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Breast 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. Adipose tissue is the major microenvironment of breast cancer. Obesity changes the composition, structure, and function of adipose tissue, which is associated with inflammation and metabolic dysfunction. Interestingly, adipose tissue is rich in ASCs/MSCs, and obesity alters the properties and functions of these cells. As a key component of the mammary stroma, ASCs play essential roles in the breast cancer microenvironment. The crosstalk between ASCs and breast cancer cells is multilateral and can occur both directly through cell–cell contact and indirectly via the secretome released by ASC/MSC, which is considered to be the main effector of their supportive, angiogenic, and immunomodulatory functions.
ASC/MSC Source | Study Design | Functions and Molecular Mechanisms | Ref. |
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Breast cancer promoting effects of ASCs/MSCs derived from human tissues | |||
Human ASCs derived from visceral and subcutaneous adipose tissue | MCF7, MDA-MB-231 BC cell lines and MCF10A in vitro |
Direct co-culture of ASCs promoted proliferation of BC cells with an upregulation of AURKA, PLK1, BCL6, IL6, and IL8, whereas indirect co-culture led to EMT of BC cells via STAT3 and ERK signaling. | [19] |
Human ASCs obtained from ATCC | MCF7 and BT474 BC cell lines in vitro | Supernatant of ASCs increased BC cell proliferation and radiotherapy resistance by IGF1 secretion. BC cells overexpressed IGF1R upon radiotherapy. | [57] |
Human BM-MSCs | MCF7, T47D, and SK-Br-3 BC cell lines in vitro |
BM-MSC supernatant increased proliferation of BC cells independent of IL6 and VEGF, but both signaling proteins stimulated migration by the activation of MAPK, AKT, and p38 MAPK. | [58] |
Human BC-derived MSCs | MCF7 BC cell line in vitro | Mammary MSCs increased proliferation and cisplatin resistance of MCF7 cells by triggering the IL6/STAT3 pathway. | [59] |
Human MSCs from primary BC tissue | Co-transplantation BC xenograft mouse model of MCF7 and MSCs in vivo and in vitro |
Mammary MSCs promoted BC proliferation and mammosphere formation via EGF/EGFR/AKT signaling. | [60] |
Human ASCs from adipose tissues | MCF-7, BT-474, T-47D, and 4T1 BC cell lines in vitro and in vivo |
PDGF-D secreted by ASCs stimulated tumor growth in vivo, mammosphere formation in vitro, and EMT in BC cells. | [61] |
Human MSCs from supraclavicular lymph node (LN-MSCs) and liver (Lv-MSCs) | MDA-MB-231, –436, –468, MCF7 BC cell lines, and MCF10A cells in vitro and in vivo |
The engulfment of MSCs by BC cells increased the gene expression of WNT5A, MSR1, ELMO1, IL1RL2, ZPLD1, and SIRPB1. This further increased BC cell migration, invasion, and mammosphere formation in vitro and the tumor metastasis in vivo. | [62] |
Human ASCs from facial or abdominal liposuction | MCF7 BC cell line in vitro | ASCs co-cultured with MCF7 stimulated EMT in BC cells. The data also suggest that EMT was induced by the cross-interactions with the TGFβ/Smad and PI3K/AKT pathways. | [63] |
Human ASCs isolated from SAT via bariatric surgery, and mammary ASCs from subcutaneous breast preadipocytes | MCF7 and SUM149 BC cell lines in vitro, and orthotopic grafting of 4T1 cells into the mammary fat pad in vivo | Both ASCs subtypes suppressed the cytotoxicity of cisplatin and paclitaxel. Depletion of ASCs by D-CAN, a proapoptotic peptide targeting specific ASCs, reduced spontaneous BC lung metastases in a mouse allograft model and a BC xenograft model, when combined with cisplatin treatment. | [64] |
Human ASCs isolated from breast adipose tissues of breast cancer patients and normal individuals underwent cosmetic mammoplasty surgery | Breast tissue and BC tissue samples in vitro | ASCs isolated from breast cancer patients displayed elevated levels of IL10 and TGFβ1, and the supernatant stimulated the expression of IL4, TGFβ1, IL10, CCR4, and CD25 in PBLs. | [65] |
