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Inhibitory effects of cannabinoid CB 1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis
Author(s) -
Portella Giuseppe,
Laezza Chiara,
Laccetti Paolo,
De Petrocellis Luciano,
Di Marzo Vincenzo,
Bifulco Maurizio
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-1129fje
Subject(s) - angiogenesis , cancer research , cannabinoid , cannabinoid receptor , metastasis , lewis lung carcinoma , receptor , in vivo , cell growth , endocrinology , chemistry , medicine , biology , cancer , antagonist , biochemistry , microbiology and biotechnology
Stimulation of cannabinoid CB 1 receptors by 2‐methyl‐arachidonyl‐2′‐fluoro‐ethylamide (Met‐F‐AEA) inhibits the growth of a rat thyroid cancer cell‐derived tumor in athymic mice by inhibiting the activity of the oncogene product p21 ras . Here we report that Met‐F‐AEA also blocks the growth of tumors previously induced in nude mice by the s.c. injection of the same rat thyroid carcinoma cells. Met‐F‐AEA significantly inhibited, in tumors as well as transformed cells, the expression of the vascular endothelial growth factor, an angiogenetic factor known to be up‐regulated by p21 ras , as well as of one of its receptors, flt‐1/VEGFR‐1. The levels of the cyclin‐dependent kinase inhibitor p27(kip1), which is down‐regulated by p21 ras , were instead increased by Met‐F‐AEA. All these effects were antagonized by the selective CB 1 receptor antagonist SR141716A. Met‐F‐AEA inhibited in vitro the growth of a metastasis‐derived thyroid cancer cell line more potently than a primary cancer cell line. Therefore, the hypothesis that CB 1 receptor stimulation interferes not only with angiogenesis but also with metastatic processes was tested in a widely used model of metastatic infiltration in vivo, the Lewis lung carcinoma (3LL) in C57Bl/6 mice. Three weeks from the paw injection of 3LL cells, Met‐F‐AEA reduced significantly the number of metastatic nodes, in a way antagonized by SR141716A. Our findings indicate that CB 1 receptor agonists might be used therapeutically to retard tumor growth in vivo by inhibiting at once tumor growth, angiogenesis, and metastasis.