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

Oncogene volume 30, pages 642–653 (2011)Cite this article

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Abstract

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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Abbreviations

BBN:

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

BCG:

Bacillus Calmette-Guérin

ECM:

extracellular matrix

MFGE8:

milk fat globule-epidermal growth factor-factor VIII

pTNM:

pathologic tumor node metastasis classification

SAM:

significance analysis of microarrays

Tregs:

regulatory T cells

MIT:

muscle-invasive tumors

NMIT:

non-muscle-invasive tumors

VEGF:

vascular endothelial growth factor

vWF:

von Willebrand Factor

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Acknowledgements

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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Author notes

  1. N Stransky

    Present address: 14Present address: Broad Institute of MIT and Harvard, 7 Cambridge center, Cambridge, MA 02142, USA.,

  2. G Sugano and I Bernard-Pierrot: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut Curie Research Center, Paris, France

    G Sugano, I Bernard-Pierrot, C Battail, N Stransky, S Krumeich, M-L Lepage, S Amigorena, F Radvanyi & C Théry

  2. INSERM U932, Paris, France

    G Sugano, S Krumeich, S Amigorena & C Théry

  3. CNRS UMR144, Paris, France

    I Bernard-Pierrot, C Battail, N Stransky, M-L Lepage & F Radvanyi

  4. Department of Tumor Biology, Institut Curie Hospital, Paris, France

    M Laé & X Sastre-Garau

  5. INSERM U955, Créteil, France

    Y Allory & C C Abbou

  6. Department of Urology, AP-HP Henri Mondor-Albert Chenevier Group, Créteil, France

    Y Allory & C C Abbou

  7. Department of Pathology, AP-HP Henri Mondor-Albert Chenevier Group, Créteil, France

    Y Allory & P Maille

  8. Department of Translational Research, Institut Curie Hospital, Paris, France

    M-H Donnadieu

  9. University Paris 12, Faculty of Medicine, Créteil, France

    C C Abbou

  10. INSERM U946, Fondation Jean Dausset, CEPH, Paris, France

    S Benhamou

  11. CNRS FRE 2939, Genomes and Cancers, Institut Gustave Roussy, Villejuif, France

    S Benhamou

  12. Department of Urology, Hôpital Foch, Suresnes, France

    T Lebret

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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). https://doi.org/10.1038/onc.2010.446

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Keywords

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

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