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- Title
A truncated form of CD9-partner 1 (CD9P-1), GS-168AT2, potently inhibits in vivo tumour-induced angiogenesis and tumour growth.
- Authors
Colin, S; Guilmain, W; Creoff, E; Schneider, C; Steverlynck, C; Bongaerts, M; Legrand, E; Vannier, J P; Muraine, M; Vasse, M; Al-Mahmood, S
- Abstract
<bold>Background: </bold>Tetraspanins are transmembrane proteins known to contribute to angiogenesis. CD9 partner-1 (CD9P-1/EWI-F), a glycosylated type 1 transmembrane immunoglobulin, is a member of the tetraspanin web, but its role in angiogenesis remains to be elucidated.<bold>Methods: </bold>We measured the expression of CD9P-1 under angiogenic and angiostatic conditions, and the influence of its knockdown onto capillary structures formation by human endothelial cells (hECs). A truncated form of CDP-1, GS-168AT2, was produced and challenged vs hEC proliferation, migration and capillaries' formation. Its association with CD9P-1, CD9, CD81 and CD151 and the expressions of these later at hEC surface were analysed. Finally, its effects onto in vivo tumour-induced angiogenesis and tumour growth were investigated.<bold>Results: </bold>Vascular endothelial growth factor (VEGF)-induced capillary tube-like formation was inhibited by tumour necrosis factor α and was associated with a rise in CD9P-1 mRNA expression (P<0.05); accordingly, knockdown of CD9P-1 inhibited VEGF-dependent in vitro angiogenesis. GS-168AT2 dose-dependently inhibited in vitro angiogenesis, hEC migration and proliferation (P<0.05). Co-precipitation experiments suggest that GS-168AT2 corresponds to the sequence by which CD9P-1 physiologically associates with CD81. GS-168AT2 induced the depletion of CD151, CD9 and CD9P-1 from hEC surface, correlating with GS-168AT2 degradation. Finally, in vivo injections of GS-168AT2 inhibited tumour-associated angiogenesis by 53.4±9.5% (P=0.03), and reduced tumour growth of Calu 6 tumour xenografts by 73.9±16.4% (P=0.007) without bodyweight loss.<bold>Conclusion: </bold>The truncated form of CD9P-1, GS-168AT2, potently inhibits angiogenesis and cell migration by at least the downregulation of CD151 and CD9, which provides the first evidences for the central role of CD9P-1 in tumour-associated angiogenesis and tumour growth.
- Subjects
NEOVASCULARIZATION; TUMOR growth prevention; IMMUNOGLOBULINS; VASCULAR endothelial growth factors; LUNG cancer; CELL migration; PROTEIN metabolism; REVERSE transcriptase polymerase chain reaction; FLOW cytometry; RESEARCH; UMBILICAL veins; ENDOTHELIUM; CELL culture; CATTLE; ANIMAL experimentation; WESTERN immunoblotting; RESEARCH methodology; LUNG tumors; CELL physiology; APOPTOSIS; RNA; PRECIPITIN tests; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; PATHOLOGIC neovascularization; IMMUNOENZYME technique; POLYMERASE chain reaction; AORTA; MICE; RECOMBINANT proteins
- Publication
British Journal of Cancer, 2011, Vol 105, Issue 7, p1002
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/bjc.2011.303