Journal Article

Reduction of brain metastases in plasminogen activator inhibitor-1-deficient mice with transgenic ocular tumors

C.M. Maillard, C. Bouquet, M.M. Petitjean, M. Mestdagt, E. Frau, M. Jost, A.M. Masset, P.H. Opolon, F. Beermann, M.M. Abitbol, J.M. Foidart, M.J. Perricaudet and A.C. Noël

in Carcinogenesis

Volume 29, issue 11, pages 2236-2242
Published in print November 2008 | ISSN: 0143-3334
Published online August 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn204
Reduction of brain metastases in plasminogen activator inhibitor-1-deficient mice with transgenic ocular tumors

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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.

Journal Article.  5042 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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