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Blood, 19 February 2009, Vol. 113, No. 8, pp. 1845-1855.
Prepublished online as a Blood First Edition Paper on November 25, 2008; DOI 10.1182/blood-2008-05-160671.
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Submitted May 31, 2008
Accepted November 14, 2008
Cooperation between integrin  5 and tetraspan TM4SF5 regulates VEGF-mediated angiogenic activity
Suyong Choi, Sin-Ae Lee, Tae Kyoung Kwak, Hyeon Jung Kim, Mi Ji Lee, Sang-Kyu Ye, Sung-Hoon Kim, Semi Kim, and Jung Weon Lee*
Cancer Research Institute, Cell Dynamics Research Center, College of Medicine, Seoul National University, Seoul, Korea, Republic of
Cancer Research Institute, Cell Dynamics Research Center, Department of Molecular & Clinical Oncology, College of Medicine, Seoul National University, Seoul, Korea, Republic of
Cancer Research Institute, Cell Dynamics Research Center, Department of Tumor Biology, College of Medicine, Seoul National University, Seoul, Korea, Republic of
Cancer Research Institute, Cell Dynamics Research Center, Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea, Republic of
Cancer Research Institute, Cell Dynamics Research Center, Department of Pharmacology, College of Medicine, Seoul National University, Seoul, Korea, Republic of
CPMRC, College of Oriental Medicine, Kyunghee University, Seoul, Korea, Republic of
KRIBB, Taejon, Korea, Republic of
* Corresponding author; email: jwl{at}snu.ac.kr.
Tetraspan TM4SF5 is highly expressed in a diverse number of tumor types. Here we explore the mechanistic roles of TM4SF5 in angiogenesis. We found that TM4SF5 overexpression correlates with VEGF expression in SNU449 hepatocytes and with vessel formation in clinical hepatocarcinoma samples. Conditioned media from TM4SF5-expressing cells enhanced viability and tube formation of primary HUVEC endothelial cells, and outgrowth of endothelial cells from aorta ring segments, which was abolished by treatment with an anti-VEGF antibody. TM4SF5 retained integrin  5 on the cell surface for VEGF induction, and preincubation with anti-integrin 5 antibody abolished TM4SF5-mediated VEGF expression and secretion. TM4SF5-mediated effects required integrin 5, c-Src, and STAT3. In addition, tumors from nude mice injected with TM4SF5-expressing cells and from clinical human hepatocarcinoma tissues showed enhanced integrin 5 expression, vessel formation and signaling activity, which were inhibited by administration of anti-integrin 5 or -VEGF antibody. This study suggests that TM4SF5 facilitates angiogenesis of neighboring endothelial cells through VEGF induction, mediated by cooperation between TM4SF5 and integrin 5 of epithelial cells.
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