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Nicotine Synergizes with High-Fat Diet to Induce an Anti-Inflammatory Microenvironment to Promote Breast Tumor Growth
Mediators of Inflammation ( IF 4.6 ) Pub Date : 2020-12-14 , DOI: 10.1155/2020/5239419
Thalia Jimenez 1 , Theodore Friedman 1, 2 , Jaydutt Vadgama 2, 3, 4 , Vineeta Singh 1 , Alexandria Tucker 1 , Javier Collazo 1 , Satyesh Sinha 1, 2 , Amiya Sinha Hikim 1, 2 , Rajan Singh 1, 3, 5 , Shehla Pervin 1, 3, 5
Affiliation  

Breast cancer results from a complex interplay of genetics and environment that alters immune and inflammatory systems to promote tumorigenesis. Obesity and cigarette smoking are well-known risk factors associated breast cancer development. Nicotine known to decrease inflammatory signals also modulates immune responses that favor breast cancer development. However, the mechanisms by which nicotine and obesity contribute to breast cancer remain poorly understood. In this study, we examined potential mechanisms by which nicotine (NIC) and high-fat diet (HFD) promote growth of HCC70 and HCC1806 xenografts from African American (AA) triple negative (TN) breast cancer cells. Immunodeficient mice fed on HFD and treated with NIC generated larger HCC70 and HCC1806 tumors when compared to NIC or HFD alone. Increased xenograft growth in the presence of NIC and HFD was accompanied by higher levels of tissue-resident macrophage markers and anti-inflammatory cytokines including IL4, IL13, and IL10. We further validated the involvement of these players by in vitro and ex vivo experiments. We found a proinflammatory milieu with increased expression of IL6 and IL12 in xenografts with HFD. In addition, nicotine or nicotine plus HFD increased a subset of mammary cancer stem cells (MCSCs) and key adipose browning markers CD137 and TMEM26. Interestingly, there was upregulation of stress-induced pp38 MAPK and pERK1/2 in xenografts exposed to HFD alone or nicotine plus HFD. Scratch-wound assay showed marked reduction in proliferation/migration of nicotine and palmitate-treated breast cancer cells with mecamylamine (MEC), a nicotine acetylcholine receptor (nAchR) antagonist. Furthermore, xenograft development in immune-deficient mice, fed HFD plus nicotine, was reduced upon cotreatment with MEC and SB 203580, a pp38MAPK inhibitor. Our study demonstrates the presence of nicotine and HFD in facilitating an anti-inflammatory tumor microenvironment that influences breast tumor growth. This study also shows potential efficacy of combination therapy in obese breast cancer patients who smoke.

中文翻译:

尼古丁与高脂肪饮食协同诱导抗炎微环境促进乳腺肿瘤生长

乳腺癌是遗传和环境复杂相互作用的结果,这种相互作用会改变免疫和炎症系统以促进肿瘤发生。肥胖和吸烟是众所周知的与乳腺癌发展相关的危险因素。已知能减少炎症信号的尼古丁还会调节有利于乳腺癌发展的免疫反应。然而,尼古丁和肥胖导致乳腺癌的机制仍然知之甚少。在这项研究中,我们研究了尼古丁 (NIC) 和高脂肪饮食 (HFD) 促进非裔美国人 (AA) 三阴性 (TN) 乳腺癌细胞 HCC70 和 HCC1806 异种移植物生长的潜在机制。与单独的 NIC 或 HFD 相比,以 HFD 为食并用 NIC 治疗的免疫缺陷小鼠产生更大的 HCC70 和 HCC1806 肿瘤。在 NIC 和 HFD 存在下异种移植物生长增加伴随着更高水平的组织驻留巨噬细胞标志物和抗炎细胞因子,包括 IL4、IL13 和 IL10。我们通过以下方式进一步验证了这些参与者的参与体外离体实验。我们发现了一个促炎环境,在 HFD 异种移植物中 IL6 和 IL12 的表达增加。此外,尼古丁或尼古丁加 HFD 增加了乳腺癌干细胞 (MCSC) 和关键脂肪褐变标志物 CD137 和 TMEM26 的一个子集。有趣的是,在单独暴露于 HFD 或尼古丁加 HFD 的异种移植物中,应激诱导的 pp38 MAPK 和 pERK1/2 上调。划痕试验显示,用美加明 (MEC)(一种尼古丁乙酰胆碱受体 (nAchR) 拮抗剂)处理的尼古丁和棕榈酸酯处理的乳腺癌细胞的增殖/迁移显着减少。此外,在与 MEC 和 SB 203580(一种 pp38MAPK 抑制剂)共同处理后,免疫缺陷小鼠在喂食 HFD 加尼古丁的情况下异种移植物的发育减少。我们的研究表明,尼古丁和 HFD 的存在有助于促进影响乳腺肿瘤生长的抗炎肿瘤微环境。该研究还显示了联合疗法对吸烟的肥胖乳腺癌患者的潜在疗效。
更新日期:2020-12-14
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