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Targeting soluble CD146 with a neutralizing antibody inhibits vascularization, growth and survival of CD146-positive tumors

Oncogene volume 35, pages 5489–5500 (2016)Cite this article

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Abstract

CD146 (MUC-18, MCAM) expression on cancer cells correlates with cancer progression and a bad prognosis in several tumors, including melanoma and pancreatic tumors. Deciphering the mechanism mediating the CD146 role in cancer is essential for generating new therapeutic strategies. We found that CD146 expression in cancer cells is associated with a secretion of soluble CD146 (sCD146) that constitutes an active player in tumor development. Indeed, sCD146 induces the overexpression of its binding protein, angiomotin, on both endothelial and cancer cells and promotes both paracrine effects on angiogenesis and autocrine effects on cancer cells proliferation and survival. These last effects are mediated in part through the induction and phosphorylation of c-myc in cancer cells. In mice models xenografted with human CD146-positive melanoma or pancreatic cancer cells, administration of a novel monoclonal antibody specifically targeting sCD146, but not its membrane form, successfully suppresses tumor vascularization and growth. Our findings demonstrate that sCD146 secreted by CD146-positive tumors mediates important pro-angiogenic and pro-tumoral effects. Targeting sCD146 with a novel neutralizing antibody could thus constitute an innovative therapeutic strategy for the treatment of CD146-positive tumors.

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References

  1. Lehmann JM, Riethmüller G, Johnson JP . MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily. Proc Natl Acad Sci USA 1989; 86: 9891–9895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Luca M, Hunt B, Bucana CD, Johnson JP, Fidler IJ, Bar-Eli M . Direct correlation between MUC18 expression and metastatic potential of human melanoma cells. Melanoma Res 1993; 3: 35–41.

    Article  CAS  PubMed  Google Scholar 

  3. Feng G, Fang F, Liu C, Zhang F, Huang H, Pu C . CD146 gene expression in clear cell renal cell carcinoma: a potential marker for prediction of early recurrence after nephrectomy. Int Urol Nephrol 2012; 44: 1663–1669.

    Article  CAS  PubMed  Google Scholar 

  4. Maitra A, Hansel DE, Argani P, Ashfaq R, Rahman A, Naji A et al. Global expression analysis of well-differentiated pancreatic endocrine neoplasms using oligonucleotide microarrays. Clin Cancer Res 2003; 9: 5988–5995.

    CAS  PubMed  Google Scholar 

  5. Wu GJ, Fu P, Chiang CF, Huss WJ, Greenberg NM, Wu MW . Increased expression of MUC18 correlates with the metastatic progression of mouse prostate adenocarcinoma in the TRAMP model. J Urol 2005; 173: 1778–1783.

    Article  CAS  PubMed  Google Scholar 

  6. Zeng GF, Cai SX, Wu GJ . Up-regulation of METCAM/MUC18 promotes motility, invasion, and tumorigenesis of human breast cancer cells. BMC Cancer 2011; 11: 113–126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu WF, Ji SR, Sun JJ, Zhang Y, Liu ZY, Liang AB et al. CD146 expression correlates with epithelial-mesenchymal transition markers and a poor prognosis in gastric cancer. Int J Mol Sci 2012; 13: 6399–6406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Oka S, Uramoto H, Chikaishi Y, Tnaka F . The expression of CD146 predicts a poor overall survival in patients with adenocarcinoma of the lung. Anticancer Res 2012; 32: 861–864.

    PubMed  Google Scholar 

  9. Liu JW, Nagpal JK, Jeronimo C, Lee JE, Henrique R, Kim MS et al. Hypermethylation of MCAM gene is associated with advanced tumor stage in prostate cancer. Prostate 2008; 68: 418–426.

    Article  CAS  PubMed  Google Scholar 

  10. Zeng Q, Li W, Lu D, Wu Z, Duan H, Luo Y et al. CD146, an epithelial-mesenchymal transition inducer, is associated with triple-negative breast cancer. Proc Natl Acad Sci USA 2012; 109: 1127–1132.

    Article  CAS  PubMed  Google Scholar 

  11. Imbert AM, Garulli C, Choquet E, Koubi M, Aurrand-Lions M, Chabannon C . CD146 expression in human breast cancer cell lines induces phenotypic and functional changes observed in epithelial to mesenchymal transition. PLoS One 2012; 7: 43752.

    Article  Google Scholar 

  12. Dagur PK, Biancotto A, Stansky E, Sen HN, Nussenblatt RB, McCoy JP . Secretion of interleukin-17 by CD8+ T cells expressing CD146 (MCAM). Clin Immunol 2014; 152: 36–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shih IM . The role of CD146 (Mel-CAM) in biology and pathology. J Pathol 1999; 189: 4–11.

