Diagnostic and Therapeutic Implications of the Vascular Endothelial Growth Factor Family in Cancer

  • Riaz, Syeda Kiran (Department of Biosciences, COMSATS Institute of Information Technology) ;
  • Iqbal, Yasmeen (Department of Surgery, Capital Development Hospital) ;
  • Malik, Muhammad Faraz Arshad (Department of Biosciences, COMSATS Institute of Information Technology)
  • Published : 2015.03.18


Cancer progression is attained by uncontrolled cell division and metastasis. Increase in tumor size triggers different vascular channel formation to address cell nutritional demands. These channels are responsible for transferring of nutrients and gaseous to the cancer cells. Cancer vascularization is regulated by numerous factors including vascular endothelial growth factors (VEGFs). These factors play an important role during embryonic development. Members included in this group are VEGFA, VEGFB, VEGFC, PIGF and VEGFD which markedly influence cellular growth and apoptosis. Being freely diffusible these proteins act in both autocrine and paracrine fashions. In this review, genetic characterization these molecules and their putative role in cancer staging has been elaborated. Prognostic significance of these molecules along with different stages of cancer has also been summarized. Brief outline of ongoing efforts to target hot spot target sites against these VEGFs and their cognate limitations for therapeutic implications are also highlighted.


Metastasis;VEGF family;angiogenesis;prognosis;carcinogenesis


Supported by : HEC, COMSATS-IT


  1. Reardon DA, Conrad CA, Cloughesy T, et al (2012). Phase I study of AEE788, a novel multitarget inhibitor of ErbBand VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients. Cancer Chemotherapy Pharmacol, 69, 1507-18.
  2. Ryden L, Stendahl M, Jonsson H, et al (2005). Tumor-specific VEGF-A and VEGFR2 in postmenopausal breast cancer patients with long-term follow-up. Implication of a link between VEGF pathway and tamoxifen response. Breast Cancer Res Treat, 89, 135-43.
  3. Schneider BP, Radovich M, Hancock BA, et al (2010). VEGFA amplification/deletion in human breast tumors. J Clin Oncol, 28, 15.
  4. Shariat SF (2009). Editorial comment on: large-scale real-time reverse transcription-PCR approach of angiogenic pathways in human transitional cell carcinoma of the bladder: identification of VEGFA as a major independent prognostic marker. European Urology, 56, 688-9.
  5. Sheffer M, Bacolod MD, Zuk O, et al (2009). Association of survival and disease progression with chromosomal instability: a genomic exploration of colorectal cancer. Proc Natl Acad Sci USA, 106, 7131-6.
  6. Shibuya M (2009). Unique signal transduction of the VEGF family members VEGF-A and VEGF-E. Biochem Soc Trans, 37, 1161-6.
  7. Sipos B, Klapper W, Kruse ML, et al (2004). Expression of lymphangiogenic factors and evidence of intratumoral lymphangiogenesis in pancreatic endocrine tumors. Am J Pathol, 165, 1187-97.
  8. Srivastava VK, Gara RK, Rastogi N, et al (2014). Serum vascular endothelial growth factor-A (VEGF-A) as a biomarker in squamous cell carcinoma of head and neck patients undergoing chemoradiotherapy. Asian Pac J Cancer Prev, 15, 3261-5.
  9. Stockmann C, Doedens A, Weidemann A, et al (2008). Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature, 456, 814-8.
  10. Su JL, Shih JY, Yen ML, et al (2004). Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. Cancer Res, 64, 554-64.
  11. Liu BY, Soloviev I, Chang P, et al (2010). Stromal cell-derived factor-1/CXCL12 contributes to MMTV-Wnt1 tumor growth involving Gr1+CD11b+ cells. PLoS One, 5, 8611.
