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

¹ Department of Pathology, Spedali Civili, ² Department of Microbiology, and ³ Department of Medical and Surgical Sciences, Brescia University, Brescia, Italy; ⁴ SSD-UCV Neurobiology and Neuroregenerative Therapies, Fondazione IRCCS, Neurological Institute "Carlo Besta", Milan, Italy; and ⁵ Pathology and Lab Medicine Division, Veterans Hospital Puget Sound Health Care System, Seattle, Washington

Requests for reprints: Giulio Alessandri, UCV Neurobiology and Neuroregenerative Therapies, Foundation IRCCS, Neurological Institute "Carlo Besta," Via Celoria 11, 20133 Milan, Italy. Phone: 39-022-3942272; Fax: 39-027-0638217; E-mail: cisiamo2{at}yahoo.com and giulio.alessandri{at}istituto-besta.it.

Key Words: angiogensis • CD105 • TGF-β1

Hepatocellular carcinoma (HCC) is one of most malignant and aggressive human tumors. Transforming growth factor-β1 (TGF-β1) and its coreceptor CD105 have been shown to contribute to HCC malignant progression. TGF-β1 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-β1 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-β1, Ve-cadherin (Ve-cad), CD44, β-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-β1 (5 ng/mL), particularly in the presence of a fibronectin matrix. The chemotactic effect of TGF-β1 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-β1, CD105, and angiogenic markers (Ve-cad and CD44). Because CD105 was highly expressed in microvessels at the tumor periphery and TGF-β1 staining was only found in neoplastic hepatocytes, we conclude that HCC-derived TGF-β1 may act as a chemoattractant for CD105-expressing ECs and as a promoter of tumor angiogenesis. Thus, drugs that selectively target the TGF-β1/CD105 axis may interfere with HCC-related angiogenesis and HCC progression. [Cancer Res 2008;68(20):8626–34]