Vascular endothelial cadherin promotes breast cancer progression via transforming growth factor beta signaling.
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-beta (TGF-beta), 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-beta 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-beta signaling. Our findings may have important implications for the clinical application of anti-VE-cadherin strategies.
Labelle
Myriam
M
Institute of Pathology, University of Dresden, Dresden, Germany.
Schnittler
Hans J
HJ
Aust
Daniela E
DE
Friedrich
Katrin
K
Baretton
Gustavo
G
Vestweber
Dietmar
D
Breier
Georg
G
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D016212:Transforming Growth Factor beta; D000099152:Cadherin 5