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Type 2 Diabetes Mellitus Promotes the Differentiation of Adipose Tissue-Derived Mesenchymal Stem Cells into Cancer-Associated Fibroblasts, Induced by Breast Cancer Cells.
- Source :
-
Stem cells and development [Stem Cells Dev] 2022 Nov; Vol. 31 (21-22), pp. 659-671. Date of Electronic Publication: 2022 Jul 30. - Publication Year :
- 2022
-
Abstract
- Triple-negative breast cancer (TNBC) is a highly aggressive and invasive type of breast cancer. In addition, type 2 diabetes mellitus (T2DM) is recognized as a risk factor for cancer metastasis, which is associated with mortality in patients with breast cancer. Cancer-associated fibroblasts (CAFs) generated from adipose tissue-derived mesenchymal stem cells (AT-MSCs) play a vital role in the progression of TNBC. However, to date, whether T2DM affects the ability of AT-MSCs to differentiate into CAFs is still unclear. In this study, we found that in coculture with TNBC cells [breast cancer cells (BCCs)] under hypoxic conditions, AT-MSCs derived from T2DM donors (dAT-MSCs) were facilitated to differentiate into CAFs, which showed fibroblastic morphology and the induced expression of fibroblastic markers, such as fibroblast activation protein, fibroblast-specific protein, and vimentin. This was involved in the higher expression of transforming growth factor beta receptor 2 (TGFβR2) and the phosphorylation of Smad2/3. Furthermore, T2DM affected the fate and functions of CAFs derived from dAT-MSCs. While CAFs derived from AT-MSCs of healthy donors (AT-CAFs) exhibited the markers of inflammatory CAFs, those derived from dAT-MSCs (dAT-CAFs) showed the markers of myofibroblastic CAFs. Of note, in comparison with AT-CAFs, dAT-CAFs showed a higher ability to induce the proliferation and in vivo metastasis of BCCs, which was involved in the activation of the transforming growth factor beta (TGFβ)-Smad2/3 signaling pathway. Collectively, our study suggests that T2DM contributes to metastasis of BCCs by inducing the myofibroblastic CAFs differentiation of dAT-MSCs. In addition, targeting the TGFβ-Smad2/3 signaling pathway in dAT-MSCs may be useful in cancer therapy for TNBC patients with T2DM.
- Subjects :
- Humans
Female
Cell Line, Tumor
Fibroblasts
Transforming Growth Factor beta metabolism
Cancer-Associated Fibroblasts metabolism
Cancer-Associated Fibroblasts pathology
Triple Negative Breast Neoplasms metabolism
Triple Negative Breast Neoplasms pathology
Breast Neoplasms pathology
Diabetes Mellitus, Type 2 metabolism
Mesenchymal Stem Cells
Subjects
Details
- Language :
- English
- ISSN :
- 1557-8534
- Volume :
- 31
- Issue :
- 21-22
- Database :
- MEDLINE
- Journal :
- Stem cells and development
- Publication Type :
- Academic Journal
- Accession number :
- 35734905
- Full Text :
- https://doi.org/10.1089/scd.2022.0086