Carcinogenesis Advance Access originally published online on August 27, 2008
Carcinogenesis 2008 29(11):2236-2242; doi:10.1093/carcin/bgn204
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Reduction of brain metastases in plasminogen activator inhibitor-1-deficient mice with transgenic ocular tumors
1 Laboratory of Tumor and Development Biology, GIGA-Cancer, Tour de Pathologie (B23), University of Liège, Sart-Tilman, B-4000 Liège, Belgium
2 CNRS UMR 8121 Univ Paris Sud, Vectorologie et Transfert de Gènes, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France
3 Centre d'études et de Recherches Thérapeutiques en Ophtalmologie, Faculté de Médecine Necker, 156 rue de Vaugirard, 75015 Paris, France
4 Swiss Institute for Experimental Cancer Research (ISREC), Faculty of life Sciences, Ecole Polytechnique Fédérable de Lausanne (EPFL), Chemin de Boveresses 155, CH-1066 Epalinges, Switzerland
5 Department of Gynecology and Obstetrics, CHU, B-4000 Liège, Belgium
* To whom correspondence should be addressed. Laboratory of Tumor Biology and Development, Institute of Pathology CHU-B23, University of Liège, Sart-Tilman, B-4000 Liège, Belgium. Tel: +32 4 366 25 69; Fax: +32 4 366 29 36; Email: cmaillard{at}ulg.ac.be
Correspondence may also be addressed to A.C.Nöel. Email: agnes.noel{at}ulg.ac.be
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.
Abbreviations: GAPDH, glyceraldehyde 3-phosphate dehydrogenase; FGF-1, fibroblast growth factor-1; KO, knockout; Maspin, mammary serine protease inhibitor; MMP, matrix metalloproteinase; mRNA, messenger RNA; PA, plasminogen activator; PAI, plasminogen activator inhibitor; RPE, retinal pigmented epithelium; RT–PCR, reverse transcription–polymerase chain reaction; Serpin, serine protease inhibitors; TIMP, tissue inhibitor of metalloprotease; tPA, tissue-type plasminogen activator; TRP-1, tyrosine-related protein 1; uPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor; WT, wild-type
Received April 28, 2008; revised August 21, 2008; accepted August 22, 2008.