Rutgers Endocrine Program, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
Cancer Res. 2011 Oct 1;71(19):6282-91. doi: 10.1158/0008-5472.CAN-11-1610. Epub 2011 Aug 11.
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.
神经行为应激已被证明可促进肿瘤生长和进展，并抑制免疫系统。在这项研究中，我们研究了抑制应激激素产生是否可以抑制乳腺癌发生大鼠模型中乳腺癌的发展和转移。为了增强β-内啡肽（BEP），即增强免疫活性和降低应激的内源性阿片样多肽，我们从胎神经元干细胞体外分化产生 BEP 神经元，并将其移植到接受乳腺癌发生的大鼠下丘脑。与皮质细胞移植大鼠相比，BEP 移植大鼠的乳腺肿瘤发生率、生长、恶性程度和转移减少。BEP 神经元移植还减少了肿瘤组织中的炎症和上皮间质转化。此外，BEP 神经元移植增加了外周自然杀伤（NK）细胞和巨噬细胞的活性，提高了抗炎细胞因子的血浆水平，并降低了促炎细胞因子的血浆水平。用阿片拮抗剂纳洛酮、β-受体激动剂间羟异丙肾上腺素或烟碱乙酰胆碱受体拮抗剂甲基六氢吡啶处理可逆转其抗转移作用，同时刺激 NK 细胞和巨噬细胞。总之，我们的研究结果确立了 BEP 通过改变增强固有免疫功能的自主神经系统活动，对乳腺肿瘤细胞的生长和转移起到保护作用。
