title: Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors.
abstract: Nonmelanoma skin cancer is one of the most common malignancies in humans. Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth-inhibiting effects of cannabinoids on gliomas and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB(1) and CB(2)), we studied the potential utility of these compounds in anti-skin tumor therapy. Here we show that the CB(1) and the CB(2) receptor are expressed in normal skin and skin tumors of mice and humans. In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB(1)/CB(2) agonist WIN-55,212-2 or the selective CB(2) agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors (VEGF, placental growth factor, and angiopoietin 2). Abrogation of EGF-R function was also observed in cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumors.
authors.affiliation: Project on Cellular and Molecular Biology and Gene Therapy, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, Spain.
authors.forename: M Llanos
authors.initials: ML
authors.lastname: Casanova
authors.forename: Cristina
authors.initials: C
authors.lastname: Blázquez
authors.forename: Jesús
authors.initials: J
authors.lastname: Martínez-Palacio
authors.forename: Concepción
authors.initials: C
authors.lastname: Villanueva
authors.forename: M Jesús
authors.initials: MJ
authors.lastname: Fernández-Aceñero
authors.forename: John W
authors.initials: JW
authors.lastname: Huffman
authors.forename: José L
authors.initials: JL
authors.lastname: Jorcano
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D042702:Angiopoietin-2; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D048588:Benzoxazines; D015152:Blotting, Northern; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology; D002461:Cell Line, Transformed; D016228:Endothelial Growth Factors / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D043925:Angiogenesis Inducing Agents; D042702:Angiopoietin-2; D000970:Antineoplastic Agents; D048588:Benzoxazines; D002186:Cannabinoids; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009025:Morpholines; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D001973:Bromodeoxyuridine; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC