Skip to main content

Advertisement

SpringerLink
Log in

Prognostic significance of VEGF-C immunohistochemical expression in breast cancer: a meta-analysis

  • Research Article
  • Published:
Tumor Biology

Abstract

Vascular endothelial growth factor-C (VEGF-C) is considered as a prime mediator of lymphangiogenesis and has been implicated in carcinogenesis and metastasis. Various studies examined the relationship between VEGF-C protein overexpression with the clinical outcome in patients with breast cancer but yielded conflicting results. Electronic databases updated to April 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between VEGF-C overexpression and survival of patients with breast cancer. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 11 studies (n = 1,357 patients) that evaluated the correlation between VEGF-C overexpression detected by immunohistochemistry and survival in patients with breast cancer. Combined hazard ratios suggested that VEGF-C overexpression was not associated with poor prognosis of disease-free survival (HR [hazard ratio] = 0.80, 95 % CI [confidence interval]: 0.51–1.09), overall survival (OS) (HR = 1.08, 95 % CI: 0.37–1.78) in patients with breast cancer. In the stratified analysis by patient source, significantly risks were not found among Asians or non-Asians. No significant heterogeneity was observed among all studies. VEGF-C overexpression was not associated with poor disease-free survival or overall survival in breast cancer.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Saurel CA, Patel TA, Perez EA. Changes to adjuvant systemic therapy in breast cancer: a decade in review. Clin Breast Cancer. 2010;10:196–208.

    Article  PubMed  Google Scholar 

  3. Colozza M, Azambuja E, Cardoso F, Sotiriou C, Larsimont D, Piccart MJ. Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now? Ann Oncol. 2005;16:1723–39.

    Article  CAS  PubMed  Google Scholar 

  4. Hayes DF. Prognostic and predictive factors revisited. Breast. 2008;14:493–9.

    Article  Google Scholar 

  5. Callagy GM, Webber MJ, Pharoah PD, Caldas C. Meta-analysis confirms BCL2 is an independent prognostic marker in breast cancer. BMC Cancer. 2008;8:153.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002;2:795–803.

    Article  CAS  PubMed  Google Scholar 

  7. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–27.

    Article  CAS  PubMed  Google Scholar 

  8. Karkkainen MJ, Alitalo K. Lymphatic endothelial regulation, lymphoedema, and lymph node metastasis. Semin Cell Dev Biol. 2002;13:9–18.

    Article  CAS  PubMed  Google Scholar 

  9. Da MX, Wu Z, Tian HW. Tumor lymphangiogenesis and lymphangiogenic growth factors. Arch Med Res. 2008;39:365–72.

    Article  CAS  PubMed  Google Scholar 

  10. Cao R, Björndahl MA, Religa P, Clasper S, Garvin S, Galter D, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell. 2004;6:333–45.

    Article  CAS  PubMed  Google Scholar 

  11. Chang LK, Garcia-Cardena G, Farnebo F, Fannon M, Chen EJ, Butterfield C, et al. Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci U S A. 2004;101:11658–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Leong SP, Cady B, Jablons DM, Garcia-Aguilar J, Reintgen D, Jakub J, et al. Clinical patterns of metastasis. Cancer Metastasis Rev. 2006;25:221–32.

    Article  PubMed  Google Scholar 

  13. Altman DG. Systematic reviews of evaluations of prognostic variables. BMJ. 2001;323(7306):224–8.

    Article  CAS  PubMed  Google Scholar 

  14. Zhan P, Qian Q, Yu LK. Prognostic value of COX-2 expression in patients with non-small cell lung cancer: a systematic review and meta-analysis. J Thorac Dis. 2013;5(1):40–7. doi:10.3978/j.issn.2072-1439.2013.01.02.

    PubMed Central  PubMed  Google Scholar 

  15. Zhan P, Qian Q, Wan B, Yan TD, Yu LK. Prognostic value of TTF-1 expression in patients with non-small cell lung cancer: a meta-analysis. Transl Cancer Res. 2013. doi:10.3978/j.issn.2218-676X.2013.02.08.

