Leptin produced by obesity-altered adipose stem cells promotes metastasis but not tumorigenesis of triple-negative breast cancer in orthotopic xenograft and patient-derived xenograft models

被引:54
作者
Sabol, Rachel A. [1 ]
Bowles, Annie C. [1 ]
Cote, Alex [1 ]
Wise, Rachel [1 ]
O'Donnell, Benjamen [1 ]
Matossian, Margarite D. [2 ]
Hossain, Fokhrul M. [3 ,4 ]
Burks, Hope E. [2 ]
Del Valle, Luis [4 ,5 ]
Miele, Lucio [3 ,4 ]
Collins-Burow, Bridgette M. [2 ]
Burow, Matthew E. [2 ]
Bunnell, Bruce A. [1 ,6 ]
机构
[1] Tulane Univ, Ctr Stem Cell Res & Regenerat Med, 1430 Tulane Ave,8699, New Orleans, LA 70112 USA
[2] Tulane Univ, Dept Med, Sect Hematol & Oncol, New Orleans, LA 70118 USA
[3] LSUHSC, Dept Genet, New Orleans, LA USA
[4] LSUSHC, LCRC, Stanley S Scott Canc Ctr, New Orleans, LA USA
[5] LSUHSC, Dept Pathol, New Orleans, LA USA
[6] Tulane Univ, Dept Pharmacol, New Orleans, LA 70112 USA
来源
BREAST CANCER RESEARCH | 2019年 / 21卷 / 1期
基金
美国国家卫生研究院;
关键词
Adipose stem cells; Obesity; Triple-negative breast cancer; Metastasis; Patient-derived xenograft; EXPRESSION; PATTERNS; STROMA;
D O I
10.1186/s13058-019-1153-9
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Breast cancer is the second leading cause of cancer deaths in the USA. Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with high rates of metastasis, tumor recurrence, and resistance to therapeutics. Obesity, defined by a high body mass index (BMI), is an established risk factor for breast cancer. Women with a high BMI have increased incidence and mortality of breast cancer; however, the mechanisms(s) by which obesity promotes tumor progression are not well understood. Methods: In this study, obesity-altered adipose stem cells (obASCs) were used to evaluate obesity-mediated effects of TNBC. Both in vitro and in vivo analyses of TNBC cell lines were co-cultured with six pooled donors of obASCs (BMI>30) or ASCs isolated from lean women (lnASCs) (BMI < 25). Results: We found that obASCs promote a pro-metastatic phenotype by upregulating genes associated with epithelial-to-mesenchymal transition and promoting migration in vitro. We confirmed our findings using a TNBC patient-derived xenograft (PDX) model. PDX tumors grown in the presence of obASCS in SCID/beige mice had increased circulating HLA1(+) human cells as well as increased numbers of CD44(+)CD24(-) cancer stem cells in the peripheral blood. Exposure of the TNBC PDX to obASCs also increased the formation of metastases. The knockdown of leptin expression in obASCs suppressed the pro-metastatic effects of obASCs. Conclusions: Leptin signaling is a potential mechanism through which obASCs promote metastasis of TNBC in both in vitro and in vivo analyses.
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页数:14
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