A Role for Adipocytes and Adipose Stem Cells in the Breast Tumor Microenvironment and Regenerative Medicine

Abstract

Obesity rates are climbing, representing a confounding and contributing factor to many disease states, including cancer. With respect to breast cancer, obesity plays a prominent role in the etiology of this disease, with certain subtypes such as triple-negative breast cancer having a strong correlation between obesity and poor outcomes. Therefore, it is critical to examine the obesity-related alterations to the normal stroma and the tumor microenvironment (TME). Adipocytes and adipose stem cells (ASCs) are major components of breast tissue stroma that have essential functions in both physiological and pathological states, including energy storage and metabolic homeostasis, physical support of breast epithelial cells, and directing inflammatory and wound healing responses through secreted factors. However, these processes can become dysregulated in both metabolic disorders, such as obesity and also in the context of breast cancer. Given the well-established obesity-neoplasia axis, it is critical to understand how interactions between different cell types in the tumor microenvironment, including adipocytes and ASCs, govern carcinogenesis, tumorigenesis, and ultimately metastasis. ASCs and adipocytes have multifactorial roles in cancer progression; however, due to the plastic nature of these cells, they also have a role in regenerative medicine, making them promising tools for tissue engineering. At the physiological level, the interactions between obesity and breast cancer have been examined; here, we will delineate the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment. We will define the current state of understanding of how adipocytes and ASCs contribute to tumor progression through their role in the tumor microenvironment and how this is altered in the context of obesity. We will also introduce recent developments in utilizing adipocytes and ASCs in novel approaches to breast reconstruction and regenerative medicine.

Crosstalk between tumor-associated macrophages and tumor cells promotes chemoresistance via CXCL5/PI3K/AKT/mTOR pathway in gastric cancer

“…Interaction between tumor cells and TAMs is complicated and involved cytokines, metabolites and exosomes [43,44]. In addition to TAMs, fibroblasts, lymphocytes, adipose cells and dendritic cells are included in the cell components of TME, and have been demonstrated to promote tumor malignant progression [45][46][47][48]. In our study, we only focused on the chemokines CXCL5 derived from TAMs and illuminated its critical role in 5-FU-resistnace, without evaluating its role in the invasion, angiogenesis or metastasis of gastric cancer, future study should focus on the effect of other components of the TME on the malignant progression in gastric cancer.…”

Decreased differentiation capacity and altered expression of extracellular matrix components in irradiation‐mediated senescent human breast adipose‐derived stem cells

“…[30][31][32][33] On the other hand, recent studies have shown that ASCs, through their interactions with cancer and immune cells, may contribute to tumor progression. 39,55 In the present study, we isolated human ASCs derived from breast tissue. ASCs' cultures were characterized by the expression of the mesenchymal stem cell surface markers CD105, CD73, CD44, and CD90, while they exhibited decreased expression of the hematopoietic stem cell surface marker CD45.…”

“…The latter play a supportive role in the tissue as they provide energy, participate in hormonal regulation, are capable of multilineage differentiation and secrete cytokines involved in wound healing, tissue repair, and homeostasis 30–33 . On the other hand, recent studies have shown that ASCs, through their interactions with cancer and immune cells, may contribute to tumor progression 39,55 …”

“…34,[36][37][38] Moreover, the final outcome of ASCs-breast cancer cells' interactions in tumor progression still remains controversial, since there are studies in the literature reporting both the suppression and the support or even recurrence of cancer cells by ASCs. [38][39][40] Regarding the effect of anti-cancer therapies on ASCs, the majority of the studies have shown that radiation and chemotherapy affect their viability and differentiation potential. [41][42][43] Since it has been recently shown that adipocytes can be driven into a proinflammatory, senescent-like state, 44,45 aim of the current study was to investigate whether ionizing radiation used to treat breast cancer leads to the premature senescence of human breast stromal ASCs and to explore the characteristics of these senescent ASCs in terms of their ability to differentiate and their secretome.…”

“…However, despite their prominence in the stroma of the mammary tissue, knowledge on the role of ASCs in breast cancer is mostly confined to their effect on the proliferative, migratory, and invasive capacity, as well as on the drug resistance of cancer cells 34,36–38 . Moreover, the final outcome of ASCs‐breast cancer cells' interactions in tumor progression still remains controversial, since there are studies in the literature reporting both the suppression and the support or even recurrence of cancer cells by ASCs 38–40 . Regarding the effect of anti‐cancer therapies on ASCs, the majority of the studies have shown that radiation and chemotherapy affect their viability and differentiation potential 41–43 .…”