Cancer-educated mammary adipose tissue-derived stromal/stem cells in obesity and breast cancer: spatial regulation and function

Journal of Experimental & Clinical Cancer Research

Research

Christine Solbach¹  Babek Kahn Safdar¹  Nina-Naomi Kreis¹  Roman Allert¹  Andreas Ritter¹  Juping Yuan¹  Alexandra Friemel¹  Julia Maria Wildner¹  Samira Catharina Hoock¹  Frank Louwen¹  Susanne Roth¹ 

[1] Obstetrics and Prenatal Medicine, Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590, Frankfurt, Germany;

关键词: Breast adipose tissue-derived mesenchymal stromal/stem cells;    Cancer-associated fibroblasts;    Obesity;    Breast cancer;    Epithelial-to-mesenchymal transition;    Chemoresistance;    Cancer stem cells;    Tumor microenvironment;   

DOI  :  10.1186/s13046-022-02592-y

 received in 2022-09-26, accepted in 2022-12-29,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundBreast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity is associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Breast adipose tissue-derived mesenchymal stromal/stem cells (bASCs) are crucial components of the tumor microenvironment. A key step initially involved in this process might be the de-differentiation of bASCs into tumor supporting phenotypes.MethodsIn the present work, we isolated bASCs from adipose tissues adjacent to the tumor (aT bASCs) from lean- (ln-aT bASCs, BMI ≤ 25) and breast cancer patients with obesity (ob-aT bASCs, BMI ≥ 35), and analyzed their phenotypes with functional assays and RNA sequencing, compared to their counterparts isolated from adipose tissues distant from the tumor (dT bASCs).ResultsWe show that ln-aT bASCs are susceptible to be transformed into an inflammatory cancer-associated phenotype, whereas ob-aT bASCs are prone to be cancer-educated into a myofibroblastic phenotype. Both ln-aT- and ob-aT bASCs compromise their physiological differentiation capacity, and upregulate metastasis-promoting factors. While ln-aT bASCs stimulate proliferation, motility and chemoresistance by inducing epithelial-mesenchymal transition of low malignant breast cancer cells, ob-aT bASCs trigger more efficiently a cancer stem cell phenotype in highly malignant breast cancer cells.ConclusionBreast cancer-associated bASCs are able to foster malignancy of breast cancer cells by multiple mechanisms, especially, induction of epithelial-mesenchymal transition and activation of stemness-associated genes in breast cancer cells. Blocking the de-differentiation of bASCs in the tumor microenvironment could be a novel strategy to develop an effective intervention for breast cancer patients.SignificanceThis study provides mechanistic insights into how obesity affects the phenotype of bASCs in the TME. Moreover, it highlights the molecular changes inside breast cancer cells upon cell-cell interaction with cancer-educated bASCs.Graphical abstract

【 授权许可】

CC BY   
© The Author(s) 2023

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