Human ASCs isolated from breast tumor (T-MSC) and normal breast adipose tissue (N-MSC) | Breast tissue and BC tissue samples in vitro, PBLs in vitro | The TME altered the secretome of T-MSCs with increased secretion of TGFβ, PGE2, IDO, VEGF, and lowered secretion of MMP2/9 compared to N-MSCs. T-MSCs also stimulated the proliferation of PBLs. | [66] |
Human ASCs isolated from normal breast adipose tissue (nASCs) or that of a woman with breast cancer (cASCs) | Breast tissue and BC tissue samples in vitro, B cells and Tregs in vitro | nASCs reduced proliferation of B cells in direct co-culture, and the TNFα+/IL10+ B cells ratio decreased in all co-cultures with ASCs, to a barely significantly higher extent in cASCs. nASCs shifted the cytokine profile of B cells toward an anti-inflammatory profile. | [67] |
Human ASCs isolated from the breast adipose tissue of reduction mammoplasty patients with different BMI | MCF7 and SUM159PT BC cell lines and HMEC breast cell line in vitro | Supernatant of all analyzed ASCs stimulated proliferation, migration, and invasion of breast cancer cells and increased the number of lipid droplets in their cytoplasm. This was mechanistically associated with the upregulated expression of the fatty acid receptor CD36, presenting the capacity of ASCs to induce metabolic reprogramming via CD36-mediated fatty acid uptake. | [68] |
Human primary subcutaneous pre-adipocytes (pre-hASCs, Lonza) | MCF7, T47D, ZR-75-1, SK-BR-3 BC cell lines and murine 3T3-L1 pre-adipocytes in vitro | Conditioned medium of ASCs stimulated proliferation and migration of MCF7, T47D, SK-BR-3, and ZR-75-1 cells. Additionally, supernatant of ASCs upregulated the expression of S100A7 and its knockdown abrogated the tumorigenic effect of ASCs on the tested breast cancer cells. | [69] |
Breast cancer promoting effects of ASCs/MSCs derived from murine tissue | |||
Murine MSCs derived from spontaneous lymphomas, mouse bone marrow, and mouse ears | Syngeneic tumor transplantation mouse model in vivo | TNFα dependent monocyte/macrophage recruitment led to increased tumor volume upon co-injection with MSCs, associated with CCR2 dependent immunosuppression of neutrophils, monocytes, and macrophages. | [70] |
Murine BM-MSCs and MSCs isolated from murine lung cancers | 4T1 BC mouse model in vivo |
BM-MSCs and MSCs from lung cancers were able to recruit CXCR2+ neutrophils into the tumor by TNFα via activation of CXCL1, CXCL2, and CXCL5 and promoted tumor metastasis. | [71] |
Murine BM-MSCs | Murine mammary cancer cell lines PyMT-Luc, 17LC3-Luc and LLC in vitro |
Secretion of CXCL5 by BM-MSCs increased, but without significance, while proliferation of murine BC cell lines was unchanged, whereas CXCL1 and CXCL5 promoted BC cell migration. | [72] |
Murine and human BM-MSCs | 4T1 BC mouse model in vivo and in vitro |
Both types of BM-MSCs stimulated 4T1 BC cell proliferation in vivo and in vitro upon direct cell–cell contact. BM-MSCs also promoted vessel formation of HUVECs in vitro and in vivo in DU145 tumors via TGFβ, VEGF, and IL6 release. | [73] |
Murine ASCs isolated from abdominal cavity | 4T1 BC mouse cell line in vitro and CT26 murine colon cancer cell line in vitro |
Co-culture of ASCs induced stemcellrelated genes in cancer cells such as SOX2, NANOG, ALDH1, and ABCG2. ASCs accelerated tumor growth. Secretion of IL6 regulated stemcellrelated genes and activated JAK2/STAT3 in murine cancer cells. | [74] |
Breast cancer promoting effects of obese ASCs/MSCs | |||
Human ASCs isolated from breast cancer tissue of lean and obese patients | Human BC patient-derived xenograft cells in vivo | Adipsin secreted by obese ASCs stimulated factor B and C3a, which induced BC proliferation and expression of CSC genes CD44, CXCR4, SNAI2, SNAI1, ZEB1, and BMI1. | [75] |
Human lean and obese ASCs isolated from abdominal lipo- aspirates of subcutaneous adipose tissue |
MCF7, ZR75, or T47D BC cell lines in vitro and MCF7 xenograft mouse model in vivo |
Leptin secreted from obese ASCs enhanced BC proliferation and increased the expression of EMT and metastasis-related genes such as Serpine1, MMP2, and IL6. | [76] |
Human lean (ln) and obese (ob) ASCs from abdominal lipo- aspirates of subcutaneous adipose tissue |
MCF7 and MDA-MB-231 BC cell lines in vitro |
