Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer

详细信息    查看全文

• 作者：Martin P Barr (1)
  Steven G Gray (1)
  Kathy Gately (1)
  Emily Hams (2)
  Padraic G Fallon (2)
  Anthony Mitchell Davies (3)
  Derek J Richard (4)
  Graham P Pidgeon (5)
  Kenneth J O鈥橞yrne (1) (4)
  
  1. Thoracic Oncology Research Group ; School of Clinical Medicine ; Institute of Molecular Medicine ; Trinity Centre for Health Sciences ; St. James鈥檚 Hospital & Trinity College Dublin ; Dublin ; Ireland
  2. School of Medicine ; Trinity Biomedical Sciences Institute ; Trinity College Dublin ; Dublin ; Ireland
  3. Irish National Centre for High Content Screening & Analysis ; School of Clinical Medicine ; Trinity College Dublin ; Dublin ; Ireland
  4. Cancer & Ageing Research Program ; Queensland University of Technology ; Brisbane ; Australia
  5. Department of Surgery ; Institute of Molecular Medicine ; St James鈥檚 Hospital & Trinity College Dublin ; Dublin ; Ireland
  
• 关键词：NSCLC ; VEGF ; Neuropilins ; Survival ; Cell signaling
• 刊名：Molecular Cancer
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：14
• 期：1
• 全文大小：2,982 KB
• 参考文献：1. Hicklin, DJ, Ellis, LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23: pp. 1011-27 CrossRef
  2. Kawakami, T, Tokunaga, T, Hatanaka, H, Kijima, H, Yamazaki, H, Abe, Y (2002) Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in non small cell lung carcinoma. Cancer 95: pp. 2196-201 CrossRef
  3. Hong, TM, Chen, YL, Wu, YY, Yuan, A, Chao, YC, Chung, YC (2007) Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res 13: pp. 4759-68 CrossRef
  4. Sandler, A, Gray, R, Perry, MC, Brahmer, J, Schiller, JH, Dowlati, A (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355: pp. 2542-50 CrossRef
  5. Soria, JC, Mauguen, A, Reck, M, Sandler, AB, Saijo, N, Johnson, DH (2013) Meta-analysis of Bevacizumab in advanced NSCLC collaborative group. Systematic review and meta-analysis of randomised, phase II/III trials adding Bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 24: pp. 20-30 CrossRef
  6. Liang W, Zhang L. Multi-targeted antiangiogenic tyrosine kinase inhibitors in advanced non-small cell lung cancer: A meta-analysis of randomized controlled trials. / J Clin Oncol 2013, 31: Suppl; abstract 8089.
  7. Cutsem, E, Haas, S, Kang, K, Ohtsu, A, Tebbutt, NC, Ming Xu, J (2012) Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol 30: pp. 2119-27 CrossRef
  8. O鈥橞yrne, KJ, Koukourakis, MI, Giatromanolaki, A, Cox, G, Turley, H, Steward, WP (2000) Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer. Br J Cancer 82: pp. 1427-32 CrossRef
  9. Soker, S, Miao, HQ, Nomi, M, Takashima, S, Klagsbrun, M (2002) VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. J Cell Biochem 85: pp. 357-68 CrossRef
  10. Soker, S, Takashima, S, Miao, HQ, Neufeld, G, Klagsbrun, M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92: pp. 735-45 CrossRef
  11. Gluzman-Poltorak, Z, Cohen, T, Shibuya, M, Neufeld, G (2001) Vascular endothelial growth factor receptor-1 and neuropilin-2 form complexes. J Biol Chem 276: pp. 18688-94 CrossRef
  12. Pan, Q, Chathery, Y, Wu, Y, Rathore, N, Tong, RK, Peale, F (2007) Neuropilin-1 binds to VEGF121 and regulates endothelial cell migration and sprouting. J Biol Chem 282: pp. 24049-56 CrossRef
  13. Cai, H, Reed, RR (1999) Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1. J Neurosci 19: pp. 6519-27
  14. Pan, Q, Chanthery, Y, Liang, WC, Stawicki, S, Mak, J, Rathore, N (2007) Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11: pp. 53-67 CrossRef
  15. Gagnon, ML, Bielenberg, DR, Gechtman, Z, Miao, HQ, Takashima, S, Soker, S (2000) 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 97: pp. 2573-8 CrossRef
  16. Hansel, DE, Wilentz, RE, Yeo, CJ, Schulick, RD, Montgomery, E, Maitra, A (2004) Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract. Am J Surg Pathol 28: pp. 347-56 CrossRef
  17. Baba, T, Kariya, M, Higuchi, T, Mandai, M, Matsumura, N, Kondoh, E (2007) Neuropilin-1 promotes unlimited growth of ovarian cancer by evading contact inhibition. Gynecol Oncol 105: pp. 703-11 CrossRef
  18. Castro-Rivera, E, Ran, S, Thorpe, P, Minna, JD (2004) Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonises this effect. Proc Natl Acad Sci USA 101: pp. 11432-7 CrossRef
  19. Mercurio, AM, Lipscomb, EA, Bachelder, RE (2005) Non-angiogenic functions of VEGF in breast cancer. J Mammary Gland Biol Neoplasia 10: pp. 283-90 CrossRef
  20. Bachelder, RE, Crago, A, Chung, J, Wendt, MA, Shaw, LM, Robinson, G (2001) Vascular endothelial growth factor is an autocrine survival factor for neuropilin- expressing breast carcinoma cells. Cancer Res 61: pp. 5736-40
  21. Barr, MP, Byrne, AM, Duffy, AM, Condron, CM, Devocelle, M, Harriott, P (2005) A peptide corresponding to the neuropilin-1-binding site on VEGF(165) induces apoptosis of neuropilin-1-expressing breast tumour cells. Br J Cancer 92: pp. 328-33
  22. Bachelder, RE, Lipscomb, EA, Lin, X, Wendt, MA, Chadborn, NH, Eickholt, BJ (2003) Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Res 63: pp. 5230-3
  23. Cao, Y, Wang, L, Nandy, D, Zhang, Y, Basu, A, Radisky, D (2008) Neuropilin-1 upholds dedifferentiation and propagation phenotypes of renal cell carcinoma cells by activating Akt and sonic hedgehog axes. Cancer Res 68: pp. 8667-72 CrossRef
  24. Wey, JS, Gray, MJ, Fan, F, Belcheva, A, McCarty, MF, Stoeltzing, O (2005) Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells. Br J Cancer 93: pp. 233-41 CrossRef
  25. Wu, D, Zhau, HE, Huang, WC, Iqbal, S, Habib, FK, Sartor, O (2007) cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis. Oncogene 26: pp. 5070-7 CrossRef
  26. Hamerlik, P, Lathia, JD, Rasmussen, R, Wu, Q, Bartkova, J, Lee, M (2012) Autocrine VEGF-VEGFR2-Neuropilin-1 signalling promotes glioma stem-like cell viability and tumor growth. J Exp Med 209: pp. 507-20 CrossRef
  27. Beck, B, Driessens, G, Goossens, S, Youssef, KK, Kuchnio, A, Caauwe, A (2011) A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478: pp. 399-403 CrossRef
  28. Jubb, AM, Strickland, LA, Liu, SD, Mak, J, Schmidt, M, Koeppen, H (2012) Neuropilin-1 expression in cancer and development. J Pathol 226: pp. 50-60 CrossRef
  29. Lu, Y, Xiang, H, Liu, P, Tong, RR, Watts, RJ, Koch, AW (2009) Identification of circulating neuropilin-1 and dose-dependent elevation following antineuropilin-1 antibody administration. MAbs 1: pp. 364-9 CrossRef
  
• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

Background The VEGF pathway has become an important therapeutic target in lung cancer, where VEGF has long been established as a potent pro-angiogenic growth factor expressed by many types of tumors. While Bevacizumab (Avastin) has proven successful in increasing the objective tumor response rate and in prolonging progression and overall survival in patients with NSCLC, the survival benefit is however relatively short and the majority of patients eventually relapse. The current use of tyrosine kinase inhibitors alone and in combination with chemotherapy has been underwhelming, highlighting an urgent need for new targeted therapies. In this study, we examined the mechanisms of VEGF-mediated survival in NSCLC cells and the role of the Neuropilin receptors in this process. Methods NSCLC cells were screened for expression of VEGF and its receptors. The effects of recombinant VEGF and its blockade on lung tumor cell proliferation and cell cycle were examined. Phosphorylation of Akt and Erk1/2 proteins was examined by high content analysis and confocal microscopy. The effects of silencing VEGF on cell proliferation and survival signaling were also assessed. A Neuropilin-1 stable-transfected cell line was generated. Cell growth characteristics in addition to pAkt and pErk1/2 signaling were studied in response to VEGF and its blockade. Tumor growth studies were carried out in nude mice following subcutaneous injection of NP1 over-expressing cells. Results Inhibition of the VEGF pathway with anti-VEGF and anti-VEGFR-2 antibodies or siRNA to VEGF, NP1 and NP2 resulted in growth inhibition of NP1 positive tumor cell lines associated with down-regulation of PI3K and MAPK kinase signaling. Stable transfection of NP1 negative cells with NP1 induced proliferation in vitro, which was further enhanced by exogenous VEGF. In vivo, NP1 over-expressing cells significantly increased tumor growth in xenografts compared to controls. Conclusions Our data demonstrate that VEGF is an autocrine growth factor in NSCLC signaling, at least in part, through NP1. Targeting this VEGF receptor may offer potential as a novel therapeutic approach and also support the evaluation of the role of NP1 as a biomarker predicting sensitivity or resistance to VEGF and VEGFR-targeted therapies in the clinical arena.