Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells and Breast Cancer: Comparison
Please note this is a comparison between Version 1 by Andreas Ritter and Version 2 by Vivi Li.

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. 

  • ASCs/MSCs
  • obesity
  • breast cancer
  • tumor microenvironment
  • cancer-associated fibroblasts
  • cancer-associated stem cells
  • epithelial–mesenchymal transition
  • therapy resistance

1. Introduction

The prevalence of obesity has tripled during the last decades, posing a major challenge to the entire society and health care systems worldwide [1][2][3][1,2,3]. Obesity, a condition of increased adiposity resulting from an imbalance between food intake and energy expenditure [4], is categorized according to body mass index (BMI) ≥30 kg/m2 [5]. Obesity associates with multiple disorders, including diabetes, hypertension, and cardiovascular diseases [6]. In addition, it is characterized by an increased incidence of cancer in various organs, such as the colon, rectum, kidney, pancreas, gallbladder, liver, thyroid, breast, ovary, and endometrium [7][8][9][7,8,9]. Obesity associates with inflammation and metabolic dysfunction, which greatly promote cancer development. Among various adipose tissue cell types, adipose tissue-derived mesenchymal stromal/stem cells (ASCs), belonging to mesenchymal stromal/stem cells (MSCs), are dramatically altered during obesity progression [10]. Obesity-associated ASCs are of crucial importance, contributing to the establishment of the breast cancer microenvironment and promoting the progression of breast cancer.

2. Crosstalk between ASCs and Breast Cancer Cells

The crosstalk between ASCs and breast cancer cells can occur directly via cell–cell interaction and indirectly via the secretome released by the cells. Cancer cells secrete numerous chemotaxis signals [11][59], which recruit ASCs from local adipose tissues as well as MSCs from bone marrow into malignant tissue [12][60]. Cancer-educated ASCs/MSCs may differentiate into cancer-associated ASCs/MSCs or cancer-associated fibroblasts (CAFs) [13][61]. These ASCs/MSCs in turn promote breast cancer progression [14][62]. In particular, the ASC/MSC secretome, which is composed of a large number of secreted proteins, peptides and extracellular vesicles (EVs), is considered to be the main effector of their regenerative, tropic, trophic, angiogenic, and immunomodulatory functions. Regarding the indirect manner, both breast cancer cells and ASCs/MSCs are potent in secreting a large number of soluble bioactive factors [13][15][61,63]. In particular, MSCs have the ability to migrate into malignant areas and stimulate cancer development by secreting a range of paracrine factors such as chemokines C-X-C ligand 1 (CXCL1), CXCL2, CXCL5, CXCL7, and CXCL12/stromal-cell-derived factor 1 (SDF1); cytokines such as IL6, IL8, and transforming growth factor β (TGFβ); and growth factors including epidermal growth factor (EGF), insulin-like growth factor 1 (IGF1), and vascular endothelial growth factor (VEGF) [13][16][17][58,61,64]. It has been shown that MSCs facilitate angiogenesis by paracrine secretion of angiogenic growth factors such as platelet-derived growth factor (PDGF) and VEGF [16][18][58,65]. ReseaOurchers' own studies also demonstrate that ASCs isolated from subcutaneous as well as visceral adipose tissue released numerous cytokines, chemokines, and growth factors involved in inflammation, angiogenesis, and cell migration and proliferation, such as IL6, IL8, TNFα, CXCL1/2/3, CXCL5, monocyte chemotactic and activating factor (CCL2), and EGF [19][20][21][32,48,66]. Moreover, both breast cancer cells and MSC/ASC-derived EVs are essential for the crosstalk between MSCs/ASCs and breast cancer cells [15][22][23][63,67,68]. EVs are a heterogeneous group of membrane-bound vesicles released from cells by invagination and budding. They facilitate cell-to-cell interactions via contact with neighboring cells or internalization by recipient cells, which includes fusion with membrane and endocytosis [24][69]. According to the biogenesis, biophysical properties, and function, EVs can be classified into three main subtypes, namely exosomes (30–150 nm), microvesicles (MVs) (50–1000 nm), and apoptotic blebs (1000–5000 nm) [25][70]. Among these EVs, exosomes and MVs are of particular importance in cell–cell communication [25][70]. Both of them contain lipids, proteins, and genetic material, such as DNA, messenger RNA (mRNA), microRNA (miRNA), and long non-coding RNAs (lncRNA) that can be delivered to and reprogram the recipient cells [26][71]. Studies have shown that MSC/ASC-EVs exert both inhibitory and promoting effects in several situations and different stages of breast cancer. Through the transfer of various tumor-related factors, EVs promote proliferation, angiogenesis, metastasis, and drug resistance of malignant tumor cells [27][28][72,73], as shown in breast cancer cells stimulated with Her2-loaded EVs [27][72]. These data suggest that ASCs/MSCs may secrete molecules that act in concert with the secretome of breast cancer cells to remodel the microenvironment. The direct crosstalk between ASCs and breast cancer cells is strictly dependent on their close contact that is established in the TME. Interestingly, tunneling nanotubes (TNTs) have emerged as a new important means of cell–cell communication. TNTs are thin membrane protrusions that connect cells over long distances allowing the exchange of various cellular components, including organelles, proteins, calcium ions, viruses, and bacteria [29][74]. Notably, TNTs are able to connect multiple cells forming functional cellular networks [30][75]. TNTs are therefore considered as novel bridges of intercellular communication in physiological and pathological cell processes [31][76]. Interestingly, MSCs have been shown to form TNTs and transfer mitochondria and other components to target cells [32][33][34][77,78,79]. This occurs under both physiological and pathological conditions, where cells are under stress, leading to changes in cellular energy metabolism and functions [31][76]. In this context, it is feasible to hypothesize that the protective role of ASCs/MSCs in breast cancer cell survival may be partially mediated through the formation of TNTs, in particular, when breast cancer cells are under stress from chemotherapy or radiotherapy. Moreover, the activation of several signaling pathways requires direct cell–cell contact via their membrane-bound ligands and receptors, such as the canonical Notch signaling pathway [35][80]. Notch signaling is linked to the maintenance of breast cancer stem cells [36][81] and induction of epithelial-to-mesenchymal transition (EMT) resulting in an increase in migration and invasion of breast cancer cells [37][82]. In fact, direct co-culture of obese ASCs enhanced Notch signaling in ER+ breast cancer cells co-responsible for radiation resistance [38][83]. Finally, cell–cell fusion, a process that merges the lipid bilayers of two different cells, plays a crucial role during embryonic development as well as in tissue regeneration [39][40][84,85]. Studies also provide evidence that cell–cell fusion is closely related to cancer development and metastasis [41][86]. Although this highly regulated process is not yet fully understood, bone-marrow-derived cells were reported to be able to fuse to cancer cells, and the fused hybrids acquired more malignant characteristics and enhanced self-renewal ability [42][87]. In line with this observation, MSCs were reported to fuse with diverse malignant cells to promote proliferation and metastasis, including with lung cancer cells [43][88], liver cancer cells [44][89], and gastric cancer cells [45][90]. In particular, it was demonstrated that MSCs were fused with breast cancer cells and promoted their metastatic capacity [46][91]. Recently, is has been revealed that ASCs are able to fuse spontaneously with breast cancer cells, where breast cancer stem cell (CSC) markers CD44+CD24/lowEpCAM+ are enriched in this fused population [47][92]. These studies suggest cell fusion as a direct interaction between ASCs/MSCs and cancer cells. Further investigations are needed to explore the molecular mechanisms by which ASCs/MSCs and malignant cells are able to fuse and how this process promotes malignancy. In sum, as illustrated in Figure 1, the crosstalk between ASCs/MSCs and breast cancer cells is multilateral and majorly mediated by indirect patterns such as the secretion of soluble bioactive factors and EVs released by ASCs as well as breast cancer cells. Although observed mainly in vitro, the interaction of breast cancer cells with ASCs/MSCs may be supported by direct cell–cell contacts including the formation of TNTs, binding of membrane-bound ligands to receptors, and cell–cell fusion. These communications may reshape the TME and fuel breast cancer progression and therapy resistance.
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.

