Abstract
Vascular endothelial growth factor (VEGF) is related to the radiation resistance of tumors, resulting in the failure of tumor radiotherapy. The purpose of this study was to discuss the role of VEGF in radiotherapy resistance of esophageal squamous cell carcinoma (ESCC). We used the VEGF kit by ELISA to detect the serum VEGF level of ESCC patients who only received radiotherapy. The expression of VEGF in ESCC cells after siRNA treatment was verified by Western blot. The sensitivity of ESCC cells to radiation after knocking down VEGF was analyzed by Clonogenic assay and Cell counting kit (CCK-8). The results showed that the level of serum VEGF in patients with ESCC before and after radiotherapy was related to the clinical response, and it was confirmed that knocking down the expression of VEGF in ESCC cells improved the sensitivity to radiation.
Similar content being viewed by others
References
Buckley AM, Lynam-Lennon N, O’Neill H, O’Sullivan J (2020) Targeting hallmarks of cancer to enhance radiosensitivity in gastrointestinal cancers. Nat Rev Gastroenterol Hepatol 17(5):298–313. https://doi.org/10.1038/s41575-019-0247-2
Chen Y, Li X, Guo L, Xiaoyuan Wu, He C, Zhang S, Xiao Y, Yang Y, Hao D (2015) Combining radiation with autophagy inhibition enhances suppression of tumor growth and angiogenesis in esophageal cancer. Mol Med Rep 12(2):1645–1652. https://doi.org/10.3892/mmr.2015.3623
Chen Li, Lin G, Chen K, Wan F, Liang R, Sun Y, Chen X, Zhu X (2020) VEGF knockdown enhances radiosensitivity of nasopharyngeal carcinoma by inhibiting autophagy through the activation of mTOR pathway. Sci Rep 10(1):16328. https://doi.org/10.1038/s41598-020-73310-x
Cummings D, Wong J, Palm R, Hoffe S, Almhanna K, Vignesh S (2021) Epidemiology, diagnosis, staging and multimodal therapy of esophageal and gastric tumors. Cancers 13(3):582. https://doi.org/10.3390/cancers13030582
Dong D, Yan Fu, Chen F, Zhang J, Jia H, Li J, Wang H, Wen J (2021) Hyperoxia sensitizes hypoxic HeLa cells to ionizing radiation by downregulating HIF1α and VEGF expression. Mol Med Rep 23(1):1–9. https://doi.org/10.3892/mmr.2020.11700
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Janet Dancey S, Arbuck SG, Mooney M (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026
El Alaoui-Lasmaili K, Faivre B (2018) Antiangiogenic therapy: markers of response, “normalization” and resistance. Crit Rev Oncol Hematol 128:118–129. https://doi.org/10.1016/j.critrevonc.2018.06.001
Gao H, Xue J, Zhou L, Lan J, He J, Na F, Yang L, Deng L, You Lu (2015) Bevacizumab radiosensitizes non-small cell lung cancer xenografts by inhibiting DNA double-strand break repair in endothelial cells. Cancer Lett 365(1):79–88. https://doi.org/10.1016/j.canlet.2015.05.011
Hu C, Jiang X (2017) The effect of anti-angiogenic drugs on regulatory T cells in the tumor microenvironment. Biomed Pharmacother 88:134–137. https://doi.org/10.1016/j.biopha.2017.01.051
Hu X, Xing L, Wei X, Liu X, Pang R, Qi Li, Song S (2012) Nonangiogenic function of VEGF and enhanced radiosensitivity of HeLa cells by inhibition of VEGF expression. Oncol Res Featur Preclin Clin Cancer Ther 20(2–3):93–101. https://doi.org/10.3727/096504012X13473664562664
Hu L, Kong Ze, Meng Q, Wang J, Zhou M, Jingping Yu, Jiang X (2020) The safety and efficacy of apatinib treatment in addition to concurrent chemoradiotherapy in patients with nonoperative locally advanced esophageal squamous cell carcinoma. Med Sci Monit 26:e927221. https://doi.org/10.12659/MSM.927221
Huang J, Koulaouzidis A, Marlicz W, Lok V, Chu C, Ngai CH, Zhang L, Chen P, Wang S, Yuan J (2021) Global burden, risk factors, and trends of esophageal cancer: an analysis of cancer registries from 48 countries. Cancers 13(1):141. https://doi.org/10.3390/cancers13010141
Kang M, Wang F, Liao X, Zhou P, Wang R (2018) Intensity-modulated radiotherapy combined with endostar has similar efficacy but weaker acute adverse reactions than IMRT combined with chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma. Medicine 97(25):e11118. https://doi.org/10.1097/MD.0000000000011118
Koo HJ, Lee M, Kim J, Woo CW, Jeong S-Y, Choi EK, Kim N, Lee JS (2016) Synergistic effect of anti-angiogenic and radiation therapy: quantitative evaluation with dynamic contrast enhanced MR imaging. PLoS ONE 11(2):e0148784. https://doi.org/10.1371/journal.pone.0148784
Lee H-J, Yoon C, Joong Park D, Kim Y-J, Schmidt B, Lee Y-J, Tap WD, Eisinger-Mathason TSK, Choy E, Kirsch DG (2015) Inhibition of vascular endothelial growth factor A and hypoxia-inducible factor 1α maximizes the effects of radiation in sarcoma mouse models through destruction of tumor vasculature. Int J Radiat Oncol Biol Phys 91(3):621–630. https://doi.org/10.1016/j.ijrobp.2014.10.047
Lee YH, Tai D, Connie Yip Su, Choo P, Chew V (2020) Combinational immunotherapy for hepatocellular carcinoma: radiotherapy, immune checkpoint blockade and beyond. Front Immunol 11:568759. https://doi.org/10.3389/fimmu.2020.568759
