Psychological stressors have been implicated in the progression of various tumor types. We investigated a role for stress in tumor immune cell chemotaxis in the B16F10 mouse model of malignant melanoma. We exposed female mice to 6-hour periods of restraint stress (RST) for 7 days, then implanted B16F10 malignant melanoma tumor cells and continued the RST paradigm for 14 additional days. We determined serum corticosterone and liver catecholamine concentrations in these mice. To evaluate the tumor microenvironment, we performed IHC and examined cytokine expression profiles using ELISA-based analysis of tumor homogenates. We found that tumors in mice subjected to RST grew significantly slower, had reduced tumor C-C motif ligand 2 (CCL2), and contained fewer F4/80-positive macrophages than tumors from unstressed mice. We observed a concomitant increase in norepinephrine among the RST mice. An in vitro assay confirmed that norepinephrine downregulates CCL2 production in both mouse and human macrophages, and that pretreatment with the pan-β-adrenergic receptor inhibitor nadolol rescues this activity. Furthermore, RST had no effect on tumor growth in transgenic CCL2-deficient mice. This study suggests that stress reduces malignant melanoma by reducing recruitment of tumor-promoting macrophages by CCL2.

中文翻译：

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压力诱导的去甲肾上腺素下调巨噬细胞中的 CCL2 以抑制恶性黑色素瘤模型中的肿瘤生长

心理压力因素与各种肿瘤类型的进展有关。我们研究了压力在恶性黑色素瘤 B16F10 小鼠模型中肿瘤免疫细胞趋化性中的作用。我们将雌性小鼠暴露于 6 小时的束缚应激 (RST) 下 7 天，然后植入 B16F10 恶性黑色素瘤肿瘤细胞并继续使用 RST 范式 14 天。我们测定了这些小鼠的血清皮质酮和肝脏儿茶酚胺浓度。为了评估肿瘤微环境，我们进行了 IHC 并使用基于 ELISA 的肿瘤匀浆分析检查了细胞因子表达谱。我们发现接受 RST 的小鼠的肿瘤生长显着减慢，肿瘤 CC 基序配体 2 (CCL2) 减少，并且含有的 F4/80 阳性巨噬细胞比未受应激小鼠的肿瘤少。我们观察到 RST 小鼠中去甲肾上腺素的伴随增加。一项体外试验证实，去甲肾上腺素可下调小鼠和人类巨噬细胞中 CCL2 的产生，并且用泛β-肾上腺素能受体抑制剂纳多洛尔预处理可挽救这种活性。此外，RST 对转基因 CCL2 缺陷小鼠的肿瘤生长没有影响。这项研究表明，压力通过减少 CCL2 对促肿瘤巨噬细胞的募集来减少恶性黑色素瘤。