Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Biomedical Research Support Center, Nagasaki University School of Medicine, Nagasaki, Japan.
J Hepatobiliary Pancreat Sci. 2023 Jul;30(7):935-943. doi: 10.1002/jhbp.1295. Epub 2022 Dec 13.
BACKGROUND/PURPOSE: Sympathetic nerve stimulation by stress exacerbates various solid tumors, including pancreatic cancer (PCa). The relationship between cancer and immunity has been suggested; however, there is limited information about the effects of nerve stimulation on immunity and cancer. We aimed to investigate the involvement of sympathetic nerve stimulation in immune cells and its effects on PCa using a restraint stress mouse model.
In the in vitro experiment, the mouse-derived PCa cell line (LTPA) was cultured in a noradrenalin-supplemented medium. In the in vivo experiment, mice were divided into non-stress and stress groups.
LTPA proliferated significantly more when cultured in a noradrenalin-supplemented medium than in a normal medium. Flow cytometry analysis of blood immune cells revealed a significant decrease in B cells, T cells, and macrophages and a significant increase in myeloid-derived suppressor cells (MDSCs) in the stress group. Furthermore, a significant increase in blood noradrenaline levels was observed in the stress group (p < .01). In the PCa mice model, immune cells in the blood showed a similar trend, and the stress group had a poor prognosis. Furthermore, immunostaining at the tumor site showed that there was a lower number of B and T cells in the stress group. In addition, MDSCs were present at the tumor margins.
These results suggest that sympathetic nerve stimulation is not only directly involved in PCa growth but also exacerbates PCa by creating an immunosuppressive environment in the blood and tumor tissue.
背景/目的：应激引起的交感神经刺激可加重各种实体瘤，包括胰腺癌（PCa）。癌症与免疫之间的关系已被提出；然而，关于神经刺激对免疫和癌症的影响的信息有限。我们旨在使用束缚应激小鼠模型研究交感神经刺激在免疫细胞中的作用及其对 PCa 的影响。
在体外实验中，培养小鼠源性 PCa 细胞系（LTPA）在去甲肾上腺素补充培养基中。在体内实验中，将小鼠分为非应激组和应激组。
与正常培养基相比，LTPA 在去甲肾上腺素补充培养基中培养时增殖显著增加。对血液免疫细胞的流式细胞术分析显示，应激组 B 细胞、T 细胞和巨噬细胞显著减少，髓样来源抑制细胞（MDSCs）显著增加。此外，应激组的血液去甲肾上腺素水平显著升高（p<.01）。在 PCa 小鼠模型中，血液中的免疫细胞也呈现出类似的趋势，应激组的预后较差。此外，肿瘤部位的免疫组化染色显示，应激组肿瘤边缘的 B 细胞和 T 细胞数量较少。此外，MDSCs 存在于肿瘤边缘。
这些结果表明，交感神经刺激不仅直接参与 PCa 生长，而且通过在血液和肿瘤组织中创造免疫抑制环境来加重 PCa。
