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 (TβRII^iΔEC), by crossbreeding TβRII-floxed mice with Pdgfb-icreER mice. We established tumor-bearing mice by transplanting Lewis lung carcinoma (LLC) cells. TβRII^iΔEC 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.