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

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

^* To whom correspondence should be addressed. E-mail: sshih2{at}bidmc.harvard.edu.

	Abstract

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-1 subunits gave a similar staining pattern and interacted constitutively with TM4SF1, whereas integrin subunits often associated with angiogenesis (V, 3, 5) 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]

Key Words: TM4SF1, endothelial cells, filopodia, angiogenesis