International Journal of Colorectal Disease

, Volume 19, Issue 6, pp 510–517

Vascular endothelial growth factor in colorectal cancer

  • Markus Guba
  • Hendrik Seeliger
  • Axel Kleespies
  • Karl-Walter Jauch
  • Christiane Bruns
Review

Abstract

Background

Angiogenesis plays an important role in colorectal cancer progression. Evidence from preclinical and clinical studies indicates that vascular endothelial growth factor (VEGF) is the predominant angiogenic factor in human colorectal cancer and is associated with formation of metastases and poor prognosis. Based on these results it was hypothesized that attacking one or more of the VEGF-mediated mechanisms may be promising in the treatment of colorectal cancer.

Aims

This article reviews the role of VEGF in colon cancer and summarizes recent advances in the treatment of colorectal cancer by anti-VEGF strategies.

Keywords

Anti-angiogenic therapy Clinical trials targeting VEGF Colorectal cancer Colorectal cancer metastases Prognostic value VEGF VEGF pathway 

References

  1. 1.
    Akagi K, Ikeda Y, Miyazaki M, Abe T, Kinoshita J, Maehara Y, Sugimachi K (2000) Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues. Br J Cancer 83:887–891Google Scholar
  2. 2.
    Akbulut H, Altuntas F, Akbulut KG, Ozturk G, Cindoruk M, Unal E, Icli F (2002) Prognostic role of serum vascular endothelial growth factor, basic fibroblast growth factor and nitric oxide in patients with colorectal carcinoma. Cytokine 20:184–190CrossRefPubMedGoogle Scholar
  3. 3.
    Aotake T, Lu CD, Chiba Y, Muraoka R, Tanigawa N (1999) Changes of angiogenesis and tumor cell apoptosis during colorectal carcinogenesis. Clin Cancer Res 5:135–142PubMedGoogle Scholar
  4. 4.
    Arbiser JL, Moses MA, Fernandez CA, Ghiso N, Cao Y, Klauber N, Frank D, Brownlee M, Flynn E, Parangi S, Byers HR, Folkman J (1997) Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways. Proc Natl Acad Sci U S A 94:861–866CrossRefPubMedGoogle Scholar
  5. 5.
    Bamba H, Ota S, Kato A, Adachi A, Itoyama S, Matsuzaki F (1999) High expression of cyclooxygenase-2 in macrophages of human colonic adenoma. Int J Cancer 83:470–475CrossRefPubMedGoogle Scholar
  6. 6.
    Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410Google Scholar
  7. 7.
    Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D (1999) Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284:808–812CrossRefPubMedGoogle Scholar
  8. 8.
    Berlin JD (2002) Targeting vascular endothelial growth factor in colorectal cancer. Oncology (Huntingt) 16:13–15Google Scholar
  9. 9.
    Bruns CJ, Liu W, Davis DW, Shaheen RM, McConkey DJ, Wilson MR, Bucana CD, Hicklin DJ, Ellis LM (2000) Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases. Cancer 89:488–499CrossRefPubMedGoogle Scholar
  10. 10.
    Cassano A, Bagala C, Battelli C, Schinzari G, Quirino M, Ratto C, Landriscina M, Barone C (2002) Expression of vascular endothelial growth factor, mitogen-activated protein kinase and p53 in human colorectal cancer. Anticancer Res 22:2179–184PubMedGoogle Scholar
  11. 11.
    Dormond O, Foletti A, Paroz C, Ruegg C (2001) NSAIDs inhibit alpha V beta 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nat Med 7:1041–1047CrossRefPubMedGoogle Scholar
  12. 12.
    DuBois RN, Smalley WE (1996) Cyclooxygenase, NSAIDs, and colorectal cancer. J Gastroenterol 31:898–906PubMedGoogle Scholar
  13. 13.
    Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676Google Scholar
  14. 14.
    Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31PubMedGoogle Scholar
  15. 15.
    Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613PubMedGoogle Scholar
  16. 16.
    Guba M, Cernaianu G, Koehl G, Geissler EK, Jauch KW, Anthuber M, Falk W, Steinbauer M (2001) A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Res 61:5575–5579PubMedGoogle Scholar
  17. 17.
    Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128–135PubMedGoogle Scholar
  18. 18.
    Gunsilius E, Tschmelitsch J, Eberwein M, Schwelberger H, Spizzo G, Kahler CM, Stockhammer G, Lang A, Petzer AL, Gastl G (2002) In vivo release of vascular endothelial growth factor from colorectal carcinomas. Oncology 62:313–317CrossRefPubMedGoogle Scholar
  19. 19.
    Hull MA, Booth JK, Tisbury A, Scott N, Bonifer C, Markham AF, Coletta PL (1999) Cyclooxygenase 2 is up-regulated and localized to macrophages in the intestine of Min mice. Br J Cancer 79:1399–1405CrossRefPubMedGoogle Scholar
