Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein(MVP)

被引：98

作者：

Lehuede, Camille ^{[1
,2
]}

Li, Xia ^{[1
,7
]}

Dauvillier, Stephanie ^{[1
]}

Vaysse, Charlotte ^{[1
,3
]}

Franchet, Camille ^{[4
]}

Clement, Emily ^{[1
]}

Esteve, David ^{[1
]}

Longue, Melanie ^{[5
]}

Chaltiel, Leonor ^{[5
]}

Le Gonidec, Sophie ^{[2
]}

Lazar, Ikrame ^{[1
]}

Geneste, Aline ^{[6
]}

Dumontet, Charles ^{[6
]}

Valet, Philippe ^{[2
]}

Nieto, Laurence ^{[1
]}

Fallone, Frederique ^{[1
]}

Muller, Catherine ^{[1
]}

机构：

[1] Univ Toulouse, IPBS, UPS, CNRS,UMR 5089, 205 Route Narbonne, F-31077 Toulouse, France

[2] Univ Toulouse, Inst Malad Metabol & Cardiovasc I2MC, INSERM, UPS, Toulouse, France

[3] CHU Toulouse, Inst Univ Canc Toulouse Oncopole, Dept Chirurg Oncol, Toulouse, France

[4] CHU Toulouse, Inst Univ Canc Toulouse Oncopole, Serv Anatomopathol, Toulouse, France

[5] Inst Univ Canc Toulouse Oncopole, Inst Claudius Regaud, Dept Biostat, Toulouse, France

[6] INSERM, CRCL, CNRS, UMR 1052, Lyon, France

[7] Chongqing Med Univ, Affiliated Hosp 1, Dept Oncol, Chongqing, Peoples R China

来源：

BREAST CANCER RESEARCH | 2019年 / 21卷 / 1期

关键词：

Adipocytes; Breast cancer; Obesity; Doxorubicin; Multidrug resistance; Mammary adipose tissue; BODY-MASS INDEX; MULTIDRUG-RESISTANCE; TUMOR PROGRESSION; DRUG-RESISTANCE; CELLS; DOXORUBICIN; EXPRESSION; INFLAMMATION; WOMEN; LRP;

D O I：

10.1186/s13058-018-1088-6

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：17

共 56 条

[1] Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front [J].