Skip to main content
Top
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Breast Cancer | Research

Neuropilin-1 and placental growth factor as prognostic factors in metastatic breast cancer

Authors: Niina Mäenpää, Leena Tiainen, Mari Hämäläinen, Tiina Luukkaala, Minna Tanner, Outi Lahdenperä, Pia Vihinen, Peeter Karihtala, Pirkko-Liisa Kellokumpu-Lehtinen, Eeva Moilanen, Arja Jukkola

Published in: BMC Cancer | Issue 1/2024

Login to get access

Abstract

Background

Angiogenesis is crucial for tumor development, progression, and metastasizing. The most important regulator of angiogenesis is the vascular endothelial growth factor (VEGF) family, which is involved in multiple pathways in tumor microenvironment. The objective of this study was to investigate the prognostic value of the VEGF family in patients treated for metastatic breast cancer. The emphasis was on neuropilin-1 (NRP-1) and placental growth factor (PlGF).

Materials and methods

An analysis of eight members of the VEGF family was performed using baseline plasma samples of 65 patients treated for metastatic HER2 negative breast cancer in a phase II first-line bevacizumab plus chemotherapy trial. The patients were divided into two groups, high or low, according to the median for each VEGF family member. Progression-free survival (PFS) and overall survival (OS) were determined for each VEGF family member.

Results

The patients with low plasma levels of NRP-1 and PlGF had a longer OS than those with high plasma levels [multivariable adjusted hazard ratios (HRs) 2.54 (95% confidence interval (CI) 1.11–5.82, p = 0.02) and 3.11 (95% CI 1.30–7.47, p = 0.01), respectively]. The patients with low levels of both NRP-1 and PlGF had a remarkably long OS with HR of 6.24, (95% CI 1.97–19.76, p = 0.002). In addition, high baseline NRP-1 level was associated with a significantly shorter PFS [multivariable adjusted HR 2.90 (95% CI 1.02–8.28, p = 0.04)] than that in the low-level group, and a high baseline vascular endothelial growth factor receptor-2 level was associated with a longer PFS [multivariable adjusted HR 0.43 (95% CI 0.19–0.98, p = 0.04)].

Conclusion

Especially NRP-1 and PlGF have prognostic potential in metastatic breast cancer patients treated with a bevacizumab-taxane combination. Patients with low plasma levels of NRP-1 or PlGF have longer OS than patients with high levels. Patients with both low NRP-1 and PlGF levels appear to have excellent long-term survival.