Li S, Chen H, Man J, Zhang T, Yin X, He Q, Yang X, Ming Lu (2021) Changing trends in the disease burden of esophageal cancer in China from 1990 to 2017 and its predicted level in 25 years. Cancer Med 10(5):1889–1899. https://doi.org/10.1002/cam4.3775
Liu S, Fei Wu, Zhang Y, Qin R, Zhu N, Li Y, Wang M, Zeng Q, Xie D, Li Y (2020) Apatinib combined with radiotherapy enhances antitumor effects in an in vivo nasopharyngeal carcinoma model. Cancer Control 27(1):1073274820922553. https://doi.org/10.1177/1073274820922553
Ma Y, Xinyu Su, Li X, Zhi X, Jiang K, Xia J, Li H, Yan C, Zhou L (2021) Combined detection of peripheral blood VEGF and inflammation biomarkers to evaluate the clinical response and prognostic prediction of non-operative ESCC. Sci Rep 11(1):15305. https://doi.org/10.21203/rs.3.rs-199215/v1
McLaughlin M, Patin EC, Pedersen M, Wilkins A, Dillon MT, Melcher AA, Harrington KJ (2020) Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer 20(4):203–217. https://doi.org/10.1038/s41568-020-0246-1
Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, Jemal A, Kramer JL, Siegel RL (2019) Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin 69(5):363–385. https://doi.org/10.3322/caac.21565
Poon RTP, Fan ST, Wong J (2003) Clinical significance of angiogenesis in gastrointestinal cancers: a target for novel prognostic and therapeutic approaches. Ann Surg 238(1):9–28. https://doi.org/10.1097/01.sla.0000075047.47175.35
Qin S, Li A, Yi M, Shengnan Yu, Zhang M, Kongming Wu (2019) Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J Hematol Oncol 12(1):27. https://doi.org/10.1186/s13045-019-0718-5
Ren Y, Wang SB, Zhou L, Liu SQ, Lei Ya Du, Li T, Jiang MQ, Lei KJ, Tan BX, Jia YM (2021) Continuous low-dose apatinib combined with WBRT significantly reduces peritumoral edema and enhances the efficacy of symptomatic multiple brain metastases in NSCLC. Technol Cancer Res Treat 20:15330338211011968. https://doi.org/10.1177/15330338211011968
Shi J, Zhang Y, Wang J, Li J, Li Z (2020) Anlotinib combined with chemoradiotherapy exhibits significant therapeutic efficacy in esophageal squamous cell carcinoma. Front Oncol 10:995. https://doi.org/10.3389/fonc.2020.00995
Siemann DW, Chaplin DJ, Horsman MR (2017) Realizing the potential of vascular targeted therapy: the rationale for combining vascular disrupting agents and anti-angiogenic agents to treat cancer. Cancer Invest 35(8):519–534. https://doi.org/10.1080/07357907.2017.1364745
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660
Wang F, Peng L, Wang Y, Liu X (2020) Silencing vascular endothelial growth factor C increases the radiosensitivity in nasopharyngeal carcinoma CNE-2 cells. J Cell Biochem 121(2):1182–1191. https://doi.org/10.1002/jcb.29352
Willett CG, Boucher Y, Di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10(2):145–147. https://doi.org/10.1038/nm988
Willett CG, Boucher Y, Duda DG, Di Tomaso E, Munn LL, Tong RT, Kozin SV, Petit L, Jain RK, Chung DC (2005) Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: Continued experience of a phase I trial in rectal cancer patients [18]. J Clin Oncol 23(31):8136–8139. https://doi.org/10.1200/JCO.2005.02.5635
Yang Li, Zhao W, Zuo W, Wei L, Song X, Wang X, Zheng G, Zheng M (2012) Silencing of osteopontin promotes the radiosensitivity of breast cancer cells by reducing the expression of hypoxia inducible factor 1 and vascular endothelial growth factor. Chin Med J 125(2):293–299. https://doi.org/10.3760/cma.j.issn.0366-6999.2012.02.024
Zhu H, Yang Xi, Ding Y, Liu J, Jing Lu, Zhan L, Qin Q, Zhang H, Chen X, Yang Y (2015) Recombinant human endostatin enhances the radioresponse in esophageal squamous cell carcinoma by normalizing tumor vasculature and reducing hypoxia. Sci Rep 5(1):14503. https://doi.org/10.1038/srep14503
Acknowledgements
Thanks to all participants in this study.
Funding
This research was supported by Huai’an Science Project (No.HAB202029); National Natural Science Foundation of China (No.81872484; No.82073365); Jiangsu Science and technology planning project (No.BE2019605).
Author information
Authors and Affiliations
Contributions
XYS conceived and designed the experiment. CY and YYM and HL collected the patient’s peripheral blood. JHX and HLL and QJ outline the patient’s radiotherapy field and verify the treatment plan. XL performed the experiments and wrote the manuscript draft. XYS and ZYZ and LQZ edited the paper. All the authors have read and approved the final manuscript and agree to be accountable for all aspects of the study.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Ethical approval
Peripheral blood was collected with the permission of the ethics society of Huai'an Hospital Affiliated to Xuzhou Medical University (HEYLL No.201932) and the written consent of the patient.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Li, X., Su, X., Yan, C. et al. Role of vascular endothelial growth factor in radiotherapy resistance to esophageal squamous cell carcinoma. J Cancer Res Clin Oncol 149, 2543–2550 (2023). https://doi.org/10.1007/s00432-022-04122-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-022-04122-x