  12. Liu H, Wang S, Huang C (2011). VEGFA+936C/T and -634G/C polymorphisms and gastric cancer risk: a meta-analysis. Asian Pac J Cancer Prev, 12, 1979-83.
  13. Los M, Roodhart JML, Voest EE (2007). Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist, 1, 443-50.
  14. McColl BK, Paavonen K, Karnezis T, et al (2007). Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. FASEB J, 21, 1088-98.
  15. Meco D, Servidei T, Zannoni GF, et al (2010). Dual inhibitor AEE788 reduces tumor growth in preclinical models of medulloblastoma. Transl Oncol, 3, 326-35.
  16. Meiron M, Anunu R, Scheinman EJ, Hashmueli S, Levi BZ (2001). New isoforms of VEGF are translated from alternative initiation CUG codons located in its 5'UTR. Biochem Biophys Res Commun, 282, 1053-60.
  17. Mendel DB, Schreck RE, West DC, et al (2000). The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function. Clin Cancer Res, 12, 4848-58.
  18. Millauer B, Wizigmann-Voos S, Schnurch H, et al (1993). High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell, 72, 835-46.
  19. Mitsuhashi A, Suzuka K, Yamazawa K, et al (2005). Serum vascular endothelial growth factor (VEGF) and VEGF-C levels as tumor markers in patients with cervical carcinoma. Cancer, 103, 724-30.
  20. Mylona E, Alexandrou P, Giannopoulou I et al (2007). The prognostic value of vascular endothelial growth factors (VEGFs)-A and -B and their receptor, VEGFR-1, in invasive breast carcinoma. Gynecol Oncol, 104, 557-63.
  21. Nilsson I, Bahram F, Li X, Gualandi L, et al (2010). VEGF receptor 2/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts. EMBO J, 29, 1377-8.
  22. Pereira ER, Liao N, Neale GA, Hendershot LM (2010). Transcriptional and post-transcriptional regulation of proangiogenic factors by the unfolded protein response. PLoS One, 5, 12521.
  23. Pignot G, Bieche I, Vacher S, et al (2009). Large-scale real-time reverse transcription-PCR approach of angiogenic pathways in human transitional cell carcinoma of the bladder: identification of VEGFA as a major independent prognostic marker. Eur Urol, 56, 678-88.
  24. Qi JH, Ebrahem Q, Moore N, et al (2003). A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med, 9, 407-15.
  25. Qi WX, Fu S, Zhang Q, et al (2014). Efficacy and toxicity of anti- VEGF agents in patients with castration-resistant prostate cancer: a meta-analysis of prospective clinical studies. Asian Pac J Cancer Prev, 15, 8177-82.
  26. Grailer JJ, Steeber DA (2013). Vascular endothelial growth factor receptor inhibitor SU5416 suppresses lymphocyte generation and immune responses in mice by increasing plasma corticosterone. PLoS ONE, 8, 75390.
  27. Hose D, Moreaux J, Meissner T, et al (2009). Induction of angiogenesis by normal and malignant plasma cells. Blood, 114, 128-43.
  28. Jin Y, Li JP, Tang LY, et al (2011). Expression and significance of VEGF, EGFR and MMP-9 in non-small cell lung carcinomas. Asian Pac J Cancer Prev, 12, 1473-6.
  29. Kabashima A, Maehara Y, Kakeji Y, Sugimachi K (2001). Overexpression of vascular endothelial growth factor C is related to lymphogenous metastasis in early gastric carcinoma. Oncology, 60, 146-50.
  30. Kanda M, Nomoto S, Nishikawa Y, et al (2008). Correlations of the expression of vascular endothelial growth factor B and its isoforms in hepatocellular carcinoma with clinicopathological parameters. Surg Oncol, 98, 190-6.
  31. Khemapech N, Pitchaiprasert S, Triratanachat S (2012). Prevalence and clinical significance of mammalian target of rapamycin phosphorylation (p-mTOR) and vascular endothelial growth factor (VEGF) in clear cell carcinoma of the ovary. Asian Pac J Cancer Prev, 13, 6357-62.
  32. Kim DH, Xu W, Ma C, et al (2009). Genetic variants in the candidate genes of the apoptosis pathway and susceptibility to chronic myeloid leukemia. Blood, 113, 2517-25.