    Article  CAS  PubMed  Google Scholar 

  14. Anfosso F, Bardin N, Francès V, Vivier E, Camoin-Jau L, Sampol J et al. Activation of human endothelial cells via S-endo-1 antigen (CD146) stimulates the tyrosine phosphorylation of focal adhesion kinase p125(FAK). J Biol Chem 1998; 273: 26852–26856.

    Article  CAS  PubMed  Google Scholar 

  15. Anfosso F, Bardin N, Vivier E, Sabatier F, Sampol J, Dignat-George F . Outside-in signaling pathway linked to CD146 engagement in human endothelial cells. J Biol Chem 2001; 276: 1564–1569.

    Article  CAS  PubMed  Google Scholar 

  16. Bardin N, Anfosso F, Masse JM, Cramer E, Sabatier F, Le Bivic A et al. Identification of CD146 as a component of the endothelial junction involved in the control of cell-cell cohesion. Blood 2001; 98: 3677–3684.

    Article  CAS  PubMed  Google Scholar 

  17. Bardin N, Blot-Chabaud M, Despoix N, Kebir A, Harhouri K, Arsanto JP et al. CD146 and its soluble form regulate monocyte transendothelial migration. Arterioscler Thromb Vasc Biol 2009; 29: 746–753.

    Article  CAS  PubMed  Google Scholar 

  18. Kebir A, Harhouri K, Guillet B, Liu JW, Foucault-Bertaud A, Lamy E et al. CD146 short isoform increases the proangiogenic potential of endothelial progenitor cells in vitro and in vivo. Circ Res 2010; 107: 66–75.

    Article  CAS  PubMed  Google Scholar 

  19. Bardin N, Francès V, Combes V, Sampol J, Dignat-George F . CD146: biosynthesis and production of a soluble form in human cultured endothelial cells. FEBS Lett 1998; 421: 12–14.

    Article  CAS  PubMed  Google Scholar 

  20. Bardin N, Moal V, Anfosso F, Daniel L, Brunet P, Sampol J et al. Soluble CD146, a novel endothelial marker, is increased in physiopathological settings linked to endothelial junctional alteration. Thromb Haemost 2003; 90: 915–920.

    Article  CAS  PubMed  Google Scholar 

  21. Ilie M, Long E, Hofman V, Selva E, Bonnetaud C, Boyer J et al. Clinical value of circulating endothelial cells and of soluble CD146 levels in patients undergoing surgery for non-small cell lung cancer. Br J Cancer 2014; 110: 1236–1243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Harhouri K, Kebir A, Guillet B, Foucault-Bertaud A, Voytenko S, Piercecchi-Marti MD et al. Soluble CD146 displays angiogenic properties and promotes neovascularization in experimental hind-limb ischemia. Blood 2010; 115: 3843–3851.

    Article  CAS  PubMed  Google Scholar 

  23. Stalin J, Harhouri K, Hubert L, Subrini C, Lafitte D, Lissitzky JC et al. Soluble melanoma cell adhesion molecule (sMCAM/sCD146) promotes angiogenic effects on endothelial progenitor cells through angiomotin. J Biol Chem 2013; 288: 8991–9000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Roudier E, Chapados N, Decary S, Gineste C, Le Bel C, Lavoie JM et al. Angiomotin p80/p130 ratio: a new indicator of exercise-induced angiogenic activity in skeletal muscles from obese and non-obese rats? J Physiol 2009; 587: 4105–4119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jiang WG, Watkins G, Douglas-Jones A, Holmgren L, Mansel RE . Angiomotin and angiomotin like proteins, their expression and correlation with angiogenesis and clinical outcome in human breast cancer. BMC Cancer 2006; 6: 16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Satchi-Fainaro R, Ferber S, Segal E, Ma L, Dixit N, Ijaz A et al. Prospective identification of glioblastoma cells generating dormant tumors. PLoS One 2012; 7: 44395.

    Article  Google Scholar 

  27. Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q et al. Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev 2011; 25: 51–63.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wu GJ, Varma VA, Wu MW, Wang SW, Qu P, Yang H et al. Expression of a human cell adhesion molecule, MUC18, in prostate cancer cell lines and tissues. Prostate 2001; 48: 305–315.

    Article  CAS  PubMed  Google Scholar 

  29. Zabouo G, Imbert AM, Jacquemier J, Finetti P, Moreau T, Esterni B et al. CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines. Breast Cancer Res 2009; 11: 1–14.

    Article  Google Scholar 

  30. Ben-Baruch A . The multifaceted roles of chemokines in malignancy. Cancer Metastasis Rev 2006; 25: 357–371.

    Article  CAS  PubMed  Google Scholar 

  31. Raman D, Baugher PJ, Thu YM, Richmond A . Role of chemokines in tumor growth. Cancer Lett 2007; 256: 137–165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mao B, Zhao G, Lv X, Chen HZ, Xue Z, Yang B et al. Sirt1 deacetylates c-Myc and promotes c-Myc/Max association. Int J Biochem Cell Biol 2011; 43: 1573–1581.

