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The L6 Protein TM4SF1 Is Critical for Endothelial Cell Function and Tumor Angiogenesis

¹ Center for Vascular Biological Research and Department of Pathology, and ² Imaging Core Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Shou-Ching Shih and Harold F. Dvorak, Pathology Department, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Boston, MA 02215. Phone: 617-667-8156/617-667-8529; Fax: 617-667-3591; E-mail: sshih2{at}bidmc.harvard.edu and hdvorak{at}bidmc.harvard.edu.

Key Words: TM4SF1 • endothelial cells • filopodia • angiogenesis

Transmembrane-4-L-six-family-1 (TM4SF1) was originally described as a cancer cell protein. Here, we show that it is highly expressed in the vascular endothelium of human cancers and in a banded pattern in the filopodia of cultured endothelial cells (EC). TM4SF1 knockdown prevented filopodia formation, inhibited cell mobility, blocked cytokinesis, and rendered EC senescent. Integrin-5 and integrin-β1 subunits gave a similar staining pattern and interacted constitutively with TM4SF1, whereas integrin subunits often associated with angiogenesis (V, β3, β5) interacted with TM4SF1 only after vascular endothelial growth factor (VEGF)-A or thrombin stimulation. TM4SF1 knockdown substantially inhibited maturation of VEGF-A¹⁶⁴–induced angiogenesis. Thus, TM4SF1 is a key regulator of EC function in vitro and of pathologic angiogenesis in vivo and is potentially an attractive target for antiangiogenesis therapy. [Cancer Res 2009;69(8):3272–7]