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01-05-2012 | Clinical Trial

Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer

Authors: Else Maae, Dorte Aalund Olsen, Karina Dahl Steffensen, Erik Hugger Jakobsen, Ivan Brandslund, Flemming Brandt Sørensen, Anders Jakobsen

Published in: Breast Cancer Research and Treatment | Issue 1/2012

Abstract

Placenta growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) are angiogenic growth factors interacting competitively with the same receptors. VEGF-A is essential in both normal and pathologic conditions, but the functions of PlGF seem to be restricted to pathologic conditions such as ischemic heart disease, arthritis and tumor growth. Angiogenesis is a complex process with several growth factors involved. Because PlGF modulates VEGF-A responses, we investigated their mutual relationship and impact on breast cancer prognosis. Quantitative PlGF and VEGF-A levels were measured in 229 tumor tissue specimen from primarily operated patients with unilateral breast cancer. Non-malignant breast tissue was also dissected near the tumor and quantitative measurements were available for 211 patients. PlGF and VEGF-A protein levels in homogenized tissue lysates were analyzed using the Luminex system. We found significantly higher median levels of PlGF and VEGF-A in tumor tissue compared to non-malignant tissue (PlGF: 69.8 vs. 31.4 pg/mg, p < 0.001 and VEGF-A: 1148.2 vs. 163.5 pg/mg, p < 0.001). PlGF and VEGF-A were correlated in both malignant tissue (r = 0.41, p < 0.001) and in non-malignant tissue (r = 0.69, p < 0.001). The proportion of node positive patients was higher with high PlGF expression (61.4%) than with low PlGF expression (45.6%) in tumor tissue, p = 0.024. High levels of PlGF and VEGF-A in tumor tissue were associated with significant shorter recurrence-free survival (RFS) in both univariate analysis (PlGF: p = 0.023; VEGF-A: p = 0.047) and in multivariate analysis (PlGF: p = 0.026; VEGF-A: p = 0.036). Neither PlGF nor VEGF-A expression in non-malignant tissue were predictors for RFS. In conclusion, our results support the mutual relationship between PlGF and VEGF-A and encourage further investigations as prognostic markers in breast cancer patients.

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Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186PubMedCrossRef

Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395PubMedCrossRef

Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676PubMedCrossRef

Maglione D, Guerriero V, Viglietto G, li-Bovi P, Persico MG (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 88:9267–9271PubMedCrossRef

Fischer C, Mazzone M, Jonckx B, Carmeliet P (2008) FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 8:942–956PubMedCrossRef

Parr C, Watkins G, Boulton M, Cai J, Jiang WG (2005) Placenta growth factor is over-expressed and has prognostic value in human breast cancer. Eur J Cancer 41:2819–2827PubMedCrossRef

Escudero-Esparza A, Martin TA, Douglas-Jones A, Mansel RE, Jiang WG (2010) PGF isoforms, PLGF-1 and PGF-2 and the PGF receptor, neuropilin, in human breast cancer: prognostic significance. Oncol Rep 23:537–544PubMed

Chen CN, Hsieh FJ, Cheng YM, Cheng WF, Su YN, Chang KJ et al (2004) The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer. Cancer Lett 213:73–82PubMedCrossRef

Wei SC, Tsao PN, Yu SC, Shun CT, Tsai-Wu JJ, Wu CH et al (2005) Placenta growth factor expression is correlated with survival of patients with colorectal cancer. Gut 54:666–672PubMedCrossRef

10.

Ho MC, Chen CN, Lee H, Hsieh FJ, Shun CT, Chang CL et al (2007) Placenta growth factor not vascular endothelial growth factor A or C can predict the early recurrence after radical resection of hepatocellular carcinoma. Cancer Lett 250:237–249PubMedCrossRef

11.

Pompeo E, Albonici L, Doldo E, Orlandi A, Manzari V, Modesti A et al (2009) Placenta growth factor expression has prognostic value in malignant pleural mesothelioma. Ann Thorac Surg 88:426–431PubMedCrossRef

12.

Nagaoka S, Yoshida T, Akiyoshi J, Akiba J, Hisamoto T, Yoshida Y et al (2010) The ratio of serum placenta growth factor to soluble vascular endothelial growth factor receptor-1 predicts the prognosis of hepatocellular carcinoma. Oncol Rep 23:1647–1654PubMed

13.

