Table 3.
Subtypes of cancer associated ASCs/CAFs in breast cancer.
| Fibroblast/CAF Source | Study Design | Functions and Molecular Mechanisms | Ref. |
|---|---|---|---|
| Human adipose progenitors (APs) isolated from adipose tissue and breast-APs (B-APs) isolated from breast adipose tissue | MCF-7 and T47D cell lines in vitro | Primary cilia of APs were required for de-differentiation of APs into CAFs stimulated by breast cancer cells. Inhibition of cilia stopped the malignant transition of APs. Primary cilia mediated TGFβ1 signaling to APs. | [234] |
| Human lean and obese ASCs from abdominal lipoaspirates of subcutaneous adipose tissue | MCF7 cell line in vitro | Co-culture of breast cancer cells with lean and obese ASCs induced a CAF-like phenotype with elevated gene expression of NG2, ACTA2, VEGF, FAP, and FSP. This cancer-educated phenotype was enhanced in obese ASCs compared to lean counterparts. Obese ASCs were more potent in inducing the expression of pro-tumorgenic factors in breast cancer cells including Serpin1, CCL5, TARC, IL24, IL6, IGFBP3, adiponectin, and leptin. | [126] |
| Human adipocytes/pre-adipocytes isolated from breast cancer tissue or reduction mammoplasty | Co-culture with murine 3T3-F442A pre-adipocytes cell line, murine 4T1 breast cancer cell line, human breast cancer cell line SUM159PT in vitro | Co-culture of breast cancer cells with mature adipocytes or pre-adipocytes led to enhanced secretion of fibronectin and collagen I. This was associated with enhanced migration/invasion and the expression of known CAF marker FSP1. The de-differentiation process was triggered by the reactivation of the Wnt/β-catenin pathway in response to Wnt3a. | [251] |
| Human ASCs isolated from unprocessed subcutaneous adipose tissue | MDA-MB-231 and MCF7 cell lines and supernatant, in vitro | ASCs were de-differentiated in response to supernatant of breast cancer cells, shown by the expression of ACTA2, SDF1, CCL5, and tenascin-C, mediated by TGFβ1/Smad3. | [94] |
| Immortalized human AD-MSC cell line ASC52telo (ATCC) | Capan-1 and MIAPaCa-2 human PDAC cell lines and stroma-rich cell-derived xenograft (Sr-CDX) mouse model in vitro/in vivo | The SR-CDX model resembled the PDAC phenotype induced by CAFs with accelerated tumor growth, stromal cell proliferation, chemoresistance, and dense stroma. Single-cell RNA sequencing revealed that the CAFs in the TME were derived from the transplanted AD-MSCs, which de-differentiated into known and unknown CAF subtypes. | [245] |
| Data sets from multiple pan-cancer biopsy tissues | Single-cell RNA sequencing data sets from multiple cancer biopsies to recapitulate ASC de-differentiation process in vitro | This analysis revealed that CAFs originated from a particular subset of ASCs present in the stroma vascular fraction of normal adipose tissue. The transition stages of ASCs were recapitulated toward a cance-associated phenotype by using a rich pancreatic cancer dataset. At the endpoint of this transition process, the cells presented the following upregulated genes: MMP11, COL11A1, C1QTNF3, CTHRC1, COL12A1, COL10A1, COL5A2, THBS2, AEBP1, LRRC15, and ITGA11. | [246] |
| Immortalized human AD-MSC cell line ASC52telo (ATCC) | Capan-1, SUIT-2, and MIAPaCa-2 human PDAC cell lines and stroma-rich cell-derived xenograft (Sr-CDX) mouse model in vitro | AD-MSCs acted as precursors for CAFs in vitro. AD-MSCs could be induced into myCAFS and iCAFs upon co-culture with PDAC cells. Direct co-culture led to a myCAF phenotype, whereas indirect co-culture induced an iCAF gene expression pattern. | [247] |
| Human ASCs (ADSC-GM) from Lonza | MDA-MB-231 breast cancer cell line and HUVECs in vitro | EVs from MDA-MB-231 converted ASCs into a myCAF-like phenotype, with increased VEGF and ECM remodeling, and partly driven by MAPK signaling. | [252] |
Abbreviations: AP, adipose progenitors; ASCs, adipose-tissue-derived mesenchymal stromal/stem cells; MSCs, mesenchymal stromal/stem cells; BM-MSCs, bone-marrow-derived mesenchymal stromal/stem cells; IL6, interleukin 6; CAF, cancer-associated fibroblast; myCAF, myofibroblast cancer-associated fibroblast; EMT, epithelial-to-mesenchymal transition; VEGF, vascular endothelial growth factor; MAPK, mitogen-activated protein kinase; AKT, protein kinase B; EGF, epithelial growth factor; BC, breast cancer; C1QTNF3, complement C1q tumor necrosis-factor-related protein 3; CTHRC1, collagen triple helix repeat-containing protein 1; THBS2, thrombospondin-2; AEBP1, adipocyte enhancer-binding protein 1; LRRC15, leucine-rich repeat-containing protein 15; ACTA2, actin alpha 2; MMP, matrix metallopeptidase.