title: Sympathectomy reduces tumor weight and affects expression of tumor-related genes in melanoma tissue in the mouse.
abstract: Accumulated evidence indicates that sympathetic nerves may potentiate tumor growth, including melanoma. To elucidate possible mechanisms for this effect, we performed chemical sympathectomy by intraperitoneal (i.p.) injection of the neurotoxin 6-hydroxydopamine hydrobromide (100 mg/kg of body weight); in nine adult male C57BL/6J mice; nine control mice received i.p. vehicle (VEH). Seven days later, all mice were injected subcutaneously with 3 × 10(3) B16-F10 melanoma cells. Mice were euthanized 20 d after injection of melanoma cells, for measurement of tumor weight and expression of genes related to sympathetic signaling, apoptosis, hypoxia and angiogenesis in tumor tissue. To assess potential involvement of the hypothalamo-pituitary-adrenocortical axis in the effect of sympathectomy on melanoma growth, concentrations of plasma corticosterone and level of glucocorticoid receptor mRNA in tumor tissue were determined. We found that sympathectomy significantly attenuated melanoma growth (tumor weight 0.29 ± 0.16 g versus 1.02 ± 0.30 g in controls; p < 0.05). In tumor tissue from sympathectomized mice, we found significantly increased gene expression (measured by real-time PCR), relative to VEH-injected controls, of tyrosine hydroxylase, neuropeptide Y and glucocorticoid receptor (all p < 0.05), and alpha1, beta1 and beta3 adrenergic receptors (all p < 0.025), and factors related to apoptosis (Bcl-2 and caspase-3; p < 0.05) and hypoxia (hypoxia inducible factor 1 alpha) (p = 0.005). Plasma corticosterone concentrations were significantly elevated (p < 0.05) in these mice. Our findings indicate that sympathectomy induces complex changes in the tumor microenvironment reducing melanoma growth. Such complex changes should be considered in the prediction of responses of cancer patients to interventions affecting sympathetic signaling in tumor tissue and its environment.
authors.affiliation: a Institute of Experimental Endocrinology , Biomedical Research Center, Slovak Academy of Sciences , Bratislava , Slovakia ;
authors.forename: Lubica
authors.initials: L
authors.lastname: Horvathova
authors.affiliation: b Institute of Physiology, Faculty of Medicine , Comenius University in Bratislava , Bratislava , Slovakia ;
authors.forename: Alexandra
authors.initials: A
authors.lastname: Padova
authors.affiliation: a Institute of Experimental Endocrinology , Biomedical Research Center, Slovak Academy of Sciences , Bratislava , Slovakia ;
authors.forename: Andrej
authors.initials: A
authors.lastname: Tillinger
authors.affiliation: a Institute of Experimental Endocrinology , Biomedical Research Center, Slovak Academy of Sciences , Bratislava , Slovakia ;
authors.forename: Jana
authors.initials: J
authors.lastname: Osacka
authors.affiliation: c Cancer Research Institute , Biomedical Research Center, Slovak Academy of Sciences , Bratislava , Slovakia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Bizik
authors.affiliation: a Institute of Experimental Endocrinology , Biomedical Research Center, Slovak Academy of Sciences , Bratislava , Slovakia ;|b Institute of Physiology, Faculty of Medicine , Comenius University in Bratislava , Bratislava , Slovakia ;
authors.forename: Boris
authors.initials: B
authors.lastname: Mravec
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D051379:Mice; D008810:Mice, Inbred C57BL; D009478:Neuropeptide Y / Q000378:metabolism; D016627:Oxidopamine / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013563:Sympathectomy, Chemical; D013564:Sympathetic Nervous System / Q000601:surgery*; D047368:Tumor Burden; D059016:Tumor Microenvironment; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D009478:Neuropeptide Y; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D053148:Caspase 3
keywords: 6-Hydroxydopamine; apoptosis; corticosterone; neuropeptide Y; norepinephrine; tumor growth