期刊
CARCINOGENESIS
卷 29, 期 11, 页码 2236-2242出版社
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgn204
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资金
- European Union [LSHC-CT-2003-503297, LSHC-CT-2004-503224]
- Framework Programme 6-NOE [LSHM-CT-2004-512040 EMBIC]
- Fonds de la Recherche Scientifique Medicale
- Fonds National de la Recherche Scientifique (Belgium)
- Belgium), Fondation contre le Cancer
- INSERM Cooperation
- Fonds speciaux de la Recherche (University of Liege)
- Centre Anticancereux pres l'Universite de Liege
- Fonds Leon Fredericq (University of Liege)
- Region Wallonne [616476]
- Fonds Social Europe en
- Fonds d'Investissements de la Recherche Scientifique (CHU, Liege, Belgium)
- Interuniversity Attraction Poles Programme-Belgian Science Policy (Brussels, Belgium)
Plasminogen activator inhibitor-1 is known to play a paradoxical positive role in tumor angiogenesis, but its contribution to metastatic spread remains unclear. We studied the impact of plasminogen activator inhibitor (PAI)-1 deficiency in a transgenic mouse model of ocular tumors originating from retinal epithelial cells and leading to brain metastasis (TRP-1/SV40 Tag mice). PAI-1 deficiency did not affect primary tumor growth or vascularization, but was associated with a smaller number of brain metastases. Brain metastases were found to be differentially distributed between the two genotypes. PAI-1-deficient mice displayed mostly secondary foci expanding from local optic nerve infiltration, whereas wild-type animals displayed more disseminated nodules in the scissura and meningeal spaces. SuperArray GEarray analyses aimed at detecting molecules potentially compensating for PAI-1 deficiency demonstrated an increase in fibroblast growth factor-1 (FGF-1) gene expression in primary tumors, which was confirmed by reverse transcription-polymerase chain reaction and western blotting. Our data provide the first evidence of a key role for PAI-1 in a spontaneous model of metastasis and suggest that angiogenic factors, such as FGF-1, may be important for primary tumor growth and may compensate for the absence of PAI-1. They identify PAI-1 and FGF-1 as important targets for combined antitumor strategies.
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