Skip to main content

Advertisement

Log in

Vascular endothelial growth factor-A and -C: expression and correlations with lymphatic metastasis and prognosis in colorectal cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Previous studies obtained contradicting results regarding the correlation between expression of VEGF-A, VEGF-C and colorectal cancer patients’ clinicopathological features and prognosis. Moreover, the association between the growth factors’ expression and lymphatic vessel invasion (LVI) with intratumoral and peritumoral difference has not been reported. In this study, 81 primary colorectal cancer samples were immunohistochemically stained for VEGF-A, VEGF-C and podoplanin. The expression of VEGF-A and VEGF-C in marginal portion was significantly higher than those in central portion (P = 0.000 for both). The expression of VEGF-A in marginal portion was correlated with lymph node metastasis (P = 0.031). The expression of VEGF-C in marginal portion was correlated with TNM stage (P = 0.045), peritumoral LVI (P = 0.048) and lymph node metastasis (P = 0.019). The group with high VEGF-A expression in marginal portion showed worse survival than the low expression group (P = 0.039). Patients with high expression of VEGF-C in the marginal portion were not significantly different from those with low VEGF-C expression (P = 0.121). Patients with high expression of both VEGF-A and VEGF-C in the marginal portion showed the worst survival (P = 0.015). In conclusion, increased expression of VEGF-A and VEGF-C in marginal portion of colorectal cancer was correlated with lymph node metastasis. VEGF-C facilitates colorectal cancer cells invade into peritumoral lymphatic vessels, and different mechanisms may exist in the invasion of tumor cells into peritumoral and intratumoral lymphatic vessels. Assessment the expression of both VEGF-A and VEGF-C in the marginal portion of tumor may help to identify patients with colorectal cancer with unfavourable overall survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.

    Article  PubMed  CAS  Google Scholar 

  2. Shayan R, Achen MG, Stacker SA. Lymphatic vessels in cancer metastasis: bridging the gaps. Carcinogenesis. 2006;27:1729–38.

    Article  PubMed  CAS  Google Scholar 

  3. Carmeliet P, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380:435–9.

    Article  PubMed  CAS  Google Scholar 

  4. Roy H, Bhardwaj S, Ylä-Herttuala S. Biology of vascular endothelial growth factors. FEBS Lett. 2006;580:2879–87.

    Article  PubMed  CAS  Google Scholar 

  5. Yamazaki Y, Morita T. Molecular and functional diversity of vascular endothelial growth factors. Mol Divers. 2006;10:515–27.

    Article  PubMed  CAS  Google Scholar 

  6. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002;20:4368–80.

    Article  PubMed  CAS  Google Scholar 

  7. Nagy NA, et al. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med. 2002;196:1497–506.

    Article  PubMed  CAS  Google Scholar 

  8. Stacker SA, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001;7:186–91.

    Article  PubMed  CAS  Google Scholar 

  9. Duff SE, et al. Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy. Br J Cancer. 2003;89:426–30.

    Article  PubMed  CAS  Google Scholar 

  10. Jeltsch M, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science. 1997;276:1423–5.

    Article  PubMed  CAS  Google Scholar 

  11. Enholm B, et al. Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin. Circ Res. 2001;88:623–9.

    PubMed  CAS  Google Scholar 

  12. Karkkainen MJ, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004;5:74–80.

    Article  PubMed  CAS  Google Scholar 

  13. Pepper MS. Lymphangiogenesis and tumor metastasis: myth or reality? Clin Cancer Res. 2001;7:462–8.

    PubMed  CAS  Google Scholar 

  14. Boone B, et al. The role of VEGF-C staining in predicting regional metastasis in melanoma. Virchows Arch. 2008;453:257–65.

    Article  PubMed  CAS  Google Scholar 

  15. Furudoi A, et al. Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma. Oncology. 2002;62:157–66.

    Article  PubMed  CAS  Google Scholar 

  16. Mohammed RAA, et al. Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis. Br J Cancer. 2007;96:1092–100.

    Article  PubMed  CAS  Google Scholar 

  17. Kaio E, et al. Clinical significance of angiogenic factor expression at the deepest invasive site of advanced colorectal carcinoma. Oncology. 2003;64:61–73.