    Google Scholar 

  16. Zhan P, Wang Q, Qian Q, Yu LK. Megestrol acetate in cancer patients with anorexia-cachexia syndrome: a meta-analysis. Transl Cancer Res. 2013;2(2):74–9. doi:10.3978/j.issn.2218-676X.2013.04.13.

    Google Scholar 

  17. Zhan P, Wang Q, Qian Q, Yu LK. Risk of venous thromboembolism with the erythropoiesis-stimulating agents (ESAs) for the treatment of cancer-associated anemia: a meta-analysis of randomized control trials. Chin Clin Oncol. 2013. doi:10.3978/j.issn.2304-3865.2013.01.02.

    Google Scholar 

  18. Zhan P, Qian Q, Yu LK. Prognostic significance of vascular endothelial growth factor expression in hepatocellular carcinoma tissue: a meta-analysis. Hepatobiliary Surg Nutr. 2013. doi:10.3978/j.issn.2304-3881.2013.06.06.

    Google Scholar 

  19. Zhan P, Qian Q, Yu LK. Serum VEGF level is associated with the outcome of patients with hepatocellular carcinoma: a meta-analysis. Hepatobiliary Surg Nutr. 2013. doi:10.3978/j.issn.2304-3881.2013.06.07.

    Google Scholar 

  20. Zhan P, Ji YN, Yu LK. VEGF is associated with the poor survival of patients with prostate cancer: a meta-analysis. Transl Androl Urol. 2013. doi:10.3978/j.issn.2223-4683.2013.07.01.

    Google Scholar 

  21. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform metaanalyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–34.

    Article  CAS  PubMed  Google Scholar 

  22. Yusuf S, Peto R, Lewis J, et al. Blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335–71.

    Article  CAS  PubMed  Google Scholar 

  23. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  24. Egger M, Smith GD, Schneider M. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed  Google Scholar 

  25. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.

    Article  CAS  PubMed  Google Scholar 

  26. Kinoshita J, Kitamura K, Kabashima A, Saeki H, Tanaka S, Sugimachi K. Clinical significance of vascular endothelial growth factor-C (VEGF-C) in breast cancer. Breast Cancer Res Treat. 2001;66:159–64.

    Article  CAS  PubMed  Google Scholar 

  27. Yang W, Klos K, Yang Y, Smith TL, Shi D, Yu D. ErbB2 overexpression correlates with increased expression of vascular endothelial growth factors A, C, and D in human breast carci-noma. Cancer. 2002;94:2855–61.

    Article  CAS  PubMed  Google Scholar 

  28. Nakamura Y, Yasuoka H, Tsujimoto M, Yang Q, Tsukiyama A, Imabun S, et al. Clinicopathological significance of vascular endothelial growth factor-C in breast carcinoma with long-term follow-up. Mod Pathol. 2003;16:309–14.

    Article  PubMed  Google Scholar 

  29. Mylona E, Alexandrou P, Mpakali A, Giannopoulou I, Liapis G, Markaki S, et al. Clinico-pathological and prognostic significance of vascular endothelial growth factors (VEGF)-C and -D and VEGF receptor 3 in inva-sive breast carcinoma. Eur J Surg Oncol. 2007;33:294–300.

    Article  CAS  PubMed  Google Scholar 

  30. Mohammed RA, Green A, El-Shikh S, Paish EC, Ellis IO, Martin SG. 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  CAS  PubMed Central  PubMed  Google Scholar 

  31. Gisterek I, Matkowski R, Kozlak J, Dus D, Lacko A, Szelachowska J, et al. Evaluation of prognostic value of VEGF-C and VEGF-D in breast cancer—10 years follow-up analysis. Anticancer Res. 2007;27:2797–802.

    CAS  PubMed  Google Scholar 

  32. Zhang XH, Huang DP, Guo GL, Chen GR, Zhang HX, Wan L, et al. Coexpression of VEGF-C and COX-2 and its association with lymphangiogenesis in human breast cancer. BMC Cancer. 2008;8:4.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Gu Y, Qi X, Guo S. Lymphangiogenesis induced by VEGF-C and VEGF-D promotes metastasis and a poor outcome in breast carcinoma: a retrospective study of 61 cases. Clin Exp Metastasis. 2008;25:717–25.