Increased proliferation of BC cells by leptin expression via estrogen stimulation and increased protein levels of CDKN2A, GSTP1, PGR, and ESR1 in BC cells co-cultured with ob-ASCs. | [77] |
Human and murine ASCs isolated from lean and obese individuals |
Tumor and stromal cell transplantation in a mammary mouse xenograft model in vivo and MCF7 BC cell line in vitro |
Obese ASCs secreted higher levels of IGF1, promoting tumor growth and metastasis, which could be partially ameliorated by weight loss. | [78] |
Human lean and obese ASCs from abdominal lipoaspirates of subcutaneous adipose tissue | BT20, MDA-MB-231, MDA-MB-468, MCF7, and HCC1806 BC cell lines in vitro and patient-derived xenograft mouse model | Obesity increased the tumorigenic capacity of ASCs indicated by increased EMT genes Serpine1, SNAI2, and TWIST1. This effect was likely mediated via leptin, since its knockdown led to reduced pro-metastatic effects of obese ASCs. |
[79] |
Human ASCs isolated from lipoaspirate of subcutaneous adipose tissue from lean and obese patients. | MCF7, T47D, and ZR-75 BC cell lines in vitro | Obese ASCs induced a cancer-stem-like phenotype in BC cells with elevated gene expression of Notch1, Notch3, DLL1, and JAG2. This led to radioresistance and reduced oxidative stress after radiation in co-cultured BC cells mediated by leptin. |
[38] |
Human lean and obese ASCs derived from mammary adipose tissue | MDA-MB231 BC cell line and MCF10AT1 in vitro |
Obese ASCs activated BC cell migration more effectively compared to lean ASCs by direct co-culture. Obese ASCs had an increased potential for ECM remodeling. | [80] |
Human lean and obese ASCs from abdominal lipoaspirates of subcutaneous adipose tissue | MCF7 BC cell line in vitro | The known CAF markers NG2, ACTA2, VEGF, FAP, and FSP were elevated in obese ASCs. Obese ASCs were more potent in inducing the gene expression of pro-tumorigenic factors in BC cells including Serpin1, CCL5, TARC (CCL17), IL24, IL6, IGFBP3, adiponectin, and leptin. | [81] |
Human lean and obese ASCs isolated from elective liposuction | MCF7 BC cell line in vitro and patient-derived mammary xenograft (PDX) mouse model in vivo |
The increased tumor growth rate observed in obese-ASCs-enriched PDX tumors was leptin dependent. The increased metastatic capacity was leptin independent and was associated with increased gene expression of Serpine1 and ABCB1 in tumor cells. | [82] |
Fibroblast/CAF Source | Study Design | Functions and Molecular Mechanisms | Ref. |
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Impact of cancer cells on the fibroblast phenotype | |||
FBs and CAFs isolated from surgical explantation and human BM-MSCs obtained from AOU Meyer Hospital (Florence) | Co-culture experiments with FBs, CAFs, and BM-MSCs with PC3, DU145, and LNCaP prostate cancer cell lines in vitro | Prostate cancer cells secreted TGFβ1 and recruited BM-MSCs into the TME. This in turn led to an elevated secretion of TGFβ1 in cancer-educated BM-MSCs. Blocking TGFβ1 reduced the recruitment of BM-MSCs into the tumor as well as their trans-differentiation. | [113] |
Pancreatic ductal adenocarcinoma (PDAC) tissue | Single-cell RNA sequencing to characterize CAF subpopulations in PDAC | The analysis revealed intertumoral heterogeneity between CAFs, ductal cancer cells, and immune cells in extremely dense and loose types of PDACs. A highly metabolic active subtype (meCAFs) was identified. Patients with abundant meCAFs had a significantly increased risk for metastasis and poor prognosis. These patients, however, showed a highly increased response to immunotherapy. | [119] |
Murine normal pancreatic and cancer tissue | Single-cell RNA sequencing to characterize CAF subpopulations (normal vs. pancreatic cancer tissue) | The analysis revealed a landscape of CAFs in pancreatic cancer during in vivo tumor development. The LRRC15+ CAF lineage was shown to be TGFβ-dependent and correlated with a poor patient outcome treated with immunotherapy in multiple solid tumor entities. | [120] |