3. Mutual Interaction between ASCs/MSCs and Breast Cancer Cells

The communication between MSCs/ASCs and breast cancer cells has been an intensive research focus. The related studies are mostly performed using in vitro models to investigate the effects of ASCs/MSCs or their conditioned medium on proliferation, survival, migration, and invasion of breast cancer cell lines. Breast cancer cell lines are classified based on the status of three important cell surface receptors conventionally used for breast cancer subtyping, ER, PR, and HER2 [48][93]. Most studies used the following breast cancer cell lines: low metastatic breast cancer cell line BT474 (ER+, PR+, HER2+), MCF-7 (ER+, PR+, HER2) and T47D (ER+, PR+, HER2), metastatic breast cancer cell lines HCC1954 (ER, PR, HER2+, with wild type breast cancer gene 1 (BRCA1)), SKBR3 (ER, PR, HER2+, with wild type BRCA1), and MDA-MB-453 (ER, PR, HER2+, with wild type BRCA1), and highly metastatic breast cancer cell lines MDA-MB-231 (triple negative, with wild type BRCA1), MDA-MB-468 (triple negative, with wild type BRCA1), MDA-MB-436 (triple negative, mutated BRCA1), and SUM149 (triple negative, mutated BRCA1) [48][93]. Regarding ASCs/MSCs, while tumor adjacent cells [49][94] or “cancer-educated” MSCs [50][95] were recently used, most of the studies employed ASCs/MSCs isolated from non-breast sources, including abdominal adipose tissue, bone marrow, and peripheral blood [16][19][51][32,58,96]. It is well-known that ASCs/MSCs from different tissues and organs have distinct transcriptomic, biochemical, and secretory profiles, as well as biologic functions in tissue-specific homeostasis, immune modulation, and vasculogenesis/angiogenesis [52][97]. This, together with other diversities, such as different BMI, varied donor age, variable ASC/MSC passages, and individual experiment settings, often leads to inconclusive results with breast-cancer-supportive and -suppressive functions [16][53][58,98], which may not reflect the situation in vivo in breast cancer tissue.

3.1. ASCs/MSCs Influence Breast Cancer and Related Molecular Mechanisms

Much attention has been paid to elucidating how ASCs/MSCs impact breast cancer cells as well as their TME (Table 1). Although their exact roles are not yet completely understood, ASCs/MSCs are described as both pro- or anti-tumorigenic, depending on the type and source of ASCs/MSCs, the use of breast cancer cell lines, and the in vitro or in vivo models. The studies concerning the anti-tumorigenic impact of MSCs are limited. MSCs have been reported to exert their negative impact on breast cancer by impairing angiogenesis via secretion of exosomes [54][99], reducing migration and invasion via the release of tissue inhibitor of metalloproteinase (TIMPs) [55][100], and decreasing breast tumor growth via down regulation of the STAT3 signaling pathway [56][101]. Nevertheless, the majority of studies report pro-tumorigenic effects of ASCs/MSCs on breast cancer cells, which are multilayered, as depicted in Table 1. The related molecular mechanisms are discussed in detail.