Abstract B81: Angiomodulin (AGM/IGFBP-rP1) is overexpressed in tumor vasculature and regulates adhesion of vascular endothelial cells via integrin αvβ3: Possible roles in tumor angiogenesis

Abstract

Abstract Angiomodulin (AGM) is a member of insulin-like growth factor binding protein (IGFBP) superfamily and often called IGFBP-rP1. Our past studies identified this protein as a tumor-derived cell adhesion factor (TAF) that is highly accumulated in blood vessels of human cancer tissues (PNAS 93:8384, 1996). Recently we found that AGM is overexpressed in not only vasculature but also stromal fibroblasts in some human cancers (Cancer Sci 4:691, 2012). AGM stimulates the growth of fibroblasts and their expression of fibronectin and α-smooth muscle actin, inducing their morphological change to a myofibroblast-like shape. It is supposed that AGM activates cancer-associated fibroblasts (CAFs) and increases cancer stroma. In contrast to these findings, tumor-suppressing activity of AGM has been reported by other studies. To clarify the roles of AGM in tumor progression, we here investigated the distribution of AGM in benign and invasive breast cancers and its regulatory factors and biological activities. Immunohistochemical analysis showed that AGM was greatly expressed in tumor 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 markedly induced by VEGF in vascular endothelial cells but by TGF-β in fibroblasts. Although AGM did not significantly affect the growth of endothelial cells, it potently promoted the adhesion of endothelial cells through integrins. Experiments with neutral anti-integrin antibodies revealed that the cell adhesion activity was mediated mainly by integrin αvβ3 and weakly by integrin α2β1. AGM induced cytoskeletal change in endothelial cells. Furthermore, AGM and integrin αvβ3 were colocalized at high levels in tumor vasculature. These results suggest that AGM regulates angiogenesis and other vascular functions as a ligand of integrin αvβ3 in cancer tissues. The data also indicate that AGM is induced by different mechanisms and plays different roles in tumor progression between CAFs and vasculature. Citation Format: Kaoru Miyazaki, Eriko Komiya, Hiroki Sato, Yohei Miyagi, Shouichi Higashi. Angiomodulin (AGM/IGFBP-rP1) is overexpressed in tumor vasculature and regulates adhesion of vascular endothelial cells via integrin αvβ3: Possible roles in tumor angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B81.