RT Journal Article
SR Electronic
T1 Secreted MMP9 promotes angiogenesis more efficiently than constitutive active MMP9 bound to the tumor cell surface
JF Journal of Cell Science
JO J. Cell Sci.
FD The Company of Biologists Ltd
SP 1847
OP 1857
DO 10.1242/jcs.01035
VO 117
IS 9
A1 Mira, Emilia
A1 Lacalle, Rosa Ana
A1 Buesa, José María
A1 de Buitrago, Gonzalo González
A1 Jiménez-Baranda, Sonia
A1 Gómez-Moutón, Concepción
A1 Martínez-A, Carlos
A1 Mañes, Santos
YR 2004
UL http://jcs.biologists.org/content/117/9/1847.abstract
AB Association of matrix metalloprotease 9 (MMP9) to the cell membrane is considered important in tumor growth and angiogenesis. To dissect this regulatory mechanism, we generated raft and non-raft MMP9 chimeras to force membrane expression in the MCF-7 human breast carcinoma cell line. MMP9 targeting to non-raft cell surface domains rendered a constitutive active membrane MMP9 form, suggesting a contribution by the lipid environment in MMP activation. We generated human breast cancer xenograft models using MCF-7 cells overexpressing secreted and membrane-anchored MMP9. The non-raft MMP9 chimera was constitutively active at the cell membrane in xenografts, but this activation did not correlate with an increase in MMP9-induced angiogenesis. Capillary number and vessel perimeter were specifically increased only in tumors overexpressing wild-type MMP9 (the secreted form); this increase was inhibited when tumors were induced in doxycycline-treated mice. Xenografts from tumor cells overexpressing wild-type MMP9 showed increased vascular endothelial growth factor (VEGF)/VEGFR2 receptor association, which was also dependent on MMP9 activity. These observations indicate that membrane location can influence MMP9 activity in vitro and in vivo, and confirm the relevance of stromal-associated, but not tumor-bound MMP9 in mediating tumor-induced angiogenesis.