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Unraveling the hypoxia modulating potential of VEGF family genes in pan-cancer

  • So-Hyun Bae (Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University) ;
  • Taewon Hwang (Department of Electrical and Electronic Engineering, Yonsei University) ;
  • Mi-Ryung Han (Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University)
  • Received : 2023.08.08
  • Accepted : 2023.09.22
  • Published : 2023.12.31

Abstract

Tumor hypoxia, oxygen deprivation state, occurs in most cancers and promotes angiogenesis, enhancing the potential for metastasis. The vascular endothelial growth factor (VEGF) family genes play crucial roles in tumorigenesis by promoting angiogenesis. To investigate the malignant processes triggered by hypoxia-induced angiogenesis across pan-cancers, we comprehensively analyzed the relationships between the expression of VEGF family genes and hypoxic microenvironment based on integrated bioinformatics methods. Our results suggest that the expression of VEGF family genes differs significantly among various cancers, highlighting their heterogeneity effect on human cancers. Across the 33 cancers, VEGFB and VEGFD showed the highest and lowest expression levels, respectively. The survival analysis showed that VEGFA and placental growth factor (PGF) were correlated with poor prognosis in many cancers, including kidney renal cell and liver hepatocellular carcinoma. VEGFC expression was positively correlated with glioma and stomach cancer. VEGFA and PGF showed distinct positive correlations with hypoxia scores in most cancers, indicating a potential correlation with tumor aggressiveness. The expression of miRNAs targeting VEGF family genes, including hsa-miR-130b-5p and hsa-miR-940, was positively correlated with hypoxia. In immune subtypes analysis, VEGFC was highly expressed in C3 (inflammatory) and C6 (transforming growth factor β dominant) across various cancers, indicating its potential role as a tumor promotor. VEGFC expression exhibited positive correlations with immune infiltration scores, suggesting low tumor purity. High expression of VEGFA and VEGFC showed favorable responses to various drugs, including BLU-667, which abrogates RET signaling, an oncogenic driver in liver and thyroid cancers. Our findings suggest potential roles of VEGF family genes in malignant processes related with hypoxia-induced angiogenesis.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1C1C1012288).