Trial registration

ClinicalTrials.gov identifier: NCT00979641, registration date 18/09/2009. The regional Ethics Committee: R08142M, registration date 18/11/2008.
Literature
1.
go back to reference Hoff PM, Machado KK. Role of angiogenesis in the pathogenesis of cancer. Cancer Treat Rev. 2012;38(7):825–33.CrossRefPubMed Hoff PM, Machado KK. Role of angiogenesis in the pathogenesis of cancer. Cancer Treat Rev. 2012;38(7):825–33.CrossRefPubMed
4.
go back to reference Bielenberg DR, Pettaway CA, Takashima S, Klagsbrun M. Neuropilins in neoplasms: expression, regulation, and function. Exp Cell Res. 2006;312(5):584–93.CrossRefPubMed Bielenberg DR, Pettaway CA, Takashima S, Klagsbrun M. Neuropilins in neoplasms: expression, regulation, and function. Exp Cell Res. 2006;312(5):584–93.CrossRefPubMed
5.
go back to reference Niland S, Eble JA, Neuropilin. Handyman and Power Broker in the Tumor Microenvironment. Adv Exp Med Biol. 2020;1223:31–67.CrossRefPubMed Niland S, Eble JA, Neuropilin. Handyman and Power Broker in the Tumor Microenvironment. Adv Exp Med Biol. 2020;1223:31–67.CrossRefPubMed
6.
go back to reference Gagnon ML, Bielenberg DR, Gechtman Z, Miao HQ, Takashima S, Soker S, et al. Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: in vivo expression and antitumor activity. Proc Natl Acad Sci U S A. 2000;97(6):2573–8.ADSCrossRefPubMedPubMedCentral Gagnon ML, Bielenberg DR, Gechtman Z, Miao HQ, Takashima S, Soker S, et al. Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: in vivo expression and antitumor activity. Proc Natl Acad Sci U S A. 2000;97(6):2573–8.ADSCrossRefPubMedPubMedCentral
7.
go back to reference Rossignol M, Gagnon ML, Klagsbrun M. Genomic organization of human neuropilin-1 and neuropilin-2 genes: identification and distribution of splice variants and soluble isoforms. Genomics. 2000;70(2):211–22.CrossRefPubMed Rossignol M, Gagnon ML, Klagsbrun M. Genomic organization of human neuropilin-1 and neuropilin-2 genes: identification and distribution of splice variants and soluble isoforms. Genomics. 2000;70(2):211–22.CrossRefPubMed
8.
go back to reference Albonici L, Giganti MG, Modesti A, Manzari V, Bei R. Multifaceted role of the placental growth factor (PlGF) in the Antitumor Immune Response and Cancer Progression. Int J Mol Sci. 2019;20(12). Albonici L, Giganti MG, Modesti A, Manzari V, Bei R. Multifaceted role of the placental growth factor (PlGF) in the Antitumor Immune Response and Cancer Progression. Int J Mol Sci. 2019;20(12).
9.
go back to reference Maae E, Olsen DA, Steffensen KD, Jakobsen EH, Brandslund I, Sørensen FB, et al. Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer. Breast Cancer Res Treat. 2012;133(1):257–65.CrossRefPubMed Maae E, Olsen DA, Steffensen KD, Jakobsen EH, Brandslund I, Sørensen FB, et al. Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer. Breast Cancer Res Treat. 2012;133(1):257–65.CrossRefPubMed
10.
go back to reference Parr C, Watkins G, Boulton M, Cai J, Jiang WG. Placenta growth factor is over-expressed and has prognostic value in human breast cancer. Eur J Cancer. 2005;41(18):2819–27.CrossRefPubMed Parr C, Watkins G, Boulton M, Cai J, Jiang WG. Placenta growth factor is over-expressed and has prognostic value in human breast cancer. Eur J Cancer. 2005;41(18):2819–27.CrossRefPubMed
11.
go back to reference Dewerchin M, Carmeliet P. PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb Perspect Med. 2012;2(8). Dewerchin M, Carmeliet P. PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb Perspect Med. 2012;2(8).
12.
go back to reference Tiainen L, Tanner M, Lahdenperä O, Vihinen P, Jukkola A, Karihtala P, et al. Bevacizumab Combined with Docetaxel or Paclitaxel as First-line treatment of HER2-negative metastatic breast Cancer. Anticancer Res. 2016;36(12):6431–8.CrossRefPubMed Tiainen L, Tanner M, Lahdenperä O, Vihinen P, Jukkola A, Karihtala P, et al. Bevacizumab Combined with Docetaxel or Paclitaxel as First-line treatment of HER2-negative metastatic breast Cancer. Anticancer Res. 2016;36(12):6431–8.CrossRefPubMed
13.
go back to reference Tiainen L, Korhonen EA, Leppänen V-M, Luukkaala T, Hämäläinen M, Tanner M, et al. High baseline Tie1 level predicts poor survival in metastatic breast cancer. BMC Cancer. 2019;19(1):732.CrossRefPubMedPubMedCentral Tiainen L, Korhonen EA, Leppänen V-M, Luukkaala T, Hämäläinen M, Tanner M, et al. High baseline Tie1 level predicts poor survival in metastatic breast cancer. BMC Cancer. 2019;19(1):732.CrossRefPubMedPubMedCentral
14.
go back to reference Cechova M, Chocholaty M, Babjuk M, Zima T, Havlova K, Koldova M, et al. Diagnostic and prognostic value of placental growth factor serum concentration in clear cell renal cell carcinoma. Czechoslov: Biomed Pap Med Fac Univ Palacky, Olomouc; 2021.CrossRef Cechova M, Chocholaty M, Babjuk M, Zima T, Havlova K, Koldova M, et al. Diagnostic and prognostic value of placental growth factor serum concentration in clear cell renal cell carcinoma. Czechoslov: Biomed Pap Med Fac Univ Palacky, Olomouc; 2021.CrossRef
15.
go back to reference Cheng S-J, Lee J-J, Cheng S-L, Chen H-M, Chang H-H, Wang Y-P, et al. Increased serum placenta growth factor level is significantly associated with progression, recurrence and poor prognosis of oral squamous cell carcinoma. Oral Oncol. 2012;48(5):424–8.CrossRefPubMed Cheng S-J, Lee J-J, Cheng S-L, Chen H-M, Chang H-H, Wang Y-P, et al. Increased serum placenta growth factor level is significantly associated with progression, recurrence and poor prognosis of oral squamous cell carcinoma. Oral Oncol. 2012;48(5):424–8.CrossRefPubMed