Human and murine PDAC resection specimens and normal pancreas tissue | Single-cell RNA sequencing to characterize CAF subpopulations (human and murine) | The analysis from neoplastic and TME of human and mouse PDAC tumors displayed already described myCAFs and iCAFs with distinct gene expression profiles. It further revealed a novel subtype that expressed MHC class II and CD74 called “antigen-presenting CAFS (apCAFs)”. These cells activated antigen-specific CD4+ T cells. These immunomodulatory CAFs were likely associated with a reduced immune response of PDAC tumors. | [121] |
Human breast and BC tissue | Single-cell RNA sequencing to characterize CAF subpopulations (normal vs. BC tissue) | The analysis identified different CAF subpopulations in BC tissue. CAF-S1 (CD29, FAP, α-SMA, PDGFRβ, FSP1, and CXCL12) was analyzed in detail. These cells induced an immunosuppressive TME by retaining CD4+CD25+ T cells through the signaling of OX40L, PD-L2, and JAM2, and increased CD25+FOXP3+ T lymphocytes, and B7H3, DPP4, and CD73 signaling. | [122] |
Human BC tissue and metastatic lymph nodes tissue (LN) | Single-cell RNA sequencing to characterize CAF subpopulations (BC and LN tissue) and co-culture experiments with MCF7, MDA-MB-231, and T47D | The analysis identified four CAF subpopulations in LN. Two had a myCAF gene expression pattern, CAF-S1 and CAF-S4, accumulated in LN and correlated with cancer cell invasion. CAF-S1 stimulated cancer cell migration by stimulating EMT, through CXCL12 and TGFβ signaling. CAF-S4 induced cancer cell invasion through Notch signaling. Patients with a high ratio of CAF-S4 cells were prone to develop late distant metastases. | [123] |
Murine BC tissue and normal mammary fat pad tissue | Single-cell RNA sequencing to characterize CAF subpopulations (BC compared to pancreatic cancer tissue) | The study identified six CAF subpopulations in a triple-negative syngeneic breast cancer mouse model. Among these six subpopulations, myCAFs, iCAFs, and apCAFs were found to exist in BC cancers and PDAC. The subtype expressing MHC class II proteins similar to apCAFs were also found in normal breast/pancreas tissues, indicating that this specific subtype is not TME induced. The comparison to a pancreatic tumor model suggested that similar phenotypes exist in both cancer entities without a TME-specific subtype. | [124] |
Murine and human BC tissue and normal mammary fat pad tissue | Single-cell RNA sequencing to characterize CAF subpopulations (murine, human BC tissue vs. normal mammary fat pad tissue) and co-culture experiments with human MDA-MB-231 as well as murine 4T1 and EO771. | A negative selection strategy was used to analyze 768 single-cell RNA sequencing transcriptome data of mesenchymal cells in a BC mouse model. In this approach, three distinct CAF subpopulations were defined. These populations were named “vascular”-CAFs, “matrix”-CAFs and “development”-CAFs. The found gene signatures were further verified on the transcriptional and protein levels in various experimental cancers. Human tumors and every CAF gene profile were correlated with distinctive molecular functions. | [125] |
Normal breast, BC tissue samples, and metastatic lymph nodes obtained from surgery | Comparison of multiple genome transcriptomic RNA sequencings | These approaches revealed that most of the described cancer hallmark signaling pathways were significantly upregulated in triple-negative breast cancer with a highly enriched CAF population. BGN, a soluble secreted protein, was upregulated in CAFs compared to normal cancer-adjacent fibroblasts (NAFs). The expression was negatively associated with CD8+ T cells and poor prognostic outcomes. | [126] |
Human primary bladder tumor tissues and adjacent normal mucosae tissues | Single-cell RNA sequencing to characterize CAF subpopulations (bladder cancer tissue vs. normal mucosae tissue) | iCAFs were identified as poor prognostic marker with potent pro-proliferation capacities, and their immunoregulatory function in the TME of bladder cancer was further deciphered. The LAMP3+ dendritic cell subgroup might be able to recruit regulatory T cells, which could be a step toward an immunosuppressive TME. | [127] |