  33. Klein M, Vignaud JM, Hennequin V, et al (2001). Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma. J Clin Endocrinol Metab, 86, 656-8.
  34. Kyzas PA, Stefanou D, Agnantis NJ (2005). COX-2 expression correlates with VEGF-C and lymph node metastases in patients with head and neck squamous cell carcinoma. Mod Pathol, 18, 153-60.
  35. Lee JS, Choi YD, Lee JH, et al (2004). Expression of cyclooxygenase-2 in adenocarcinomas of the uterine cervix and its relation to angiogenesis and tumor growth. Gynecol Oncol, 95, 523-9.
  36. Lee S. Rosen, et al (2001). Phase I experience with SU6668, a novel multiple receptor tyrosine kinase inhibitor in patients with advanced malignancies. Proc Am Soc Clin Oncol, 20.
  37. Levine RJ, Maynard SE, Qian C, et al (2004). Circulating angiogenic factors and the risk of preeclampsia. New Eng J Med, 350, 672-683.
  38. Li X, Aase K, Li H, von Euler G, Eriksson U (2001). Isoformspecific expression of VEGF-B in normal tissues and tumors. Growth Factors, 19, 49-59.
  39. Li YP, TianFG, Shi PC, et al (2014). 4-Hydroxynonenal promotes growth and angiogenesis of breast cancer cells through HIF-1${\alpha}$ stabilization. Asian Pac J Cancer Prev, 15, 10151-6.
  40. Liao S, Liu J, Lin P, (2011). TGF-{beta} blockade controls ascites by preventing abnormalization of lymphatic vessels in orthotopic human ovarian carcinoma models. Clin Cancer Res, 17, 1415-24.
  41. Beeghly-Fadiel A, Shu XO, Lu W, et al (2011). Genetic variation in VEGF family genes and breast cancer risk: a report from the Shanghai breast cancer genetics study. Cancer Epidemiol Biomarkers Prev, 20, 33-41.
  42. Byeon JS, Jung HY, Lee YJ, et al (2004). Clinicopathological significance of vascular endothelial growth factor-C and cyclooxygenase-2 in esophageal squamous cell carcinoma. J Gastroenterol Hepatol, 19, 648-654.
  43. Cao C, Sun SF, Lv D, et al (2013). Utility of VEGF and sVEGFR-1 in bronchoalveolar lavage fluid for differential diagnosis of primary lung cancer. Asian Pac J Cancer Prev, 14, 2443-6.
  44. Chen JD, Xiong YQ, Dong K, et al (2014). Clinical significance of joint detection of serum VEGF, SIL-2R and HGF in patients with primary hepatocellular carcinoma before and after percutaneous microwave coagulation therapy. Asian Pac J Cancer Prev, 15, 4545-8.
  45. Chen JX, Deng N, Chen X, et al (2012). A novel molecular grading model: combination of Ki67 and VEGF in predicting tumor recurrence and progression in non-invasive urothelial bladder cancer. Asian Pac J Cancer Prev, 13, 2229-34.
  46. Coen J, Bermudez S, Suzuki Y, et al (2005). VEGF-D expression predicts biochemical outcome in localized prostate cancer treated with external radiation: a ten-year cohort analysis. J Clin Oncol, 23, 16.
  47. Donnemab T, Al-Shiblicd K, Al-Saadce S, et al (2009). VEGF-A and VEGFR-3 correlate with nodal status in operable non-small cell lung cancer: inverse correlation between expression in tumor and stromal cells. Lung Cancer, 63, 277-83.
  48. Falk T, Zhang S, Sherman SJ (2009). Vascular endothelial growth factor B (VEGF-B) is up-regulated and exogenous VEGF-B is neuroprotective in a culture model of Parkinson's disease. Mol Neurodegener, 10, 49.
  49. Fauconnet S, Bernardini S, Lascombe I, et al (2009). Expression analysis of VEGF-A and VEGF-B: relationship with clinicopathological parameters in bladder cancer. Oncol Rep, 21, 1495-504.
  50. Fujimoto J, Toyoki H, Sato E, Sakaguchi H, Tamaya T (2004). Clinical implication of expression of vascular endothelial growth factor-C in metastatic lymph nodes of uterine cervical cancers. Br J Cancer, 91, 466-69.
