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

Marijana Miljkovic-Licina; Philippe Hammel; Sarah Garrido-Urbani; Boris P-L Lee; Mehdi Meguenani; Chiraz Chaabane; Marie-Luce Bochaton-Piallat; Beat A Imhof

doi:10.1158/1535-7163.MCT-12-0245

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

Mol Cancer Ther. 2012 Dec;11(12):2588-99. doi: 10.1158/1535-7163.MCT-12-0245. Epub 2012 Sep 20.

Authors

Marijana Miljkovic-Licina¹, Philippe Hammel, Sarah Garrido-Urbani, Boris P-L Lee, Mehdi Meguenani, Chiraz Chaabane, Marie-Luce Bochaton-Piallat, Beat A Imhof

Affiliation

¹ Department of Pathology and Immunology, CMU, University of Geneva, Switzerland.

PMID: 23002094
DOI: 10.1158/1535-7163.MCT-12-0245

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Angiogenesis Inhibitors
Antibodies
Bone Morphogenetic Protein 4
Glycoproteins
Smad Proteins