Targeting olfactomedin-like 3 inhibits tumor growth by impairing angiogenesis and pericyte coverage.

Abstract

Antiangiogenic drugs have been used as anticancer agents to target tumor endothelial cells or pericytes. Because of limited efficacy of the current monotherapies, there is a strong demand for the dual targeting of endothelial cells and pericytes. Here, we identify Olfactomedin-like 3 (Olfml3) as a novel proangiogenic cue within the tumor microenvironment. Tumor-derived Olfml3 is produced by both tumor endothelial cells and accompanying pericytes and deposited in the perivascular compartment. Blockade of Olfml3 by anti-Olfml3 antibodies is highly effective in reducing tumor vascularization, pericyte coverage, and tumor growth. In vitro, Olfml3 targeting is sufficient to inhibit endothelioma cell migration and sprouting. Olfml3 alone or through binding to BMP4 enhances the canonical SMAD1/5/8 signaling pathway required for BMP4-induced angiogenesis. Therefore, Olfml3 blockade provides a novel strategy to control tumor growth by targeting two distinct cell types within the tumor microenvironment using a single molecule.

• Authors: Marijana Miljkovic-Licina, Philippe Hammel, Sarah Garrido-Urbani, Boris P-L Lee, Mehdi Meguenani, Chiraz Chaabane, Marie-Luce Bochaton-Piallat, Beat A Imhof
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 12 Pg. 2588-99 (Dec 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 23002094 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antibodies
• Bone Morphogenetic Protein 4
• Glycoproteins
• Smad Proteins

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antibodies (immunology, pharmacology)
• Bone Morphogenetic Protein 4 (metabolism)
• Carcinoma, Lewis Lung (blood supply, drug therapy, metabolism, pathology)
• Female
• Gene Silencing
• Glycoproteins (antagonists & inhibitors, biosynthesis, genetics, immunology)
• Human Umbilical Vein Endothelial Cells (cytology, drug effects, metabolism)
• Humans
• Immunohistochemistry
• Mice
• Mice, Inbred C57BL
• Neovascularization, Pathologic (drug therapy, genetics, metabolism, pathology)
• Pericytes (drug effects, metabolism, pathology)
• Signal Transduction
• Smad Proteins (metabolism)
• Swine
• Transfection