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

• Published in: Carcinogenesis (New York) Vol. 29; no. 11; pp. 2236 - 2242
• Main Authors: Maillard, C.M., Bouquet, C., Petitjean, M.M., Mestdagt, M., Frau, E., Jost, M., Masset, A.M., Opolon, P.H., Beermann, F., Abitbol, M.M., Foidart, J.M., Perricaudet, M.J., Noël, A.C.
• Format: Journal Article Web Resource
• Language: English
• Published: Oxford Oxford University Press 01-11-2008; Oxford Publishing Limited (England); Irl Press at Oxford University Press
• Subjects: angiogenesis; Animals; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; Biological and medical sciences; Blotting, Western; brain metastasis; Brain Neoplasms - genetics; Brain Neoplasms - prevention & control; Brain Neoplasms - secondary; Carcinogenesis, carcinogens and anticarcinogens; Eye Neoplasms - genetics; Eye Neoplasms - pathology; Life sciences; Medical sciences; Mice; Mice, Knockout; Mice, Transgenic; Neurology; ocular tumor; Oligonucleotide Array Sequence Analysis; Ophthalmology; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - physiology; Plasminogen activator inhibitor-1; Retinal Pigment Epithelium - pathology; Reverse Transcriptase Polymerase Chain Reaction; Sciences du vivant; Simian virus 40; Tumors; Tumors and pseudotumors of the eye, orbit, eyelid, lacrimal apparatus; Tumors of the nervous system. Phacomatoses; Nervous system diseases; Brain cancer; Rodentia; Transgenic animal; Eye tumor; Malignant tumor; Cerebral metastasis; Cerebral disorder; Plasminogen activator inhibitor 1; Eye disease; Vertebrata; Reduction; Mammalia; Mouse; Central nervous system disease; Cancer
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgn204

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.