Reduced lung metastasis in endothelial cell-specific transforming growth factor β type II receptor-deficient mice with decreased CD44 expression

Transforming growth factor β (TGF-β) is abundantly present in the tumor microenvironment, contributing to cancer progression. However, the regulatory mechanism by which TGF-β affects vascular endothelial cells (ECs) in the tumor microenvironment is not well understood. Herein, we generated tamoxifen-inducible TGF-β type II receptor (TβRII) knockout mice, specifically targeting ECs (TβRIIiΔEC), by crossbreeding TβRII-floxed mice with Pdgfb-icreER mice. We established tumor-bearing mice by transplanting Lewis lung carcinoma (LLC) cells. TβRIIiΔEC mice exhibited increased tumor angiogenesis with fragile new blood vessels, increased bleeding, and hypoxia compared to control mice. Consequently, the compromised tumor microenvironment precipitated a notable surge in circulating tumor cells. Paradoxically, lung metastasis showed a significant decline. This intriguing discrepancy was explained by a reduction in the engraftment between cancer cells and ECs. Disruption of TGF-β signaling downregulated CD44 on ECs, hindering cancer cell adhesion. These findings highlight TGF-β′s role in promoting metastasis by modulating EC function. [Display omitted] •Endothelial-specific TGF-β receptor knockout leads to fragile tumor vasculature•Loss of endothelial TGF-β signaling reduces lung metastasis in tumor-bearing mice•TβRII deletion in tumor endothelial cells reduces CD44 expression and increases CTCs•CD44 downregulation inhibits cancer cell adhesion to endothelial cells Natural sciences; Biological sciences; Systems biology; Cancer systems biology; Cancer