    Article  CAS  PubMed  Google Scholar 

  33. Mizukami Y, Fujiki K, Duerr EM, Gala M, Jo WS, Zhang X et al. Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc. J Biol Chem 2006; 281: 13957–13963.

    Article  CAS  PubMed  Google Scholar 

  34. Senger DR, Perruzzi CA, Feder J, Dvorak HF . A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res 1986; 46: 5629–5632.

    CAS  PubMed  Google Scholar 

  35. Shojaei F, Ferrara N . Antiangiogenic therapy for cancer: an update. Cancer J 2007a; 13: 345–348.

    Article  CAS  PubMed  Google Scholar 

  36. Shojaei F, Ferrara N . Antiangiogenesis to treat cancer and intraocular neovascular disorders. Lab Invest 2007b; 87: 227–230.

    Article  CAS  PubMed  Google Scholar 

  37. Folkman J . Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 2007; 6: 273–286.

    Article  CAS  PubMed  Google Scholar 

  38. Ma WW, Adjei AA . Novel agents on the horizon for cancer therapy. CA Cancer J Clin 2009; 59: 111–137.

    Article  PubMed  Google Scholar 

  39. Salgaller ML . Technology evaluation: bevacizumab, Genentech/Roche. Curr Opin Mol Ther 2003; 5: 657–667.

    CAS  PubMed  Google Scholar 

  40. Gerber HP, Ferrara N . Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 2005; 65: 671–680.

    CAS  PubMed  Google Scholar 

  41. Ellis LM, Hicklin DJ . VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 2008; 8: 579–591.

    Article  CAS  PubMed  Google Scholar 

  42. Rosenfeld PJ, Brown D, Heier JS, Boyer DS, Kaiser PK, Chung CY et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419–1431.

    Article  CAS  PubMed  Google Scholar 

  43. Ueno S, Pease ME, Wersinger DM, Masuda T, Vinores SA, Licht T et al. Prolonged blockade of VEGF family members does not cause identifiable damage to retinal neurons or vessels. J Cell Physiol 2008; 217: 13–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dorrell MI, Aguilar E, Scheppke L, Barnett FH, Friedlander M . Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Proc Natl Acad Sci U S A 2007; 104: 967–972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bergers G, Hanahan D . Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008; 8: 592–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chen HX, Cleck JN . Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 2009; 6: 465–477.

    Article  CAS  PubMed  Google Scholar 

  47. Gomes FG, Nedel F, Alves AM, Nör JE, Tarquinio SB . Tumor angiogenesis and lymphangiogenesis: tumor/endothelial crosstalk and cellular/microenvironmental signaling mechanisms. Life Sci 2013; 92: 101–107.

    Article  CAS  PubMed  Google Scholar 

  48. Aulakh GK, Balachandran Y, Liu L, Singh B . Angiostatin inhibits activation and migration of neutrophils. Cell Tissue Res 2014; 355: 375–396.

    Article  CAS  PubMed  Google Scholar 

  49. Mills L, Tellez C, Huang S, Baker C, McCarty M, Green L et al. Fully human antibodies to MCAM/MUC18 inhibit tumor growth and metastasis of human melanoma. Cancer Res 2002; 62: 5106–5114.

    CAS  PubMed  Google Scholar 

  50. Yan X, Lin Y, Yang D, Shen Y, Yuan M, Zhang Z et al. A novel anti-CD146 monoclonal antibody, AA98, inhibits angiogenesis and tumor growth. Blood 2003; 102: 184–191.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Biocytex company (Marseille, France) for rsCD146, CD146 Elisa and S-Endo-1 antibody. We thank E Mas, G Pommier, N Alfaidy and D Lombardo for providing us with several cell lines. This study was financed by grants from Inserm, Aix-Marseille University and ANR. Jimmy Stalin was financed by grants from Region Provence-Alpes-Côte d’Azur, FRM and Martine Midy Fundation.

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Authors and Affiliations

  1. INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France

    J Stalin, M Nollet, P Garigue, L Vivancos, A Essaadi, A Muller, R Bachelier, A Foucault-Bertaud, A S Leroyer, N Bardin, B Guillet, F Dignat-George & M Blot-Chabaud

  2. CERIMED (European Center of Research in Medical Imaging), Aix-Marseille University, Marseille, France

    P Garigue, S Fernandez & B Guillet

  3. Advanced Accelerator Applications SRL, Colleretto Giacosa (TO), Italy

    L Fugazza

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  1. J Stalin
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Correspondence to M Blot-Chabaud.

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Stalin, J., Nollet, M., Garigue, P. et al. Targeting soluble CD146 with a neutralizing antibody inhibits vascularization, growth and survival of CD146-positive tumors. Oncogene 35, 5489–5500 (2016). https://doi.org/10.1038/onc.2016.83

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