16.
go back to reference Escudero-Esparza A, Martin TA, Douglas-Jones A, Mansel RE, Jiang WG. PGF isoforms, PLGF-1 and PGF-2 and the PGF receptor, neuropilin, in human breast cancer: prognostic significance. Oncol Rep. 2010;23(2):537–44.PubMed Escudero-Esparza A, Martin TA, Douglas-Jones A, Mansel RE, Jiang WG. PGF isoforms, PLGF-1 and PGF-2 and the PGF receptor, neuropilin, in human breast cancer: prognostic significance. Oncol Rep. 2010;23(2):537–44.PubMed
17.
go back to reference Meng Q, Duan P, Li L, Miao Y. Expression of Placenta Growth factor is Associated with unfavorable prognosis of Advanced-Stage Serous Ovarian Cancer. Tohoku J Exp Med. 2018;244(4):291–6.CrossRefPubMed Meng Q, Duan P, Li L, Miao Y. Expression of Placenta Growth factor is Associated with unfavorable prognosis of Advanced-Stage Serous Ovarian Cancer. Tohoku J Exp Med. 2018;244(4):291–6.CrossRefPubMed
18.
go back to reference Zhang Y, Liu P, Jiang Y, Dou X, Yan J, Ma C, et al. High expression of Neuropilin-1 associates with unfavorable clinicopathological features in Hepatocellular Carcinoma. Pathol Oncol Res. 2016;22(2):367–75.CrossRefPubMed Zhang Y, Liu P, Jiang Y, Dou X, Yan J, Ma C, et al. High expression of Neuropilin-1 associates with unfavorable clinicopathological features in Hepatocellular Carcinoma. Pathol Oncol Res. 2016;22(2):367–75.CrossRefPubMed
19.
go back to reference Rachner TD, Kasimir-Bauer S, Goebel A, Erdmann K, Hoffmann O, Rauner M et al. Soluble Neuropilin-1 is an independent marker of poor prognosis in early breast cancer. J Cancer Res Clin Oncol. 2021. Rachner TD, Kasimir-Bauer S, Goebel A, Erdmann K, Hoffmann O, Rauner M et al. Soluble Neuropilin-1 is an independent marker of poor prognosis in early breast cancer. J Cancer Res Clin Oncol. 2021.
20.
go back to reference Naik A, Al-Zeheimi N, Bakheit CS, Al Riyami M, Al Jarrah A, Al Moundhri MS, et al. Neuropilin-1 Associated molecules in the blood distinguish poor prognosis breast Cancer: a cross-sectional study. Sci Rep. 2017;7(1):3301.ADSCrossRefPubMedPubMedCentral Naik A, Al-Zeheimi N, Bakheit CS, Al Riyami M, Al Jarrah A, Al Moundhri MS, et al. Neuropilin-1 Associated molecules in the blood distinguish poor prognosis breast Cancer: a cross-sectional study. Sci Rep. 2017;7(1):3301.ADSCrossRefPubMedPubMedCentral
21.
go back to reference Wang H, Zhang YN, Xu DQ, Huang JG, Lv D, Shi XY, et al. Neuropilin1, a novel independent prognostic factor and therapeutic target in triple-negative breast cancer. Neoplasma. 2020;67(6):1335–42.CrossRefPubMed Wang H, Zhang YN, Xu DQ, Huang JG, Lv D, Shi XY, et al. Neuropilin1, a novel independent prognostic factor and therapeutic target in triple-negative breast cancer. Neoplasma. 2020;67(6):1335–42.CrossRefPubMed
22.
go back to reference Al-Zeheimi N, Naik A, Bakheit CS, Al Riyami M, Al Ajarrah A, Al Badi S, et al. Neoadjuvant Chemotherapy alters Neuropilin-1, PlGF, and SNAI1 expression levels and predicts breast Cancer patients response. Front Oncol. 2019;9:323.CrossRefPubMedPubMedCentral Al-Zeheimi N, Naik A, Bakheit CS, Al Riyami M, Al Ajarrah A, Al Badi S, et al. Neoadjuvant Chemotherapy alters Neuropilin-1, PlGF, and SNAI1 expression levels and predicts breast Cancer patients response. Front Oncol. 2019;9:323.CrossRefPubMedPubMedCentral
23.
go back to reference Rizzolio S, Cagnoni G, Battistini C, Bonelli S, Isella C, Van Ginderachter JA, et al. Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies. J Clin Invest. 2018;128(9):3976–90.CrossRefPubMedPubMedCentral Rizzolio S, Cagnoni G, Battistini C, Bonelli S, Isella C, Van Ginderachter JA, et al. Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies. J Clin Invest. 2018;128(9):3976–90.CrossRefPubMedPubMedCentral
24.
go back to reference Pan Q, Chanthery Y, Liang W-C, Stawicki S, Mak J, Rathore N, et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell. 2007;11(1):53–67.CrossRefPubMed Pan Q, Chanthery Y, Liang W-C, Stawicki S, Mak J, Rathore N, et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell. 2007;11(1):53–67.CrossRefPubMed
25.
go back to reference Jubb AM, Harris AL. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol. 2010;11(12):1172–83.CrossRefPubMed Jubb AM, Harris AL. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol. 2010;11(12):1172–83.CrossRefPubMed
26.
go back to reference Miles DW, de Haas SL, Dirix LY, Romieu G, Chan A, Pivot X, et al. Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer. Br J Cancer. 2013;108(5):1052–60.CrossRefPubMedPubMedCentral Miles DW, de Haas SL, Dirix LY, Romieu G, Chan A, Pivot X, et al. Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer. Br J Cancer. 2013;108(5):1052–60.CrossRefPubMedPubMedCentral
27.
go back to reference Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol. 2013;14(10):933–42.CrossRefPubMed Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol. 2013;14(10):933–42.CrossRefPubMed
Metadata
Title
Neuropilin-1 and placental growth factor as prognostic factors in metastatic breast cancer
Authors
Niina Mäenpää
Leena Tiainen
Mari Hämäläinen
Tiina Luukkaala
Minna Tanner
Outi Lahdenperä
Pia Vihinen
Peeter Karihtala
Pirkko-Liisa Kellokumpu-Lehtinen
Eeva Moilanen
Arja Jukkola
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-024-12070-7

Other articles of this Issue 1/2024

BMC Cancer 1/2024 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine