title: Angiomodulin, a marker of cancer vasculature, is upregulated by vascular endothelial growth factor and increases vascular permeability as a ligand of integrin αvβ3.
abstract: Angiomodulin (AGM) is a member of insulin-like growth factor binding protein (IGFBP) superfamily and often called IGFBP-rP1 or IGFBP-7. AGM was originally identified as a tumor-derived cell adhesion factor, which was highly accumulated in blood vessels of human cancer tissues. AGM is also overexpressed in cancer-associated fibroblasts (CAFs) and activates fibroblasts. However, some studies have shown tumor-suppressing activity of AGM. To understand the roles of AGM in cancer progression, we here investigated the expression of AGM in benign and invasive breast cancers and its functions in cancer vasculature. Immunohistochemical analysis showed that AGM was highly expressed in cancer vasculature even in ductal carcinoma in situ (DCIS) as compared to normal vasculature, while its expression in CAFs was more prominent in invasive carcinomas than DCIS. In vitro analyses showed that AGM was strongly induced by vascular endothelial cell growth factor (VEGF) in vascular endothelial cells. Although AGM stimulated neither the growth nor migration of endothelial cells, it supported efficient adhesion of endothelial cells. Integrin αvβ3 was identified as a novel major receptor for AGM in vascular endothelial cells. AGM retracted endothelial cells by inducing actin stress fibers and loosened their VE-cadherin-mediated intercellular junction. Consequently, AGM increased vascular permeability both in vitro and in vivo. Furthermore, AGM and integrin αvβ3 were highly expressed and colocalized in cancer vasculature. These results suggest that AGM cooperates with VEGF to induce the aberrant functions of cancer vasculature as a ligand of integrin αvβ3.
authors.affiliation: Department of Genome Science, Graduate School of Integrated Science and Nanobioscience, Yokohama City University, 641-12 Maioka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-0813, Japan; Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, 641-12 Maioka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-0813, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Komiya
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sato
authors.forename: Naoko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Marii
authors.initials: M
authors.lastname: Ise
authors.forename: Shouichi
authors.initials: S
authors.lastname: Higashi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyagi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Miyazaki
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002199:Capillary Permeability / Q000235:genetics; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D039302:Integrin alphaVbeta3; D008024:Ligands; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; C013065:cell aggregation factors; C086009:tumor-derived adhesion factor
keywords: Angiomodulin; IGFBP; integrin αvβ3; tumor angiogenesis; vascular permeability
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