title: Transplantation of β-endorphin neurons into the hypothalamus promotes immune function and restricts the growth and metastasis of mammary carcinoma.
abstract: Neurobehavioral stress has been shown to promote tumor growth and progression and dampen the immune system. In this study, we investigated whether inhibiting stress hormone production could inhibit the development of mammary carcinoma and metastasis in a rat model of breast carcinogenesis. To enhance β-endorphin (BEP), the endogenous opioid polypeptide that boosts immune activity and decreases stress, we generated BEP neurons by in vitro differentiation from fetal neuronal stem cells and transplanted them into the hypothalami of rats subjected to breast carcinogenesis. BEP-transplanted rats displayed a reduction in mammary tumor incidence, growth, malignancy rate, and metastasis compared with cortical cells-transplanted rats. BEP neuron transplants also reduced inflammation and epithelial to mesenchymal transition in the tumor tissues. In addition, BEP neuron transplants increased peripheral natural killer (NK) cell and macrophage activities, elevated plasma levels of antiinflammatory cytokines, and reduced plasma levels of inflammatory cytokines. Antimetastatic effects along with stimulation of NK cells and macrophages could be reversed by treatment with the opiate antagonist naloxone, the β-receptor agonist metaproterenol, or the nicotine acetylcholine receptor antagonist methyllycaconitine. Together, our findings establish a protective role for BEP against the growth and metastasis of mammary tumor cells by altering autonomic nervous system activities that enhance innate immune function.
authors.affiliation: Rutgers Endocrine Program, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA. Sarkar@aesop.rutgers.edu
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Sarkar
authors.forename: Changqing
authors.initials: C
authors.lastname: Zhang
authors.forename: Sengottuvelan
authors.initials: S
authors.lastname: Murugan
authors.forename: Madhavi
authors.initials: M
authors.lastname: Dokur
authors.forename: Nadka I
authors.initials: NI
authors.lastname: Boyadjieva
authors.forename: Maria
authors.initials: M
authors.lastname: Ortigüela
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Reuhl
authors.forename: Sepide
authors.initials: S
authors.lastname: Mojtehedzadeh
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology; D000818:Animals; D001341:Autonomic Nervous System; D002454:Cell Differentiation; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D007031:Hypothalamus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology; D008262:Macrophage Activation; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D058953:Neural Stem Cells / Q000166:cytology; D009474:Neurons / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D001615:beta-Endorphin / Q000378:metabolism*
chemical_list: D001615:beta-Endorphin