  51. Furudoi A, Tanaka S, Haruma K, et al (2002). Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma. Oncology, 62, 157-66.
  52. Ghalamkarpour A, Morlot S, Raas-Rothschild A, et al (2006). Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations. Clin Genet, 70, 330-5.
  53. Albuquerque RJC, Hayashi T, Cho WG, et al (2009). Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nature Med, 15, 1023-30.
  54. Bassiouny AR, Zaky A, Neenaa HM (2010). Synergistic effect of celecoxib on 5-fluorouracil-induced apoptosis in hepatocellular carcinoma patients. Ann Hepatol, 1, 410-8.
  55. Zhu XZ, Yin HM, Mei J (2010). Inhibition of tumors cell growth in osteosarcoma-bearing SD rats through a combination of conventional and metronomic scheduling of neoadjuvant chemotherapy. Acta Pharmacol Sin, 31, 970-6.
  56. Tang RF, Wang SX, Peng L, et al (2006). Expression of vascular endothelial growth factors A and C in human pancreatic cancer. World J Gastroenterol, 12, 280-6.
  57. Van Iterson V, Leidenius M, von Smitten K, Bono P, Heikkila P (2007). VEGF-D in association with VEGFR-3 promotes nodal metastasis in human invasive lobular breast cancer. Am J Clin Pathol, 128, 759-66.
  58. Vlajnic T, Zlobec I, Karamitopoulou E (2010). VEGFA amplification correlates with adverse outcome in colorectal cancer. Virchows Archiv, 457, 226-7.
  59. Walter JW, North PE, Waner M, et al (2002). Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer, 33, 295-303.
  60. Wang K, Peng HL, Li LK (2012). Prognostic value of vascular endothelial growth factor expression in patients with prostate cancer a systematic review with meta-analysis. Asian Pac J Cancer Prev, 13, 5665-9.
  61. Wang Z, Chen Y, Li X, et al (2012). Expression of VEGF-C/ VEGFR-3 in human laryngeal squamous cell carcinomas and its significance for lymphatic metastasis. Asian Pac J Cancer Prev, 13, 27-31.
  62. Weidenaar AC, de Jonge HJ, Fidler V, et al (2008). Addition of PTK787/ZK 222584 can lower the dosage of amsacrine to achieve equal amounts of acute myeloid leukemia cell death. Anticancer Drugs, 19, 45-54.
  63. Willett CG, Boucher Y, di Tomaso E, et al (2004). Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med, 10, 145-7.
  64. Wood JM, Bold G, Buchdunger E, et al (2000). PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res, 60, 2178-89.
  65. Xu N, Lei Z, Li XL, et al (2013). Clinical study of tumor angiogenesis and perfusion imaging using multisplice spiral computed tomography for breast cancer. Asian Pac J Cancer Prev, 14, 429-33.
  66. Yokoyama Y, Charnock-Jones DS, Licence D, et al (2003). Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma. Clin Cancer Res, 4, 1361-9.
  67. Yonemura Y, Endo Y, Tabata K, et al (2005). Role of VEGF-C and VEGF-D in lymphangiogenesis in gastric cancer. Int J Clin Oncol, 10, 318-27.
  68. Yu DC, Chen J, Ding YT (2010). Hypoxic and highly angiogenic non-tumor tissues surrounding hepatocellular carcinoma: the 'niche' of endothelial progenitor cells. Int J Mol Sci, 11, 2901-9.
  69. Zhang SJ, Hu Y, Qian HL, et al (2013). Expression and Significance of ER, PR, VEGF, CA15-3, CA125 and CEA in judging the prognosis of breast cancer. Asian Pac J Cancer Prev, 14, 3937-40.
  70. Zhang Y, Yu LK, Lu GJ, et al (2014). Prognostic values of VEGF and endostatin with malignant pleural effusions in patients with lung cancer. Asian Pac J Cancer Prev, 15, 8435-40.

Cited by

  1. Phytochemistry and pharmacological activities of Vaccaria hispanica (Miller) Rauschert: a review vol.15, pp.5, 2016,
  2. Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells vol.17, pp.3, 2016,
  3. DNA alterations in Cd133+ and Cd133- tumour cells enriched from intra-operative human colon tumour biopsies vol.17, pp.1, 2017,