References

  1. Knighton DR, Hunt TK, Scheuenstuhl H, Halliday BJ, Werb Z, Banda MJ. Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science 1983;221:1283-1285. https://doi.org/10.1126/science.6612342
  2. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl J Med 1991;324:1-8. https://doi.org/10.1056/NEJM199101033240101
  3. Ozdemir F, Akdogan R, Aydin F, Reis A, Kavgaci H, Gul S, et al. The effects of VEGF and VEGFR-2 on survival in patients with gastric cancer. J Exp Clin Cancer Res 2006;25:83-88.
  4. Carrillo de Santa Pau E, Arias FC, Caso Pelaez E, Munoz Molina GM, Sanchez Hernandez I, Muguruza Trueba I, et al. Prognostic significance of the expression of vascular endothelial growth factors A, B, C, and D and their receptors R1, R2, and R3 in patients with nonsmall cell lung cancer. Cancer 2009;115:1701-1712. https://doi.org/10.1002/cncr.24193
  5. Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995;55:3964-3968.
  6. Gunningham SP, Currie MJ, Han C, Robinson BA, Scott PA, Harris AL, et al. VEGF-B expression in human primary breast cancers is associated with lymph node metastasis but not angiogenesis. J Pathol 2001;193:325-332. https://doi.org/10.1002/path.814
  7. Neuchrist C, Erovic BM, Handisurya A, Fischer MB, Steiner GE, Hollemann D, et al. Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 expression in squamous cell carcinomas of the head and neck. Head Neck 2003;25:464-474. https://doi.org/10.1002/hed.10235
  8. Juttner S, Wissmann C, Jons T, Vieth M, Hertel J, Gretschel S, et al. Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol 2006;24:228-240. https://doi.org/10.1200/JCO.2004.00.3467
  9. Chen CN, Hsieh FJ, Cheng YM, Cheng WF, Su YN, Chang KJ, et al. The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer. Cancer Lett 2004;213:73-82. https://doi.org/10.1016/j.canlet.2004.05.020
  10. Bhandari V, Hoey C, Liu LY, Lalonde E, Ray J, Livingstone J, et al. Molecular landmarks of tumor hypoxia across cancer types. Nat Genet 2019;51:308-318. https://doi.org/10.1038/s41588-018-0318-2
  11. Vitale I, Shema E, Loi S, Galluzzi L. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat Med 2021;27:212-224. https://doi.org/10.1038/s41591-021-01233-9
  12. Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 2013;4:2612.
  13. Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 2009;462:108-112. https://doi.org/10.1038/nature08460
  14. Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl) 2015;3:83-92. https://doi.org/10.2147/HP.S93413
  15. Steven A, Seliger B. The role of immune escape and immune cell infiltration in breast cancer. Breast Care (Basel) 2018;13:16-21. https://doi.org/10.1159/000486585
  16. Srabovic N, Mujagic Z, Mujanovic-Mustedanagic J, Softic A, Muminovic Z, Rifatbegovic A, et al. Vascular endothelial growth factor receptor-1 expression in breast cancer and its correlation to vascular endothelial growth factor a. Int J Breast Cancer 2013;2013:746749.
  17. Zang J, Li C, Zhao LN, Shi M, Zhou YC, Wang JH, et al. Prognostic value of vascular endothelial growth factor in patients with head and neck cancer: a meta-analysis. Head Neck 2013;35:1507-1514. https://doi.org/10.1002/hed.23156
  18. Poon RT, Lau C, Pang R, Ng KK, Yuen J, Fan ST. High serum vascular endothelial growth factor levels predict poor prognosis after radiofrequency ablation of hepatocellular carcinoma: importance of tumor biomarker in ablative therapies. Ann Surg Oncol 2007;14:1835-1845. https://doi.org/10.1245/s10434-007-9366-z
  19. Rubenstein JL, Kim J, Ozawa T, Zhang M, Westphal M, Deen DF, et al. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2000;2:306-314. https://doi.org/10.1038/sj.neo.7900102
  20. Li J, Han T. Comprehensive analysis of the oncogenic roles of vascular endothelial growth factors and their receptors in stomach adenocarcinoma. Heliyon 2023;9:e17687.
  21. Plate KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 1992;359:845-848. https://doi.org/10.1038/359845a0
  22. Meng Q, Duan P, Li L, Miao Y. Expression of placenta growth factor is associated with unfavorable prognosis of advanced-stage serous ovarian cancer. Tohoku J Exp Med 2018;244:291-296. https://doi.org/10.1620/tjem.244.291
  23. Guo X, Chen M, Cao L, Hu Y, Li X, Zhang Q, et al. Cancer-associated fibroblasts promote migration and invasion of non-small cell lung cancer cells via miR-101-3p mediated VEGFA secretion and AKT/eNOS pathway. Front Cell Dev Biol 2021;9:764151.
  24. Liu Z, Wang J, Mao Y, Zou B, Fan X. MicroRNA-101 suppresses migration and invasion via targeting vascular endothelial growth factor-C in hepatocellular carcinoma cells. Oncol Lett 2016;11:433-438. https://doi.org/10.3892/ol.2015.3832
  25. Liu X, Kwong A, Sihoe A, Chu KM. Plasma miR-940 may serve as a novel biomarker for gastric cancer. Tumour Biol 2016;37:3589-3597. https://doi.org/10.1007/s13277-015-4019-5
  26. Yang HW, Liu GH, Liu YQ, Zhao HC, Yang Z, Zhao CL, et al. Over-expression of microRNA-940 promotes cell proliferation by targeting GSK3beta and sFRP1 in human pancreatic carcinoma. Biomed Pharmacother 2016;83:593-601. https://doi.org/10.1016/j.biopha.2016.06.057
  27. Chen X, Ying X, Wang X, Wu X, Zhu Q, Wang X. Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization. Oncol Rep 2017;38:522-528. https://doi.org/10.3892/or.2017.5697
  28. Chen G, Wang Q, Wang K. MicroRNA-218-5p affects lung adenocarcinoma progression through targeting endoplasmic reticulum oxidoreductase 1 alpha. Bioengineered 2022;13:10061-10070. https://doi.org/10.1080/21655979.2022.2063537
  29. White J, Jiang Z, Diamond M, Saed G. Hypoxia induces transforming growth factor beta 1 (TGFβ1) in human macrophages through a hypoxia inducible factor 1α (HIF-1α) - dependent mechanism. Fertil Steril 2009;92(3 Suppl):S124.
  30. Zhang C, Cheng W, Ren X, Wang Z, Liu X, Li G, et al. Tumor purity as an underlying key factor in glioma. Clin Cancer Res 2017;23:6279-6291. https://doi.org/10.1158/1078-0432.CCR-16-2598
  31. Gong Z, Zhang J, Guo W. Tumor purity as a prognosis and immunotherapy relevant feature in gastric cancer. Cancer Med 2020;9:9052-9063. https://doi.org/10.1002/cam4.3505