Endothelial Suppresses Cancer Cell Proliferation via a Paracrine TGF-β/Smad Signaling.

has been reported to play a critical role in angiogenesis and the repair of damaged blood vessels; however, its role in the tumor microenvironment remains unclear. Here, we observed the differential expression of in endothelial cells from hepatocellular carcinoma (HCC) and glioma samples. Downregulation of expression correlated with the malignant phenotype of cancer and a poor prognosis for patients. In subsequent studies, endothelial inhibition robustly promoted the growth of HCC or glioma xenografts in nude mice. Intriguingly, endothelial silencing dramatically suppressed endothelial cell expansion and tumor angiogenesis, but potently enhanced the proliferation of neighboring HCC and glioma cells. Based on the results of the ELISA assay, silencing reduced TGF-β production in endothelial cells, which attenuated the phosphorylation and nuclear translocation of Smad in neighboring cancer cells. The endothelial silencing-mediated increase in cancer cell proliferation was abolished by either a TGF-β neutralizing antibody or TGF-β receptor inhibitor, indicating the essential role for TGF-β in endothelial -mediated suppression of cancer growth. These findings not only broaden our understanding of the crosstalk between cancer cells and endothelial cells but also provide a novel prognostic biomarker and a therapeutic target for cancer treatments.