Transforming Growth Factor-β1 and CD105 Promote the Migration of Hepatocellular Carcinoma-Derived Endothelium

Hepatocellular carcinoma (HCC) is one of most malignant and aggressive human tumors. Transforming growth factor-01 (TGF-beta 1) and its coreceptor CD105 have been shown to contribute to HCC malignant progression. TGF-beta 1 and CD105 have also been implicated in angiogenesis, but their role in the vascularization of HCC has not been investigated. To fill this gap, we studied the effect of TGF-beta 1 and CD105 on HCC-derived endothelium. By using immunomagnetic beads, we isolated and cultured endothelial cells (ECs) from HCC (HCC-EC) and adjacent nonneoplastic tissue (nNL-ECs) obtained from 24 liver biopsies. HCC and nNL biopsies were also analyzed by immunohistochemistry for the expression of CD105, TGF-beta 1, Ve-cadherin (Ve-cad), CD44, beta-catenin, and E-cadherin. Compared with nNL-ECs, HCC-ECs had higher expression of CD105, enhanced spontaneous motility, and greater capacity to migrate in response to TGF-beta 1 (5 ng/mL), particularly in the presence of a fibronectin matrix. The chemotactic effect of TGF-beta 1 was blocked by anti-CD105 antibodies and correlated with the grade of HCC malignancy. Histologic examination of HCC biopsies showed that HCCs with the worse malignant features had the highest expression of TGF- I, CD105, and angiogenic markers (Ve-cad and CD44). Because CD105 was highly expressed in microvessels at the tumor periphery and TGF-beta 1 staining was only found in neoplastic hepatocytes, we conclude that HCC-derived TGF-beta 1 may act as a chemoattractant for CD105-expressing ECs and as a promoter of tumor angiogenesis. Thus, drugs that selectively target the TGF beta 1/CD105 axis may interfere with HCC-related angiogenesis and HCC progression. [Cancer Res 2008;68(20):8626-34]