Carcinogenesis Advance Access published online on August 27, 2008
Carcinogenesis, doi:10.1093/carcin/bgn204
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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), Sart-Tilman; B-4000 Liège, University of 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 CERTO, Faculté de Médecine Necker, 156 rue de Vaugirard, 75015 Paris, France
4 Swiss Institute for Experimental Cancer Research (ISREC), Chemin de Boveresses 155, CH-1066 Epalinges, Switzerland
5 Department of Gynecology and Obstetrics, CHU, Liège, Belgium
Address correspondence to: Catherine Maillard, University of Liège, Laboratory of Tumor Biology and Development, Institute of Pathology CHU-B23, B-4000 Liège- Sart-Tilman, Belgium, Tel.: +32 4 366 25 69, Fax: +32 4 366 29 36, E-mail: cmaillard{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 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 RT-PCR 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 anti-tumor strategies.
Key Words: Plasminogen activator inhibitor-1 • angiogenesis • ocular tumor • brain metastasis
Received April 28, 2008; revised August 21, 2008; accepted August 22, 2008.