Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA.
Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
Cancer Lett. 2020 Oct 28;491:132-145. doi: 10.1016/j.canlet.2020.08.010. Epub 2020 Aug 21.
Young women represent a target of E-cigarette (E-cig) companies, raising concern for potential connections with breast cancer (BC) that have not yet been elucidated. We hypothesized that E-cig promotes BC development and lung metastasis possibly through BC-monocyte/tumor-associated macrophage (TAM) crosstalk via CCL5 and V-CAM-1 axes. We demonstrated that E-cig promoted the infiltration of circulating monocytes in mammary fat pad (MFP) model. Furthermore, E-cig exposure significantly enhanced BC cell growth in MFP tumor and metastatic lung colonization; immunohistochemical stains illustrated the increase of TAMs infiltration, reduced BC cell apoptosis and increased proliferation index after E-cig exposure. In vitro studies show E-cig vapor condensate (EVC) treatment upregulated protein expressions of CCL5, V-CAM-1, and other pro-tumorigenic factors in BC cells. Mechanistically, co-culture system demonstrated both EVC and macrophages independently stimulated BC cell growth and the migration via CCL5/CCR1/CCR5 axis. During metastasis, E-Cig exposure stimulated BC cell survival via direct interaction with infiltrated macrophages, regulated by VCAM-1 and integrin αβ1. Our findings, for the first time, showed that E-cig promotes BC growth and metastasis. This study highlights the critical role of TAMs via CCL5 and VCAM-1 pathways in E-cig promoted BC tumor development.
年轻女性是电子烟（E-cig）公司的目标群体，这引发了人们对电子烟可能与乳腺癌（BC）之间潜在联系的担忧，而这些联系尚未得到阐明。我们假设，电子烟可能通过 CCL5 和 V-CAM-1 轴促进乳腺癌单核细胞/肿瘤相关巨噬细胞（TAM）之间的串扰，从而促进乳腺癌的发展和肺转移。我们证明，电子烟促进了循环单核细胞在乳腺脂肪垫（MFP）模型中的浸润。此外，电子烟暴露显著增强了 MFP 肿瘤和转移性肺定植中的乳腺癌细胞生长；免疫组织化学染色表明，电子烟暴露后 TAMs 的浸润增加，乳腺癌细胞凋亡减少，增殖指数增加。体外研究表明，电子烟蒸汽冷凝物（EVC）处理上调了乳腺癌细胞中 CCL5、V-CAM-1 和其他促肿瘤因子的蛋白表达。在机制上，共培养系统表明 EVC 和巨噬细胞均可通过 CCL5/CCR1/CCR5 轴独立刺激乳腺癌细胞生长和迁移。在转移过程中，电子烟暴露通过与浸润的巨噬细胞直接相互作用，通过 VCAM-1 和整合素 αβ1 调节乳腺癌细胞的存活。我们的研究结果首次表明，电子烟促进了乳腺癌的生长和转移。本研究强调了 TAMs 通过 CCL5 和 VCAM-1 途径在电子烟促进乳腺癌肿瘤发展中的关键作用。
