Cancer-mediated adipose reversion promotes cancer cell migration via IL-6 and MCP-1
Cancer-mediated adipose reversion promotes cancer cell migration via IL-6 and MCP-1
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DOI：
10.1007/s10549-015-3318-2
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发表时间：
2015-04-01
影响因子：
3.8
通讯作者：
Miyazaki, Masaru
中科院分区：
文献类型：
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作者：
Fujisaki, Kaoru;Fujimoto, Hiroshi;Miyazaki, Masaru
本研究的目的是研究脂肪细胞和乳腺癌细胞之间的相互作用，并确定观察到的影响的影响因素。在27例接受乳房切除术的乳腺癌患者中，从有肿瘤的乳腺象限和相应的非肿瘤象限中获取乳腺脂肪组织。在胶原凝胶中培养分离的正常乳腺脂肪细胞（NBA）和癌症相关脂肪细胞（CAA）以模拟体内环境。进行免疫组织化学、qRT-PCR 和细胞增殖测定来分析脂肪细胞表型。 MCF7和MDA-MB-231乳腺癌细胞系与脂肪细胞共培养以检测表型变化。在 NBA 和 CAA 条件培养基中评估 MCF7 和 MDA-MB-231 细胞的迁移。通过细胞因子阵列测量条件培养基中的细胞因子水平。使用含有中和抗体的条件培养基重复迁移测定。 NBA 和 CAA 在培养物中失去了其形态表型，获得了纺锤状的形状，并且 CAA 显示出更高的细胞增殖，表明恢复到不成熟的表型。在与 MCF7 或 MDA-MB-231 细胞共培养中，NBA 表现出细胞增殖增加，表明获得了 CAA 的不成熟表型。 MCF7 和 MDA-MB-231 在 CAA 条件培养基中显示出比在 NBA 条件培养基中更高的迁移。条件培养基的细胞因子阵列分析显示，CAA 条件培养基中白细胞介素 6 (IL-6) 和单核细胞趋化蛋白 1 (MCP-1) 水平较高。使用针对 IL-6 或 MCP-1 的抗体进行的中和实验表明，CAA 条件培养基的迁移增强作用被消除。在乳腺癌细胞存在的情况下，脂肪细胞恢复为不成熟和增殖的表型，并通过包括 IL-6 和 MCP-1 在内的脂肪因子促进癌细胞迁移。
The objective of this study is to investigate interactions between adipocytes and breast cancer cells, and identify the responsible factors for the observed effects. In 27 breast cancer patients undergoing mastectomy, mammary adipose tissue was obtained from the breast quadrant bearing the tumor and corresponding non-tumoral quadrant. Isolated normal breast adipocytes (NBAs) and cancer-associated adipocytes (CAAs) were cultured in collagen gels to mimic the in vivo environment. Immunohistochemistry, qRT-PCR, and cell proliferation assays were performed to analyze adipocyte phenotypes. MCF7 and MDA-MB-231 breast cancer cell lines were co-cultured with adipocytes to detect phenotypic changes. Migration of MCF7 and MDA-MB-231 cells was assessed in NBA- and CAA-conditioned media. Cytokine levels in conditioned media were measured by cytokine array. Migration assays were repeated using conditioned media containing neutralizing antibodies. NBAs and CAAs lost their morphological phenotype in culture, acquiring a spindle-like shape, and CAAs showed higher cell proliferation, suggesting reversion to an immature phenotype. In co-cultures with MCF7 or MDA-MB-231 cells, NBAs exhibited increased cell proliferation, indicating acquisition of the immature phenotype of CAAs. MCF7 and MDA-MB-231 showed higher migration in a CAA-conditioned medium than in an NBA-conditioned medium. Cytokine array analysis of conditioned media revealed higher levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in the CAA-conditioned medium. Neutralization experiments using antibodies against IL-6 or MCP-1 showed abrogation of migration-enhancing effects of the CAA-conditioned medium. Adipocytes revert to an immature and proliferative phenotype in the presence of breast cancer cells, and promote cancer cell migration via adipokines including IL-6 and MCP-1.