020) also have similar results. Radiotherapy for esophageal cancer combined with anlotinib can achieve better anti-tumor effect than single drug and radiotherapy alone. Our previous research (Ma et al. 2021) found that VEGF was related to the prognosis of ESCC during concurrent radiotherapy and chemotherapy. In this study, it was further found that the change of VEGF was still related to the prognosis and curative effect of patients who only received radiotherapy for ESCC, suggesting that VEGF (degree of change before and after radiotherapy) played a role in the radiotherapy resistance of ESCC, and it was a potential target for radiotherapy sensitization of ESCC in the future.
VEGF has been proved to be involved in the occurrence and development of tumors, and is closely related to the prognosis of patients (Siemann, Chaplin, and Horsman 2017). In recent years, many studies have found that inhibiting VEGF expression can improve the sensitivity of many types of cancer to radiotherapy (Chen et al. 2020, Hu et al. 2012, Yang et al. 2012, Wang et al. 2020). In this study, we also found that siRNA knocks down VEGF expression in ESCC cell line to significantly inhibit the growth and proliferation of cells after radiotherapy, which is similar to Chen's research results (Chen et al. 2015). VEGF has the function of regulating tumor angiogenesis. The distorted neovascularization of tumor tissue forms the microenvironment of local hypoxia, which leads to radiation resistance. Inhibition of VEGF can normalize tumor blood vessels, improve local hypoxia and thus improve the sensitivity of tumor to radiation (El Alaoui-Lasmaili and Faivre 2018). On the other hand, tumor cells may undergo gene mutation after being irradiated, which may repair their damaged functions, restore or even enhance their growth and proliferation ability, and lead to radiation resistance. Studies have proved that receiving radiation after knocking down VEGF expression can activate NF-kB pathway or PI3K/mTOR and other signal pathways (Wang et al. 2020, Chen et al. 2020), induce DNA damage of tumor cells, help to activate the apoptosis or death process of tumor cells, and further improve the lethality of radiation to tumors. In addition, radiotherapy can promote immune response and also lead to immunosuppression(McLaughlin et al. 2020). Immunosuppressive effects of radiotherapy include recruiting specific immune subsets and differentiating immune subsets into tumor-promoting phenotypes, such as regulatory T cells (Tregs), Myeloid derived suppressor cells (MDSCs), Th2 cells, Th2 CD4 + T cells and M2-tumor-associated macrophages (Lee et al. 2020). Studies have proved that inhibition of VEGF can effectively inhibit the maturation of dendritic cells, reduce the recruitment of Tregs, reduce the number and effectiveness of MDSCs (Hu and Jiang 2017), and thus improve the immunosuppression caused by radiotherapy, showing a better anti-cancer effect.
VEGF-targeted anti-angiogenesis therapy combined with radiotherapy to inhibit tumor has been the research focus and direction at present, but the mode and time of synergistic therapy still need to be further explored. There is a window period for VEGF to "normalize" tumor blood vessels, which is different for different drugs and different cancer types. The "normalization" of tissues and blood vessels in esophageal cancer occurred on the 5th day after the use of recombinant human endostatin (Zhu et al. 2015), and the "normalization" of tissues and blood vessels in colon cancer occurred on the 12th day after the use of Bevacizumab (Willett et al. 2004, Willett et al. 2005). During this time period, the combined radiotherapy can obviously inhibit the tumor. In the future, we will judge the time of vascular normalization of esophageal cancer from the changes of serum VEGF in patients receiving anti-angiogenesis therapy, and explore a more appropriate cut-in time of radiotherapy, so as to obtain better clinical effect.
Our research is limited by the small sample size and single-center research, so we need to further expand the sample size and in vitro experiments to verify the conclusion. It is still necessary to further clarify the mechanism, so as to provide the basis for becoming a radiosensitizer. Although we found that VEGF is related to radiotherapy resistance, the timing of the combined application of targeted VEGF therapy and radiotherapy still needs further exploration.
In a word, we found that the serum VEGF level is related to the radiotherapy effect in patients with ESCC, and inhibiting VEGF can enhance the sensitivity of ESCC to radiation, which indicates that VEGF is a potential target of radiotherapy for ESCC, and provides ideas for clinical targeted VEGF anti-angiogenesis therapy combined with radiotherapy to improve the curative effect of patients.