Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein(MVP)
Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein(MVP)
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DOI：
10.1186/s13058-018-1088-6
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发表时间：
2019-01-17
影响因子：
7.4
通讯作者：
Muller, Catherine
中科院分区：
文献类型：
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作者：
Lehuede, Camille;Li, Xia;Muller, Catherine
前言临床研究表明，肥胖除了促进乳腺癌的侵袭性外，还与化疗疗效的降低有关，尽管所涉及的机制仍不清楚。作为化疗是侵袭性或转移性乳腺癌的主要治疗方法之一，我们研究了脂肪细胞是否可以介导多柔比星（DOX），用于治疗乳腺癌的主要药物之一，和相关的mechanisms.MethodsWe使用的共培养系统生长乳腺癌细胞与体外分化的脂肪细胞，以及原发性乳腺脂肪细胞分离瘦和肥胖患者。通过免疫荧光、流式细胞术和细胞外囊泡分析研究药物细胞蓄积、分布和外排。结果进行了验证，通过免疫组化在一系列的瘦和肥胖的患者cancer.ResultsAdipocytes分化在体外促进DOX耐药性（与交叉耐药紫杉醇和5-氟尿嘧啶）在一个大的面板的人和小鼠乳腺癌细胞系独立于他们的亚型。在共培养的细胞中，DOX的亚细胞分布发生了改变，药物的核积聚减少，与细胞质小泡中的局部积聚相关，然后被排出到细胞外培养基中。运输相关的主要穹窿蛋白（MVP），其表达上调的脂肪细胞，介导这两个过程。与人乳腺脂肪细胞共培养也诱导乳腺癌细胞的化学抗性（以及相关的MVP诱导的DOX流出），并且它们的作用被肥胖放大。最后，在一系列人类乳腺肿瘤中，我们观察到MVP表达的梯度，在肿瘤细胞靠近脂肪细胞的浸润前沿比肿瘤中心更高，突出了我们结果的临床相关性。MVP在这些肿瘤细胞中的高表达是特别感兴趣的，因为它们更有可能传播引起化疗耐药metabolis.ConclusionsCollectively，我们的研究表明，脂肪细胞诱导MVP相关的多药耐药表型的乳腺癌细胞，这可能有助于肥胖相关的化疗耐药。
IntroductionClinical studies suggest that obesity, in addition to promoting breast cancer aggressiveness, is associated with a decrease in chemotherapy efficacy, although the mechanisms involved remain elusive. As chemotherapy is one of the main treatments for aggressive or metastatic breast cancer, we investigated whether adipocytes can mediate resistance to doxorubicin (DOX), one of the main drugs used to treat breast cancer, and the mechanisms associated.MethodsWe used a coculture system to grow breast cancer cells with in vitro differentiated adipocytes as well as primary mammary adipocytes isolated from lean and obese patients. Drug cellular accumulation, distribution, and efflux were studied by immunofluorescence, flow cytometry, and analysis of extracellular vesicles. Results were validated by immunohistochemistry in a series of lean and obese patients with cancer.ResultsAdipocytes differentiated in vitro promote DOX resistance (with cross-resistance to paclitaxel and 5-fluorouracil) in a large panel of human and murine breast cancer cell lines independently of their subtype. Subcellular distribution of DOX was altered in cocultivated cells with decreased nuclear accumulation of the drug associated with a localized accumulation in cytoplasmic vesicles, which then are expelled into the extracellular medium. The transport-associated major vault protein (MVP), whose expression was upregulated by adipocytes, mediated both processes. Coculture with human mammary adipocytes also induced chemoresistance in breast cancer cells (as well as the related MVP-induced DOX efflux) and their effect was amplified by obesity. Finally, in a series of human breast tumors, we observed a gradient of MVP expression, which was higher at the invasive front, where tumor cells are at close proximity to adipocytes, than in the tumor center, highlighting the clinical relevance of our results. High expression of MVP in these tumor cells is of particular interest since they are more likely to disseminate to give rise to chemoresistant metastases.ConclusionsCollectively, our study shows that adipocytes induce an MVP-related multidrug-resistant phenotype in breast cancer cells, which could contribute to obesity-related chemoresistance.