Predictive Significance of VEGF and HIF-1α Expression in Patients with Metastatic Colorectal Cancer Receiving Chemotherapy Combinations with Bevacizumab

  • Berk, Veli (Department of Medical Oncology, Erciyes University Medical Faculty) ;
  • Deniz, Kemal (Department of Pathology, Erciyes University Medical Faculty) ;
  • Bozkurt, Oktay (Department of Medical Oncology, Erciyes University Medical Faculty) ;
  • Ozaslan, Ersin (Department of Medical Oncology, Erciyes University Medical Faculty) ;
  • Karaca, Halit (Department of Medical Oncology, Erciyes University Medical Faculty) ;
  • Inanc, Mevlude (Department of Medical Oncology, Erciyes University Medical Faculty) ;
  • Duran, Ayse Ocak (Department of Medical Oncology, Erciyes University Medical Faculty) ;
  • Ozkan, Metin (Department of Medical Oncology, Erciyes University Medical Faculty)
  • Published : 2015.09.02


Background: There is no suggested molecular indicator for the determination of which patients will benefit from anti-angiogenetic treatment in metastatic colorectal cancers. Materials and Methods: In this study, VEGF and $HIF-1{\alpha}$ expression and their clinical significance were studied in tumor tissues of patients with colorectal cancer receiving bevacizumab-based treatment. VEGF and $HIF-1{\alpha}$ were assessed by immunohistochemistry in the primary tumors of 53 metastatic colorectal cancer patients receiving chemotherapy in combination with first line bevacizumab. Results: The clinical benefit rate in the low-VEGF expression group was 38%, while it was 62% in the high expression group. While the median progression-free survival (PFS) was 10 months in the high-VEGF expression group, it was 8 months in the low-VEGF expression group (p = 0.009). The median overall survival (OS) was found to be 26 months vs 15 months. Thus, when VEGF was strongly expressed it was in favor of that group and the difference was statistically significant (p = 0.03). High VEGF expression rate was an independent factor that correlated with OS or PFS (p=0.016 and 0.009, respectively). Conclusions: The data showed that VEGF may have predictive value for determining the treatment of CRC.


