Skip to main content

Advertisement

SpringerLink
Log in

Hypoxia inducible factor-1α correlates with VEGF-C expression and lymphangiogenesis in breast cancer

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Summary

The transcription factor Hypoxia inducible factor-1α (HIF-1α) plays a crucial role in tumor progression by regulating angiogenesis, cell survival and drug resistance. HIF-1α is also implicated in biological functions under normoxic conditions and recent data provide evidence for a possible role in tumor lymphangiogenesis by regulating the lymphatic vascular endothelial growth factor-C (VEGF-C). In breast cancer, lymphatic vessel invasion (LVI) by tumor cells and subsequent metastasis to axillary lymph nodes is a critical point in progression of the disease with severe therapeutical and prognostic implications. Aim of this study is to investigate the role of HIF-1α in VEGF-C expression, lymphangiogenesis, and LVI in lymph node positive breast cancer.

 Lymphatic microvessel density (LMVD), LVI, HIF-1α and VEGF-C protein-expression were evaluated by immunohistochemistry in 119 cases of lymph node positive invasive breast cancer.

 There was a significant correlation between HIF-1α and VEGF-C (p = 0.026, r = 0.204, Spearman’s coefficient of correlation). Further a significant association between HIF-1α-expression and the amount of peritumoral lymphangiogenesis LMVD was seen (p = 0.014, Mann–Whitney test). LMVD correlated significantly with LVI (p<0.001, Mann–Whitney test). HIF-1α was an independent prognostic factor for overall and disease free survival in uni- and multivariate analysis (p = 0.027, 0.029, 0.025, respectively, Cox regression).

 Our data provide evidence for a possible role of HIF-1α as regulator of tumor-associated lymphangiogenesis in human breast cancer and emphasizes the promising status of HIF-1α as a therapeutical target against tumor progression and metastasis.

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

Similar content being viewed by others

References

  1. Semenza GL: HIF-1 and human disease: one highly involved factor. Genes Dev 2000; 14:1983–1991

    PubMed  CAS  Google Scholar 

  2. Wang GL, Jiang BH, Rue EA, Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995; 92:5510–5514

    Article  PubMed  CAS  Google Scholar 

  3. Jiang BH, Semenza GL, Bauer C, Marti HH: Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol 1996; 271:C1172–C1180

    PubMed  CAS  Google Scholar 

  4. Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992; 359:843–845

    Article  PubMed  CAS  Google Scholar 

  5. Conway EM, Collen D, Carmeliet P: Molecular mechanisms of blood vessel growth. Cardiovasc Res 2001; 49:507–521

    Article  PubMed  CAS  Google Scholar 

  6. Teng X, Li D, Johns RA: Hypoxia up-regulates mouse vascular endothelial growth factor D promoter activity in rat pulmonary microvascular smooth-muscle cells. Chest 2002; 121:82S-83S

    Article  PubMed  Google Scholar 

  7. Currie MJ, Hanrahan V, Gunningham SP, Morrin HR, Frampton C, Han C, Robinson BA, Fox SB: Expression of vascular endothelial growth factor D is associated with hypoxia inducible factor (HIF-1alpha) and the HIF-1alpha target gene DEC1, but not lymph node metastasis in primary human breast carcinomas. J Clin Pathol 2004; 57:829–834

    Article  PubMed  CAS  Google Scholar 

  8. Katsuta M, Miyashita M, Makino H, Nomura T, Shinji S, Yamashita K, Tajiri T, Kudo M, Ishiwata T, Naito Z: Correlation of hypoxia inducible factor-1alpha with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer. Exp Mol Pathol 2005; 78:123–130

    Article  PubMed  CAS  Google Scholar 

  9. Nilsson I, Shibuya M, Wennstrom S: Differential activation of vascular genes by hypoxia in primary endothelial cells. Exp Cell Res 2004; 299:476–485

    Article  PubMed  CAS  Google Scholar 

  10. Jakesz R, Samonigg H, Gnant M, Kubista E, Depisch D, Kolb R, Mlineritsch B, Mischinger HJ, Menzel RC, Steindorfer P, Kwasny W, Tausch C, Stierer M, Taucher S, Seifert M, Hausmaninger H: Significant increase in breast conservation in 16 years of trials conducted by the Austrian Breast & Colorectal Cancer Study Group. Ann Surg 2003; 237:556–564

    Article  PubMed  Google Scholar 

  11. Elston EW, Ellis IO: Method for grading breast cancer. J Clin Pathol 1993; 46:189–190

    Article  PubMed  CAS  Google Scholar 

  12. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW: Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 1999; 59:5830–5835

    PubMed  CAS  Google Scholar 

  13. Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G:Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 2000; 60:4693–4696

    PubMed  CAS  Google Scholar 

  14. Horvat R, Hovorka A, Dekan G, Poczewski H, Kerjaschki D: Endothelial cell membranes contain podocalyxin – the major sialoprotein of visceral glomerular epithelial cells. J Cell Biol 1986; 102:484–491

    Article  PubMed  CAS  Google Scholar 

  15. Birner P, Oberhuber G, Stani J, Reithofer C, Samonigg H, Hausmaninger H, Kubista E, Kwasny W, Kandioler-Eckersberger D, Gnant M, Jakesz R: Evaluation of the United States Food and Drug Administration-approved scoring and test system of HER-2 protein expression in breast cancer. Clin Cancer Res 2001; 7:1669–1675

    PubMed  CAS  Google Scholar 

  16. Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G: Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 1992; 84:1875–1887

    Article  PubMed  CAS  Google Scholar 

  17. Weidner N: Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors. Breast Cancer Res Treat 1995; 36:169–180

    Article  PubMed  CAS  Google Scholar 

  18. Schoppmann SF, Schindl M, Breiteneder-Geleff S, Soleima A, Breitenecker G, Karner B, Birner P: Inflammatory stromal reaction correlates with lymphatic microvessel density in early-stage cervival cancer. Anticancer Res 2001; 21:3419–3423

