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

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 r...

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Bibliographic Details
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
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Summary:	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.
Bibliography:	ark:/67375/HXZ-MK2CK46B-2 istex:91D98768447B7E6C550C6CD42B9C537988E9FBC9 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 scopus-id:2-s2.0-56049102601 info:eu-repo/grantAgreement/EC/FP7/201279
ISSN:	0143-3334 1460-2180 1460-2180
DOI:	10.1093/carcin/bgn204