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.

Angiomodulin (IGFBP7) is a cerebral specific angiocrine factor, but is probably not a blood–brain barrier inducer

“…While AGM antagonizes VEGF-A-induced angiogenesis in vitro [23], knockdown of both VEGF-A and AGM together revealed a synergistic effect on angiogenesis in zebrafish embryos [20]. Finally, just like VEGF-A, AGM (at relatively high concentrations of 1-10 µg/ml) might increase vascular permeability [25]. Based on our skin permeability data ( Fig.…”

“…Based on genome-wide methylation profiling of developing BBB ECs, we found some supporting data of progressive de-methylation in genomic sites associated with AGM, which might indicate an epigenetic control mechanism of AGM expression levels (data not shown). Based on in vitro studies, AGM expression is also induced by VEGF-A [25] and therefore it is possible that there is a molecular negative feedback loop in which up regulation of AGM levels in response to VEGF-A then antagonizes VEGF-A function.…”

“…Paradoxically, VEGF-A is also a strong inducer of non-BBB properties and therefore, potential VEGF-A induction of non-barrier properties should somehow be modulated in order to allow proper induction of angiogenesis together with induction of barrier-genesis. This led us to the hypothesis that AGM might be a negative modulator of VEGF-A-induced permeability, especially in light of the reported direct binding of AGM to VEGF-A [25]. There are conflicting interpretations for experimental investigations of VEGF-A and AGM interactions.…”

“…Knockdown of both VEGF-A and AGM together revealed a synergistic effect on angiogenesis in zebrafish embryos, thus AGM interaction with the VEGF-A pathway seems essential for proper patterning of nascent vessels [20]. Finally, another study showed that AGM was strongly induced in ECs by VEGF-A, integrin (alpha-v beta-3) is a receptor for AGM, and that just like VEGF-A, AGM might increase vascular permeability [25].…”

“…AGM treatment suppresses VEGF-A-induced tube formation, cell migration and proliferation, but does not induce apoptosis [23,24]. AGM binds to collagen type IV and other extracellular matrix or basement membrane-associated factors and also to VEGF-A itself [25]. There is also evidence supporting alternative interactions.…”