Vascular Endothelial Cadherin Promotes Breast Cancer Progression via Transforming Growth Factor β Signaling

Abstract

Epithelial-to-mesenchymal transition (EMT) is an important event during carcinoma progression and leads to increased tumor cell malignancy. Here, we show that vascular endothelial (VE)-cadherin is induced during EMT in mammary tumor cells and is aberrantly expressed in invasive human breast carcinomas. VE-cadherin enhanced the capacity of fibroblastoid tumor cells to proliferate, form cord-like invasive structures, and adhere to endothelial cells, characteristics that are key contributors to their increased malignancy and metastatic potential. Consistently, VE-cadherin expression in malignant fibroblastoid tumor cells promoted the growth of experimental mammary carcinomas in vivo. Analysis of the signaling mechanisms involved revealed that VE-cadherin expression influences the levels of Smad2 phosphorylation and expression of target genes of transforming growth factor-B (TGF-B), a major mediator of advanced tumor progression and malignant tumor cell proliferation. VE-cadherin might thus promote tumor progression not only by contributing to tumor angiogenesis but also by enhancing tumor cell proliferation via the TGF-B signaling pathway. This article provides evidence for a novel function of VE-cadherin in tumor progression and reveals a previously unknown molecular link between VE-cadherin expression and TGF-B signaling. Our findings may have important implications for the clinical application of anti-VE-cadherin strategies. [Cancer Res 2008;68(5):1388-97]

An RGD Motif Present in Cadherin 17 Induces Integrin Activation and Tumor Growth

“…In agreement with this hypothesis, recent studies point out a role for these cadherins in cancer and vascular damage. CDH5 and CDH6 seem to promote cancer progression (25), thrombus formation, and vascular injury because of the induction of platelet aggregation (26). Some studies have reported an up-regulation of CDH5 in invasive human breast tumors and in a breast cancer model (25), and CDH5 induction was responsible for vasculogenic mimicry in aggressive melanomas (27).…”

“…CDH5 and CDH6 seem to promote cancer progression (25), thrombus formation, and vascular injury because of the induction of platelet aggregation (26). Some studies have reported an up-regulation of CDH5 in invasive human breast tumors and in a breast cancer model (25), and CDH5 induction was responsible for vasculogenic mimicry in aggressive melanomas (27). In platelets, a previous study revealed a role for CDH6 as a novel ligand for ␣ IIb ␤ 3 integrin, this binding being responsible for platelet aggregation and thrombus formation (26).…”

Phenotypic correction of murine hemophilia A using an iPS cell-based therapy

“…The GFP lentivirus (pSSI13772, a kind gift from Dr Bill Andrews, Sierra Sciences LLC) was prepared as described (26). Before transplantation, endothelial progenitor cells were infected with GFP lentivirus overnight with supplemental 8 g/ml Polybrene.…”

Role of cadherins in health and in developing breast cancer

“…Экспрессия VE-кадгерина счита-ется специфичной для эндотелиальных клеток. Роль VE-кадгерина заключается главным образом в контроле це-лостности и проницаемости сосудов [46]. Отмечено также существенное участие данной молекулы клеточной адге-зии в ангиогенезе [47].…”

“…Отмечено также существенное участие данной молекулы клеточной адге-зии в ангиогенезе [47]. VE-кадгерин может связываться с рецептором эндотелиального фактора роста сосудов (VEGFR2) и модулировать сигнальный путь с его участи-ем для обеспечения клеточной выживаемости и снижения пролиферации [46].…”