Cooperation between integrin alpha5 and tetraspan TM4SF5 regulates VEGF-mediated angiogenic activity.
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 vascular endothelial growth factor (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 human umbilical vein endothelial cells, and outgrowth of endothelial cells from aorta ring segments, which was abolished by treatment with an anti-VEGF antibody. TM4SF5 retained integrin alpha(5) on the cell surface for VEGF induction, and preincubation with anti-integrin alpha(5) antibody abolished TM4SF5-mediated VEGF expression and secretion. TM4SF5-mediated effects required integrin alpha(5), c-Src, and signal transducer and activator of transcription 3 (STAT3). In addition, tumors from nude mice injected with TM4SF5-expressing cells and from clinical human hepatocarcinoma tissues showed enhanced integrin alpha(5) expression, vessel formation, and signaling activity, which were inhibited by administration of anti-integrin alpha(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 alpha(5) of epithelial cells.
Choi
Suyong
S
Cancer Research Institute, Cell Dynamics Research Center, College of Medicine, Seoul National University, Seoul, South Korea.
Lee
Sin-Ae
SA
Kwak
Tae Kyoung
TK
Kim
Hyeon Jung
HJ
Lee
Mi Ji
MJ
Ye
Sang-Kyu
SK
Kim
Sung-Hoon
SH
Kim
Semi
S
Lee
Jung Weon
JW
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D000081247:CSK Tyrosine-Protein Kinase; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000378:metabolism; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D039482:Integrin alpha5 / Q000276:immunology / Q000378:metabolism*; D008113:Liver Neoplasms / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019061:src-Family Kinases
D000906:Antibodies; D017077:Culture Media, Conditioned; D039482:Integrin alpha5; D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C111029:TM4SF5 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; C000631346:CSK protein, human