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

Breast Cancer Research

Fokhrul M. Hossain¹  Lucio Miele¹  Rachel Wise²  Benjamen O’Donnell²  Annie C. Bowles²  Alex Côté²  Rachel A. Sabol²  Bruce A. Bunnell³  Hope E. Burks⁴  Bridgette M. Collins-Burow⁴  Margarite D. Matossian⁴  Matthew E. Burow⁴  Luis Del Valle⁵ 

[1] 0000 0000 8954 1233, grid.279863.1, Department of Genetics, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA, USA;Stanley S. Scott Cancer Center, Louisiana Cancer Research Center (LCRC), LSUSHC, New Orleans, LA, USA;0000 0001 2217 8588, grid.265219.b, Center for Stem Cell Research and Regenerative Medicine, Tulane University, 1430 Tulane Ave, #8699, 70112, New Orleans, LA, USA;0000 0001 2217 8588, grid.265219.b, Center for Stem Cell Research and Regenerative Medicine, Tulane University, 1430 Tulane Ave, #8699, 70112, New Orleans, LA, USA;0000 0001 2217 8588, grid.265219.b, Department of Pharmacology, Tulane University, New Orleans, LA, USA;0000 0001 2217 8588, grid.265219.b, Department of Medicine, Section of Hematology and Oncology, Tulane University, New Orleans, LA, USA;Stanley S. Scott Cancer Center, Louisiana Cancer Research Center (LCRC), LSUSHC, New Orleans, LA, USA;0000 0000 8954 1233, grid.279863.1, Department of Pathology, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA, USA;

关键词: Adipose stem cells;    Obesity;    Triple-negative breast cancer;    Metastasis;    Patient-derived xenograft;   

DOI  :  10.1186/s13058-019-1153-9

来源: publisher

【 摘 要 】

BackgroundBreast 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.MethodsIn 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).ResultsWe 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.ConclusionsLeptin signaling is a potential mechanism through which obASCs promote metastasis of TNBC in both in vitro and in vivo analyses.

【 授权许可】

CC BY