New Blocking Antibodies Impede Adhesion, Migration and Survival of Ovarian Cancer Cells, Highlighting MFGE8 as a Potential Therapeutic Target of Human Ovarian Carcinoma

PLoS One. 2013 Aug 16;8(8):e72708. doi: 10.1371/journal.pone.0072708. eCollection 2013.

Abstract

Milk Fat Globule--EGF--factor VIII (MFGE8), also called lactadherin, is a secreted protein, which binds extracellularly to phosphatidylserine and to αvβ3 and αvβ5 integrins. On human and mouse cells expressing these integrins, such as endothelial cells, phagocytes and some tumors, MFGE8/lactadherin has been shown to promote survival, epithelial to mesenchymal transition and phagocytosis. A protumoral function of MFGE8 has consequently been documented for a few types of human cancers, including melanoma, a subtype of breast cancers, and bladder carcinoma. Inhibiting the functions of MFGE8 could thus represent a new type of therapy for human cancers. Here, we show by immunohistochemistry on a collection of human ovarian cancers that MFGE8 is overexpressed in 45% of these tumors, and we confirm that it is specifically overexpressed in the triple-negative subtype of human breast cancers. We have established new in vitro assays to measure the effect of MFGE8 on survival, adhesion and migration of human ovarian and triple-negative breast cancer cell lines. Using these assays, we could identify new MFGE8-specific monoclonal antibodies, which efficiently blocked these three tumor-promoting effects of MFGE8. Our results suggest future use of MFGE8-blocking antibodies as new anti-cancer therapeutics in subgroups of ovarian carcinoma, and triple-negative breast carcinoma patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / pharmacology*
  • Antigens, Surface / immunology*
  • Antigens, Surface / metabolism
  • Biological Assay
  • Biopsy
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Survival / drug effects
  • Female
  • Humans
  • Mice
  • Milk Proteins / immunology*
  • Milk Proteins / metabolism
  • Molecular Targeted Therapy*
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / pathology*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology

Substances

  • Antibodies, Blocking
  • Antigens, Surface
  • MFGE8 protein, human
  • Milk Proteins

Grant support

This work was supported by Institut Curie, INSERM, Association pour La Recherche contre le Cancer, a prize from Fondation de France, and a two-years collaboration contract between Institut Curie, INSERM, and ThromboGenics NV, Leuven, Belgium (www.thrombogenics.com). ThromboGenics NV outlined the strategy for antibody generation, performed the mice immunization, checked the specificity of the new anti-human MFGE8 antibodies, sequenced their variable regions, and participated in the design of the tests for selection of the lead candidate antibodies.