  20. 20.
    Hurwitz HI, Fehrenbacher L, Cartwright J, Hainsworth W, Heim J, Berlin JD, Griffing S, Novotny WF, Holmgren E, Kabbinavar F (2003) American Society of Clinical Oncology Meeting (Abstract)Google Scholar
  21. 21.
    Jung YD, Nakano K, Liu W, Gallick GE, Ellis LM (1999) Extracellular signal-regulated kinase activation is required for up-regulation of vascular endothelial growth factor by serum starvation in human colon carcinoma cells. Cancer Res 59:4804–4807PubMedGoogle Scholar
  22. 22.
    Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E (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 21:60–65CrossRefPubMedGoogle Scholar
  23. 23.
    Kanai T, Konno H, Tanaka T, Baba M, Matsumoto K, Nakamura S, Yukita A, Asano M, Suzuki H, Baba S (1998) Anti-tumor and anti-metastatic effects of human-vascular-endothelial- growth-factor-neutralizing antibody on human colon and gastric carcinoma xenotransplanted orthotopially into nude mice. Int J Cancer 77:933–936CrossRefPubMedGoogle Scholar
  24. 24.
    Kang SM, Maeda K, Onoda N, Chung YS, Nakata B, Nishiguchi Y, Sowa M (1997) Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis. Int J Cancer 74:502–507CrossRefPubMedGoogle Scholar
  25. 25.
    Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K (2001) Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61:1786–1790PubMedGoogle Scholar
  26. 26.
    Kawakami M, Furuhata T, Kimura Y, Yamaguchi K, Hata F, Sasaki K, Hirata K (2003) Quantification of vascular endothelial growth factor-C and its receptor- 3 messenger RNA with real-time quantitative polymerase chain reaction as a predictor of lymph node metastasis in human colorectal cancer. Surgery 133:300–308CrossRefPubMedGoogle Scholar
  27. 27.
    Khorana AA, Ryan CK, Cox C, Eberly S, Sahasrabudhe DM (2003) Vascular endothelial growth factor, CD68, and epidermal growth factor receptor expression and survival in patients with Stage II and Stage III colon carcinoma: a role for the host response in prognosis. Cancer 97:960–968CrossRefPubMedGoogle Scholar
  28. 28.
    Kleespies A, Wellmann S, Bruns CJ, Jauch KW (2002) Int J Cancer 13[Suppl]: 130Google Scholar
  29. 29.
    Kondo Y, Arii S, Mori A, Furutani M, Chiba T, Imamura M (2000) Enhancement of angiogenesis, tumor growth, and metastasis by transfection of vascular endothelial growth factor into LoVo human colon cancer cell line. Clin Cancer Res 6:622–630PubMedGoogle Scholar
  30. 30.
    Kuenen BC, Rosen L, Smit EF, Parson MR, Levi M, Ruijter R, Huisman H, Kedde MA, Noordhuis P, van der Vijgh WJ, Peters GJ, Cropp GF, Scigalla P, Hoekman K, Pinedo HM, Giaccone G (2002) Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 20:1657–1667CrossRefPubMedGoogle Scholar
  31. 31.
    Lee JC, Chow NH, Wang ST, Huang SM (2000) Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients. Eur J Cancer 36:748–753CrossRefPubMedGoogle Scholar
  32. 32.
    Milanini J, Vinals F, Pouyssegur J, Pages G (1998) p42/p44 MAP kinase module plays a key role in the transcriptional regulation of the vascular endothelial growth factor gene in fibroblasts. J Biol Chem 273:18165–18172PubMedGoogle Scholar
  33. 33.
    Nagatsuka I, Yamada N, Shimizu S, Ohira M, Nishino H, Seki S, Hirakawa K (2002) Inhibitory effect of a selective cyclooxygenase-2 inhibitor on liver metastasis of colon cancer. Int J Cancer 100:515–519CrossRefPubMedGoogle Scholar
  34. 34.
    Okamoto K, Oshika Y, Fukushima Y, Yoshimura M, Ohnishi Y, Tokunaga T, Hashimoto T, Hatanaka H, Tomii Y, Yoshida Y, Miura S, Tsuchida T, Kijima H, Yamazaki H, Nakamura M, Ueyama Y (1999) Inhibition of liver metastasis of colon cancer by in vivo administration of anti-vascular endothelial growth factor antibody. Oncol Rep 6:553–556PubMedGoogle Scholar
  35. 35.
    Ono T, Miki C (2000) Factors influencing tissue concentration of vascular endothelial growth factor in colorectal carcinoma. Am J Gastroenterol 95:1062–1067CrossRefPubMedGoogle Scholar
  36. 36.
    Parkin DM (2001) Global cancer statistics in the year 2000. Lancet Oncol 2:533–543CrossRefPubMedGoogle Scholar
  37. 37.
    Pavco PA, Bouhana KS, Gallegos AM, Agrawal A, Blanchard KS, Grimm SL, Jensen KL, Andrews LE, Wincott FE, Pitot PA, Tressler RJ, Cushman C, Reynolds MA, Parry TJ (2000) Antitumor and antimetastatic activity of ribozymes targeting the messenger RNA of vascular endothelial growth factor receptors. Clin Cancer Res 6:2094–2103PubMedGoogle Scholar