    PubMed  CAS  Google Scholar 

  19. Jakesz R, Dittrich C, Hanusch J, Kolb R, Lenzhofer R, Moser K, Rainer H, Reiner G, Schemper M, Spona J, et al. Simultaneous and sequential determinations of steroid hormone receptors in human breast cancer. Influence of intervening therapy. Ann Surg 1985; 201:305–310

    Article  PubMed  CAS  Google Scholar 

  20. Jakesz R, Hausmaninger H, Haider K, Kubista E, Samonigg H, Gnant M, Manfreda D, Tschurtschenthaler G, Kolb R, Stierer M, Fridrik M, Mlineritsch B, Steindorfer P, Mittlbock M, Steger G: Randomized trial of low-dose chemotherapy added to tamoxifen in patients with receptor-positive and lymph node-positive breast cancer. J Clin Oncol 1999; 17:1701–1709

    PubMed  CAS  Google Scholar 

  21. Kaplan E, Meier P: Non parametric estimation from incomplete observations. J Am Statist Assoc 1985; 53:457–481

    Article  Google Scholar 

  22. Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W, Gnant M, Jakesz R, Kubista E, Birner P, Oberhuber G: Overexpression of hypoxia-inducible factor 1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 2002; 8:1831–1837

    PubMed  CAS  Google Scholar 

  23. Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E: Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 2003; 97:1573–1581

    Article  PubMed  Google Scholar 

  24. Bos R, van Diest PJ, de Jong JS, van der Groep P, van der Valk P, van der Wall E: Hypoxia-inducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology 2005; 46:31–36

    Article  PubMed  CAS  Google Scholar 

  25. Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3:721–732

    Article  PubMed  CAS  Google Scholar 

  26. Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K: Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 2001; 61:1786–1790

    PubMed  CAS  Google Scholar 

  27. Pepper MS: Lymphangiogenesis and tumor metastasis: myth or reality? Clin Cancer Res 2001; 7:462–468

    PubMed  CAS  Google Scholar 

  28. Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK: Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 2002; 296:1883–1886

    Article  PubMed  CAS  Google Scholar 

  29. Vleugel MM, Bos R, van der Groep P, Greijer AE, Shvarts A, Stel HV, van der Wall E, van Diest PJ: Lack of lymphangiogenesis during breast carcinogenesis. J Clin Pathol 2004; 57:746–751

    Article  PubMed  CAS  Google Scholar 

  30. Schoppmann SF, Bayer G, Aumayr K, Taucher S, Geleff S, Rudas M, Kubista E, Hausmaninger H, Samonigg H, Gnant M, Jakesz R, Horvat R: Prognostic value of lymphangiogenesis and lymphovascular invasion in invasive breast cancer. Ann Surg 2004; 240:306–312

    Article  PubMed  Google Scholar 

  31. van Kempen LC, Rhee JS, Dehne K, Lee J, Edwards DR, Coussens LM: Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment. Differentiation 2002; 70:610–623

    Article  PubMed  Google Scholar 

  32. Schoppmann SF, Birner P, Stockl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D: Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 2002; 161:947–695

    PubMed  CAS  Google Scholar 

  33. Coussens LM, Werb Z: Inflammation and cancer. Nature 2002; 420:860–867

    Article  PubMed  CAS  Google Scholar 

  34. Schoppmann SF, Fenzl A, Unger S, Bayer G, Geleff S, Gnant M, Horvat R, Jakesz R, Birner P: VEGF-C-expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival. Surgery, 2005, in press

  35. Hewitson KS, Schofield CJ: The HIF pathway as a therapeutic target. Drug Discov Today 2004; 9:704–711

    Article  PubMed  CAS  Google Scholar 

  36. Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM: Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem 2002; 277:29936–29944

    Article  PubMed  CAS  Google Scholar 

  37. Mabjeesh NJ, Escuin D, LaVallee TM, Pribluda VS, Swartz GM, Johnson MS, Willard MT, Zhong H, Simons JW, Giannakakou P: 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF: Cancer Cell 2003; 3:363–375

    Article  PubMed  CAS  Google Scholar 

  38. Tan C, de Noronha RG, Roecker AJ, Pyrzynska B, Khwaja F, Zhang Z, Zhang H, Teng Q, Nicholson AC, Giannakakou P, Zhou W, Olson JJ, Pereira MM, Nicolaou KC, Van Meir EG: Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway. Cancer Res 2005; 65:605–612

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, University of Vienna, Waehringer, Vienna, Austria

    Sebastian F. Schoppmann, Alexandra Fenzl, Thomas Bachleitner-Hofmann, Michael Gnant &  Raimund Jakesz

  2. Clinical Institute of Pathology, University of Vienna, Waehringer, Vienna, Austria

    Monika Schindl, Katalin Nagy, Reinhard Horvat & Peter Birner

  3. Department of Surgery, University of Vienna, Waehringer, Vienna, Austria

    Sebastian F. Schoppmann

Authors
  1. Sebastian F. Schoppmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandra Fenzl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Monika Schindl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Bachleitner-Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katalin Nagy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Gnant
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Reinhard Horvat
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Raimund Jakesz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peter Birner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sebastian F. Schoppmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schoppmann, S.F., Fenzl, A., Schindl, M. et al. Hypoxia inducible factor-1α correlates with VEGF-C expression and lymphangiogenesis in breast cancer. Breast Cancer Res Treat 99, 135–141 (2006). https://doi.org/10.1007/s10549-006-9190-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-006-9190-3

Keywords

Search

Navigation