    Article  PubMed  CAS  Google Scholar 

  18. Kojima M, et al. Clinical significance of nuclear morphometry at the invasive front of T1 colorectal cancer and relation to expression of VEGF-A and VEGF-C. Oncology. 2005;68:230–8.

    Article  PubMed  CAS  Google Scholar 

  19. Kondo K, Kaneko T, Baba M, Konno H. VEGF-C and VEGF-A synergistically enhance lymph node metastasis of gastric cancer. Biol Pharm Bull. 2007;30:633–7.

    Article  PubMed  CAS  Google Scholar 

  20. Kurahara H, et al. Impact of vascular endothelial growth factor-C and -D expression in human pancreatic cancer: its relationship to lymph node metastasis. Clin Cancer Res. 2004;10:8413–20.

    Article  PubMed  CAS  Google Scholar 

  21. Nanni O, et al. Role of biological markers in the clinical outcome of colon cancer. Br J Cancer. 2002;87:868–75.

    Article  PubMed  CAS  Google Scholar 

  22. George ML, et al. VEGF-A, VEGF-C and VEGF-D in colorectal cancer progression. Neoplasia. 2001;3:420–7.

    Article  PubMed  CAS  Google Scholar 

  23. Sobin LH, Wittekind CH. International union against Cancer. TNM classification of malignant tumors. 6th ed. New York: Wiley-Liss; 2002.

    Google Scholar 

  24. Jemal A, et al. Cancer statistics. CA Cancer J clin. 2006;56:106–30.

    Article  PubMed  Google Scholar 

  25. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82:4–6.

    Article  PubMed  CAS  Google Scholar 

  26. Duff S, et al. Vascular endothelial growth factors and receptors in colorectal cancer: implication for anti-angiogenic therapy. Eur J Cancer. 2006;42:112–7.

    Article  PubMed  CAS  Google Scholar 

  27. Mandriota SJ, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 2001;20:672–82.

    Article  PubMed  CAS  Google Scholar 

  28. Siriwardena B, et al. VEGF-C is associated with lymphatic status and invasion in oral cancer. J Clin Pathol. 2008;61:103–8.

    Article  PubMed  CAS  Google Scholar 

  29. Kinoshita J, et al. Clinical significance of vascular endothelial growth factor-C (VEGF-C) in breast cancer. Breast Cancer Res Treat. 2001;66:159–64.

    Article  PubMed  CAS  Google Scholar 

  30. Adachi Y, et al. Lymphatic vessel density in pulmonary adenocarcinoma immunohistochemically evaluated with anti-podoplanin or anti-D2-40 antibody is correlated with lymphatic invasion or lymph node metastases. Pathol Int. 2007;57:171–7.

    Article  PubMed  CAS  Google Scholar 

  31. Kabashima A, Maehara Y, Kakeji Y, Sugimachi K. Overexpression of vascular endothelial growth factor C is related to lymphogenous metastasis in early gastric carcinoma. Oncology. 2001;60:146–50.

    Article  PubMed  CAS  Google Scholar 

  32. Fukunage S, et al. Association between expression of vascular endothelial growth factor C, chemokine, receptor CXCR4 and lymph node metastasis in colorectal cancer. Oncology. 2006;71:204–11.

    Article  Google Scholar 

  33. Zhang B, et al. Expression of vascular endothelial growth factors-C and D correlate with evidence of lymphangiogenesis and angiogenesis in pancreatic adenocarcinoma. Cancer Detect Prev. 2007;31:436–42.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jian-xian Yu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, M., Lin, Hz., Ma, Sp. et al. Vascular endothelial growth factor-A and -C: expression and correlations with lymphatic metastasis and prognosis in colorectal cancer. Med Oncol 28, 151–158 (2011). https://doi.org/10.1007/s12032-010-9427-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-010-9427-1

Keywords

Navigation