  38. 38.
    Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, Kerbel RS (1995) Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 55:4575–4580PubMedGoogle Scholar
  39. 39.
    Rosen P, Amado R, Hecht J, Chang D, Mulay M, Parson MR, Laxa B, Cropp G, Hannah A, Rosen L (2000) American Society of Clinical Oncology Meeting (Abstract)Google Scholar
  40. 40.
    Seno H, Oshima M, Ishikawa TO, Oshima H, Takaku K, Chiba T, Narumiya S, Taketo MM (2002) Cyclooxygenase 2- and prostaglandin E(2) receptor EP(2)-dependent angiogenesis in Apc(Delta716) mouse intestinal polyps. Cancer Res 62:506–511PubMedGoogle Scholar
  41. 41.
    Shaheen RM, Davis DW, Liu W, Zebrowski BK, Wilson MR, Bucana CD, McConkey DJ, McMahon G, Ellis LM (1999) Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. Cancer Res 59:5412–5416PubMedGoogle Scholar
  42. 42.
    Sonoshita M, Takaku K, Sasaki N, Sugimoto Y, Ushikubi F, Narumiya S, Oshima M, Taketo MM (2001) Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice. Nat Med 7:1048–1051CrossRefPubMedGoogle Scholar
  43. 43.
    Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B (2000) The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342:1946–1952PubMedGoogle Scholar
  44. 44.
    Stopeck A, Sheldon M, Vahedian M, Cropp G, Gosalia R, Hannah A (2002) Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. Clin Cancer Res 8:2798–2805PubMedGoogle Scholar
  45. 45.
    Sunayama K, Konno H, Nakamura T, Kashiwabara H, Shoji T, Tsuneyoshi T, Nakamura S (2002) The role of cyclooxygenase-2 (COX-2) in two different morphological stages of intestinal polyps in APC(Delta474) knockout mice. Carcinogenesis 23:1351–1359CrossRefPubMedGoogle Scholar
  46. 46.
    Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM (1995) Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 55:3964–3968PubMedGoogle Scholar
  47. 47.
    Takahashi Y, Tucker SL, Kitadai Y, Koura AN, Bucana CD, Cleary KR, Ellis LM (1997) Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg 132:541–546PubMedGoogle Scholar
  48. 48.
    Takahashi Y, Ellis LM, Mai M (2003) The angiogenic switch of human colon cancer occurs simultaneous to initiation of invasion. Oncol Rep 10:9–13PubMedGoogle Scholar
  49. 49.
    Thun MJ, Namboodiri MM, Heath CW Jr (1991) Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325:1593–1596PubMedGoogle Scholar
  50. 50.
    Tokunaga T, Oshika Y, Abe Y, Ozeki Y, Sadahiro S, Kijima H, Tsuchida T, Yamazaki H, Ueyama Y, Tamaoki N, Nakamura M (1998) Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J Cancer 77:998–1002PubMedGoogle Scholar
  51. 51.
    Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716PubMedGoogle Scholar
  52. 52.
    Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N (1995) Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 95:1789–1797PubMedGoogle Scholar
  53. 53.
    Werther K, Christensen IJ, Brunner N, Nielsen HJ (2000) Soluble vascular endothelial growth factor levels in patients with primary colorectal carcinoma. The Danish RANX05 Colorectal Cancer Study Group. Eur J Surg Oncol 26:657–662CrossRefPubMedGoogle Scholar
  54. 54.
    White JD, Hewett PW, Kosuge D, McCulloch T, Enholm BC, Carmichael J, Murray JC (2002) Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res 62:1669–1675PubMedGoogle Scholar
  55. 55.
    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 81:845–850CrossRefPubMedGoogle Scholar
  56. 56.
    Yamauchi T, Watanabe M, Hasegawa H, Nishibori H, Ishii Y, Tatematsu H, Yamamoto K, Kubota T, Kitajima M (2003) The potential for a selective cyclooxygenase-2 inhibitor in the prevention of liver metastasis in human colorectal cancer. Anticancer Res 23:245–249PubMedGoogle Scholar
  57. 57.
    Yao M, Kargman S, Lam EC, Kelly CR, Zheng Y, Luk P, Kwong E, Evans JF, Wolfe MM (2003) Inhibition of cyclooxygenase-2 by rofecoxib attenuates the growth and metastatic potential of colorectal carcinoma in mice. Cancer Res 63:586–592PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Markus Guba
    • 1
  • Hendrik Seeliger
    • 1
  • Axel Kleespies
    • 1
  • Karl-Walter Jauch
    • 1
  • Christiane Bruns
    • 1
  1. 1.Department of Surgery, University Clinic GrosshadernLudwig-Maximilians-UniversityMunichGermany

Personalised recommendations