  1. Baba Y, Nosho K, Shima K, et al (2010). HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol, 176, 2292-301.
  2. Bertout JA, Patel SA, Simon MC(2008). The impact of O2 availability on human cancer. Nat Rev Cancer, 8, 967-75.
  3. Brown LF, Detmar M, Claffey K, et al (1997). Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine. EXS, 79, 233-69.
  4. Cao D, Hou M, Guan YS, Jiang M, Yang Y, Gou HF(2009). Expression of HIF-1alpha and VEGF in colorectal cancer: association with clinical outcomes and prognostic implications. BMC Cancer, 9, 432.
  5. Del Rio M, Molina F, Bascoul-Mollevi C, et al (2007). Gene expression signature in advanced colorectal cancer patients select drugs and response for the use of leucovorin, fluorouracil, and irinotecan. J Clin Oncol, 25, 773-80.
  6. De Vita F, Orditura M, Lieto E, et al (2004). Elevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma. Cancer, 100, 270-78.
  7. Dorevic G, Matusan-Ilijas K, Babarović E, et al (2009). Hypoxia inducible factor-1alpha correlates with vascular endothelial growth factor A and C indicating worse prognosis in clear cell renal cell carcinoma. J Exp Clin Cancer Res, 20, 28- 40.
  8. Dowlati A, Gray R, Sandler AB, Schiller JH, Johnson DH(2008). Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab–an Eastern Cooperative Oncology Group Study. Clin Cancer Res, 14, 1407-12.
  9. Dungwa JV, Hunt LP, Ramani P(2012). $HIF-1{\alpha}$ up-regulation is associated with adverse clinicopathological and biological factors in neuroblastomas. Histopathology, 61, 417-27.
  10. Dvorak HF, Sioussat TM, Brown LF, et al (1991). Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med, 174, 1275-8.
  11. Folkman J(1995). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med, 1, 27-31.
  12. Goldman E(1907). The growth of malignant disease in man and the lower animals with special reference to the vasculer system. Lancet, 2, 1236-40.
  13. Gordon MS, Margolin K, Talpaz M, et al (2001). Phase I safety and pharmacokinetic study of recombinant human antivascular endothelial growth factor in patients with advanced cancer. J Clin Oncol, 19, 843-50.
  14. Hebbar M, Tournigand C, Lledo G, et al (2006). Oncology Multidisciplinary Research Group (GERCOR). Phase II trial alternating FOLFOX-6 and FOLFIRI regimens in secondline therapy of patients with metastatic colorectal cancer (FIREFOX study). Cancer Invest, 24, 154-9.
  15. Hurwitz H, Fehrenbacher L, Novotny W, et al (2004). Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med, 350, 2335-42.
  16. Hurwitz HI, Yi J, Ince W, Novotny WF, Rosen O (2009). The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist, 14, 22-8.
  17. Jubb AM, Hurwitz HI, Bai W, et al (2006). Impact of vascularendothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol, 24, 217-27.
  18. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al (2003). Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol, 21, 60-65.
  19. Kajdaniuk D, Marek B, Foltyn W, Kos-Kudla B(2011). Vascular endothelial growth factor (VEGF) - part 2: in endocrinology and oncology. Endokrynol Pol, 62, 456-64.
  20. Kopetz S, Hoff PM, Morris JS, et al (2010). Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol, 28, 453-9.
  21. Kozloff M, Yood MU, Berlin J, et al; Investigators of the BRiTE study(2009). Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer:the BRiTE observational cohort study. Oncologist, 14, 862-70.
  22. Liang JF, Wang HK, Xiao H, et al (2010). Relationship and prognostic significance of SPARC and VEGF protein expression in colon cancer. J Exp Clin Cancer Res, 29, 71.
  23. Liang YX, He HC, Han ZD, et al (2009). CD147 and VEGF expression in advanced renal cell carcinoma and theirprognostic value. Cancer Invest, 27, 788-93.
  24. Mabjeesh NJ, Amir S(2007). Hypoxia-inducible factor (HIF) in human tumorigenesis. Histol Histopathol, 22, 559-72.
  25. Mahfud M, Breitenstein S, El-Badry AM, et al (2010). Impact of preoperative bevacizumab on complications after resection of colorectal liver metastases: case-matched control study. World J Surg, 34, 92-100.
  26. Okita NT, Yamada Y, Takahari D, et al (2009). Vascular endothelial growth factor receptor expression as a prognostic marker for survival in colorectal cancer. Jpn J Clin Oncol, 39, 595-600.
  27. Saad RS, Liu YL, Nathan G, Celebrezze J, Medich D, et al (2004). Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in colorectal cancer. Mod Pathol, 17, 197-203.
  28. Saltz LB, Clarke S, Diaz-Rubio E, et al (2008). Bevacizumab in combination with oxaliplatin-based chemotherapy as firstline therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol, 26, 2013-9.
  29. Tournigand C, Andre T, Achille E, et al (2004). FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol, 22, 229-37.
  30. Van Cutsem E, Rivera F, Berry S, et al (2009). Safety and efficacy of first-line bevacizumab with FOLFOX,XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol, 20, 1842-7.
  31. Watanabe T, Kobunai T, Yamamoto Y, et al (2011). Gene expression of vascular endothelial growth factor A, thymidylate synthase, and tissue inhibitor of metalloproteinase 3 in prediction of response to bevacizumab treatment in colorectal cancer patients. Dis Colon Rectum, 54, 1026-35.
  32. Wollenhaupt K, Welter H, Einspanier R, Manabe N, Brussow KP (2004). Expression of epidermal growth factor receptor (EGF-R), vascular endothelial growth factor receptor (VEGF-R) and fibroblast growth factor receptor (FGF-R) syst ems in porcine oviduct and endometrium during the time of implantation. J Reprod Dev, 50, 269-78.
  33. Wong MP, Cheung N, Yuen ST, Leung SY, Chung LP(1999). Vascular endothelial growth factor is up-regulated in the early pre-malignant stage of colorectal tumour progression. Int J Cancer, 81, 845-50.<845::AID-IJC1>3.0.CO;2-5
  34. Wu Y, Jin M, Xu H, et al (2010). Clinicopathologic significance of $HIF-1{\alpha}$, CXCR4, and VEGF expression in colon cancer. Clin Dev Immunol, 2010. doi:pii: 537531.
  35. Yang SX, Steinberg SM, Nguyen D, et al (2008). Gene expression profile and angiogenic marker correlates with response to neoadjuvant bevacizumab followed by bevacizumab plus chemotherapy in breast cancer. Clin Cancer Res, 14, 5893-9.
  36. Zhao J, Yan F, Ju H, Tang J, Qın J (2004). Correlation between serum vascular endothelial growth factor and endostatin levels in patients with breast cancer. Cancer Lett, 204, 87-95.

Cited by

  1. Circulating VEGF and eNOS variations as predictors of outcome in metastatic colorectal cancer patients receiving bevacizumab vol.7, pp.1, 2017,