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Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development


Milk fat globule—epidermal growth factor—factor VIII (MFGE8), also called lactadherin or SED1, is a secreted integrin-binding protein that promotes elimination of apoptotic cells by phagocytes leading to tolerogenic immune responses, and vascular endothelial growth factor (VEGF)-induced angiogenesis: two important processes for cancer development. Here, by transcriptomic analysis of 228 biopsies of bladder carcinomas, we observed overexpression of MFGE8 during tumor development, correlated with expression of genes involved in cell adhesion or migration and in immune responses, but not in VEGF-mediated angiogenesis. To test whether MFGE8 expression was instrumental in bladder tumor development, or a simple consequence of this development, we used genetic ablation in a mouse model of carcinogen-induced bladder carcinoma. We showed that Mfge8 was also upregulated in mouse carcinoma, and that in its absence, Mfge8-deficient animals developed less advanced tumors. Angiogenesis was similar in carcinogen-treated Mfge8-expressing or -deficient bladders, thus ruling out a major role of the proangiogenic function of Mfge8 for its protumoral role. By contrast, the tumor-promoting role of Mfge8 was not observed anymore in mice devoid of adaptive immune system, and human tumors overexpressing MFGE8 where invaded with macrophages and regulatory T cells, thus suggesting that MFGE8/lactadherin favors development of bladder tumors at least partly by an immune system-dependent mechanism. Our observations suggest future use of MFGE8-inhibiting molecules as therapies of bladder carcinomas, and of a limited number of other human cancers, in which our analysis of public databases also revealed overexpression of MFGE8.

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N-butyl-N-(4-hydroxybutyl) nitrosamine


Bacillus Calmette-Guérin


extracellular matrix


milk fat globule-epidermal growth factor-factor VIII


pathologic tumor node metastasis classification


significance analysis of microarrays


regulatory T cells


muscle-invasive tumors


non-muscle-invasive tumors


vascular endothelial growth factor


von Willebrand Factor


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We thank Drs A-C Baglin and Y Denoux (Tumorothèque, Service d'Anatomie et Cytologie Pathologiques, CMC Foch, Suresnes, France), Dr M-J Terrier-Lacombe (Service de Pathologie, Institut Gustave Roussy, Villejuif, France), and Professor K Leroy (Plateforme de Ressources Biologiques, Pôle de Recherche Clinique, APHP, Hôpital Henri Mondor, Créteil, France) for providing tumor samples. Microbiochips SAS (Paris, France) performed and analyzed antibody microarray hybridizations. This work would not have been possible without the expertise of the Animal Facility and of the Nikon Imaging Center at Institut Curie. We thank S Barrafato and F Valenty (mouse histology), K Zemplenyi (ultrasound analyses), E Chapeaublanc (preparation of Supplementary tables), B Asselain and A Savignoni (statistics) for their help, and V Soumelis, H Kitamura and JW Pollard for critical reading of the manuscript. This work was supported by grants from Association pour la Recherche Contre le Cancer and Fondation de France ‘Impulsion’ program (CT), La Ligue Nationale Contre le Cancer (FR: équipe labellisée), and the program ‘Carte d'Identité des Tumeurs’, initiated, developed and funded by Ligue Nationale Contre le Cancer. GS was a fellow from Ministére de la Recherche et des Technologies.

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Sugano, G., Bernard-Pierrot, I., Laé, M. et al. Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development. Oncogene 30, 642–653 (2011).

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  • MFGE8
  • lactadherin
  • bladder carcinoma
  • tumor microenvironment
  • immune response

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