Cheng SJ, Lee JJ, Kok SH, Chou CH, Chang HH, Chiang ML et al (2010) Expression of placenta growth factor: an independent factor for prediction of progression and prognosis of oral cancer. Head Neck 32:1363–1369PubMedCrossRef

14.

Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F et al (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8:831–840PubMed

15.

Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De MM et al (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583PubMedCrossRef

16.

Park JE, Chen HH, Winer J, Houck KA, Ferrara N (1994) Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 269:25646–25654PubMed

17.

Monsky WL, Fukumura D, Gohongi T, Ancukiewcz M, Weich HA, Torchilin VP et al (1999) Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res 59:4129–4135PubMed

18.

Marcellini M, De LN, Riccioni T, Ciucci A, Orecchia A, Lacal PM et al (2006) Increased melanoma growth and metastasis spreading in mice overexpressing placenta growth factor. Am J Pathol 169:643–654PubMedCrossRef

19.

Taylor AP, Leon E, Goldenberg DM (2010) Placental growth factor (PlGF) enhances breast cancer cell motility by mobilising ERK1/2 phosphorylation and cytoskeletal rearrangement. Br J Cancer 103:82–89PubMedCrossRef

20.

De FS, Gigante B, Persico MG (2002) Structure and function of placental growth factor. Trends Cardiovasc Med 12:241–246CrossRef

21.

Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269:26988–26995PubMed

22.

Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D et al (2003) Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9:936–943PubMedCrossRef

23.

Gasparini G (2000) Prognostic value of vascular endothelial growth factor in breast cancer. Oncologist 5(Suppl 1):37–44PubMedCrossRef

24.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). J Natl Cancer Inst 97:1180–1184PubMedCrossRef

25.

Elston CW and Ellis IO (2002) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. C. W. Elston & I. O. Ellis. Histopathology 1991; 19; 403–410. Histopathology 41:151–152

26.

Singletary SE, Allred C, Ashley P, Bassett LW, Berry D, Bland KI et al (2002) Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20:3628–3636PubMedCrossRef

27.

Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 131:18–43PubMed

28.

Hudis CA, Barlow WE, Costantino JP, Gray RJ, Pritchard KI, Chapman JA et al (2007) Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol 25:2127–2132PubMedCrossRef

29.

Smerdel MP, Steffensen KD, Waldstøm M, Andersen RF, Olsen DA, Brandslund I et al (2011) VEGF in the development of ovarian malignancy. Clinical Ovarian Cancer 4:19–25CrossRef

30.

Olsen DA, Ostergaard B, Bokmand S, Wamberg PA, Jakobsen EH, Brandslund I (2007) HER-2 protein concentrations in breast cancer cells increase before immunohistochemical and fluorescence in situ hybridization analysis turn positive. Clin Chem Lab Med 45:177–182PubMedCrossRef

31.

Miles DW, Chan A, Dirix LY, Cortes J, Pivot X, Tomczak P et al (2010) Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28:3239–3247PubMedCrossRef

32.

Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676PubMedCrossRef

33.

Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON et al (2011) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29:1252–1260PubMedCrossRef

34.

Yao J, Wu X, Zhuang G, Kasman IM, Vogt T, Phan V et al (2011) Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti-PlGF antibodies efficacy. Proc Natl Acad Sci USA 108:11590–11595PubMedCrossRef

35.

Lassen U, Nielsen D, Sørensen M, Rønnengart E, Eldrup K, Bentzon K et al (2009) A dose escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with solid tumors. Mol Cancer Ther. doi:10.1158/1535-7163.TARG-09-A111

36.

Martinsson-Niskanen T, Riisbro R, Larsson L, Winstedt L, Stenberg Y, Pakola S et al (2011) Monoclonal antibody TB-403: A first-in-human, phase i, double-blind, dose escalation study directed against placental growth factor in healthy male subjects. Clin Ther 33:1142–1149PubMedCrossRef

Title: Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer
Authors: Else Maae
Dorte Aalund Olsen
Karina Dahl Steffensen
Erik Hugger Jakobsen
Ivan Brandslund
Flemming Brandt Sørensen
Anders Jakobsen
Publication date: 01-05-2012
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-012-1957-0

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