Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer

Abstract

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. In this narrative review, we aim to address the impact of obesity on ASCs/MSCs, summarize the current knowledge regarding the potential pathological roles of ASCs/MSCs in the development of breast cancer, discuss related molecular mechanisms, underline the possible clinical significance, and highlight related research perspectives. In particular, we underscore the roles of ASCs/MSCs in breast cancer cell progression, including proliferation and survival, angiogenesis, migration and invasion, the epithelial-mesenchymal transition, cancer stem cell development, immune evasion, therapy resistance, and the potential impact of breast cancer cells on ASCS/MSCs by educating them to become cancer-associated fibroblasts. We conclude that ASCs/MSCs, especially obese ASCs/MSCs, may be key players in the breast cancer microenvironment. Targeting these cells may provide a new path of effective breast cancer treatment.

Keywords: ASCs/MSCs; breast cancer; cancer-associated fibroblasts; cancer-associated stem cells; epithelial–mesenchymal transition; obesity; therapy resistance; tumor microenvironment.

Figure 1

Simplified model representing the crosstalk between ASCs/MSCs and breast cancer cells. The communication between ASCs/MSCs and breast cancer cells may occur directly via cell–cell contact, namely TNTs, cell fusion, and the binding of membrane-bound ligands to receptors, or indirectly via released soluble bioactive factors such as cytokines, chemokines, and growth factors, and EVs including exosomes and microvesicles. EV, extracellular vesicles; ASCs, adipose tissue-derived mesenchymal stromal/stem cells; MSCs, mesenchymal stromal/stem cells; mRNA, messenger RNA; miRNA, microRNA; lncRNA, long non-coding RNA; TNTs, tunneling nanotubes.

Figure 2

Schematic representation of potential effect of ASCs/MSCs on breast cancer cells and related molecular mechanisms. ASCs/MSCs may promote breast cancer cell proliferation and survival, EMT, migration, and invasion; CSC formation; angiogenesis; immune evasion; and therapy resistance. ASCs, adipose-tissue-derived mesenchymal stromal/stem cells; MSCs, mesenchymal stromal/stem cells; IL6, interleukin 6; EMT, epithelial-to-mesenchymal transition; STAT3, signal transducer and activator of transcription 3; ERK, extracellular-signal regulated kinase; IGF1, insulin-like growth factor 1; VEGF, vascular endothelial growth factor; MAPK, mitogen-activated protein kinase; AKT, protein kinase B; CCL2, monocyte chemotactic and activating factor; EGF, epithelial growth factor; PDGF-D, platelet-derived growth factor D; Wnt, wingless/integrated; TGFβ, transforming growth factor β; PI3K, phosphoinositide 3-kinase; CCR4, C-C motif chemokine receptor 4; TNFα, tumor necrosis factor α; CD25, cluster of differentiation 25; SNAI, snail family transcriptional repressor; ZEB1, zinc finger E-box binding homebox 1; CAF, cancer-associated fibroblast; CSC, cancer stem cell; JAK2, Janus kinase 2; FABP4, fatty acid binding protein 4; PKC, protein kinase C; HGF, hepatocyte growth factor; MMP, matrix metalloprotease; bFGF, basic fibroblast growth factor; vWF, von-Willebrand factor.

Figure 3

Simplified model showing that breast cancer cells induce de-differentiation of MSCs/ASCs into at least two distinct CAF subtypes. The de-differentiation process of MSCs/ASCs in the TME of breast cancer is triggered by multiple factors including cytokines TGFβ, IL6, IL8, IL17, IL23, and TNFα, DNA damage, cellular stress, direct cell–cell contact and inflammatory stimuli. This malignant transformation shifts ASCs/MSCs into several cancer-supportive populations including two typical phenotypes: myCAFs promoting tumor growth, EMT, migration, invasion, and metastasis, and iCAFs mediating immune evasion, tumor growth, angiogenesis, and metastasis. ASCs, adipose tissue-derived mesenchymal stromal/stem cells; MSCs, mesenchymal stromal/stem cells; TGFβ, transforming growth factor β; IL6, interleukin 6; EMT, epithelial-to-mesenchymal transition; TNFα, tumor necrosis factor α; ECM, extracellular matrix; TME, tumor microenvironment; CD8, cluster of differentiation 8; myCAF, myofibroblast cancer-associated fibroblast; iCAF, inflammatory cancer-associated fibroblast; ACTA2, smooth muscle actin, TAGLN, transgelin; MYL9, myosin light chain 9; TPM, tropomyosin; FAP, fibroblast activation protein; FSP1, fibroblast-specific protein-1; PDGFRβ, platelet-derived growth factor receptor beta; LIF, leukemia inhibitory factor; CXCL, chemokines C-X-C ligand; HAS, hyaluronan synthase; CCL, monocyte chemotactic and activating factor; COL14A1, collagen type XIV alpha 1 chain.