    Article  CAS  PubMed  Google Scholar 

  34. Tezuka K, Onoda N, Takashima T, Ishikawa T, Wakasa T, Wakasa K, et al. Clinical significance of intra-tumoral sinusoidal structures showing lympho-endothelial immunoreactivity in breast cancer. Oncol Rep. 2008;20:25–32.

    PubMed  Google Scholar 

  35. Tsutsui S, Matsuyama A, Yamamoto M, Takeuchi H, Oshiro Y, Ishida T, et al. The Akt expression correlates with the VEGF-A and -C expression as well as the microvessel and lymphatic vessel density in breast cancer. Oncol Rep. 2010;23:621–30.

    Article  PubMed  Google Scholar 

  36. Zhao YC, Ni XJ, Li Y, Dai M, Yuan ZX, Zhu YY, et al. Peritumoral lymphangiogenesis induced by vascular endothelial growth factor C and D promotes lymph node metastasis in breast cancer patients. World J Surg Oncol. 2012;10:165.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Parikh AA, Ellis LM. The vascular endothelial growth factor family and its receptors. Hematol Oncol Clin North Am. 2004;18(5):951–71.

    Article  PubMed  Google Scholar 

  38. Xie K, Wei D, Shi Q, Huang S. Constitutive and inducible expression and regulation of vascular endothelial growth factor. Cytokine Growth Factor Rev. 2004;15(5):297–324.

    Article  CAS  PubMed  Google Scholar 

  39. Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI. Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci U S A. 1996;93(5):1988–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science. 1997;276(5317):1423–142.

    Article  CAS  PubMed  Google Scholar 

  41. Yulong H, Iiro R, Katri P, et al. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer res. 2005;46:4739–46.

    Google Scholar 

  42. Achen MG, Stacker SA. Tumor lymphangiogenesis and metastatic spread-new players begin to emerge. Int J Cancer. 2006;119:1755–60.

    Article  CAS  PubMed  Google Scholar 

  43. Kyzas PA, Cunha IW, Ioannidis JP. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res. 2005;11(4):1434–40.

    Article  CAS  PubMed  Google Scholar 

  44. Zhan P, Wang J, Lv XJ, Wang Q, Qiu LX, Lin XQ, et al. Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis. J Thorac Oncol. 2009;4(9):1094–103.

    Article  PubMed  Google Scholar 

  45. Des Guetz G, Uzzan B, Nicolas P, Cucherat M, Morere JF, Benamouzig R, et al. Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature. Br J Cancer. 2006;94(12):1823–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Peng L, Zhan P, Zhou Y, Fang W, Zhao P, Zheng Y, et al. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in gastric cancer: a meta-analysis. Mol Biol Rep. 2012;39(10):9473–84.

    Article  CAS  PubMed  Google Scholar 

  47. Schoenleber SJ, Kurtz DM, Talwalkar JA, Roberts LR, Gores GJ. Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br J Cancer. 2009;100(9):1385–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res. 2006;12(17):5018–22.

    Article  CAS  PubMed  Google Scholar 

  49. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400.

    Article  CAS  PubMed  Google Scholar 

  50. Begg CB, Berlin JA. Publication bias: a problem in interpreting medical data. J R Stat Soc A. 1988;151:419–63.

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (81172501).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. State Key Laboratory of Reproductive Medicine, Department of Breast Surgery, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, 210004, China

    Sheng Gao, Jing-Jing Ma & Cheng Lu

Authors
  1. Sheng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing-Jing Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cheng Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cheng Lu.

Additional information

Sheng Gao and Jing-jing Ma contributed equally to this work and should be considered as co-first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gao, S., Ma, JJ. & Lu, C. Prognostic significance of VEGF-C immunohistochemical expression in breast cancer: a meta-analysis. Tumor Biol. 35, 1523–1529 (2014). https://doi.org/10.1007/s13277-013-1211-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-013-1211-3

Keywords

Search

Navigation