Edited by: Jingxing Dai, Southern Medical University, China
Reviewed by: Amilcare Barca, University of Salento, Italy; Shabbir Ahmed Ansari, Beth Israel Deaconess Medical Center and Harvard Medical School, United States
†These authors share first authorship
This article was submitted to Lipid and Fatty Acid Research, a section of the journal Frontiers in Physiology
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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.
Between 1999 and 2018, the prevalence of obesity in the United States climbed from 30.5 to 42.3% (
ASCs and adipocytes are normal components of breast tissue anatomy that provide support through providing energy, hormonal regulation, and cytokines involved in wound healing. In obesity, these cells become altered. Patients with higher BMI have an increased amount of dysfunctional adipocytes leading to gene alteration in the expression profile, inducing inflammation and hypoxia as well as apoptosis. Select patient characteristics have been implicated in variations in ASC expression and ASC contributions to cancer development. Obesity is associated with excessive free fatty acids, cholesterol, triglycerides, hormones such as leptin, interleukins, and chemokines, which all have roles in breast cancer development (
Interestingly, these cell types may act as a double-edged sword: There is evidence that ASCs, through their interactions with breast cancer cells and immune cells, contribute to tumor progression; however, there have also been promising developments in the use of ASCs in breast reconstruction and tissue engineering. Therefore, it is critical to understand the cell-cell interactions in the tumor microenvironment that contribute to these dual functions. In this review, we will characterize both adipocytes and adipose stem cells’ role in normal physiology and the breast cancer tumor microenvironment, particularly in the context of obesity. Exploring the many roles of ASCs allows for the creation of laboratory models that better address the complexity of the breast cancer tumor microenvironment. Therefore, we will also discuss recent developments in using ASCs in a novel approach to breast reconstruction and in experimental models of breast cancer.
Adipocytes and ASCs represent significant components of breast tissue stroma with important endocrine signaling functions that contribute to both normal breast physiology and pathological processes such as the development of cancer (
Adipocytes constitute the major cellular component of adipose tissue and have important roles in both energy storage and endocrine functions. There are two major types of adipose tissues, each with different characteristics. Brown adipose tissue, characterized by abundant mitochondria, oxidizes lipids during cold-induced thermogenesis, whereas white adipose tissue, the primary type of adipose tissue in the breast, both insulates the body and acts as an energy reservoir through both storage of triglycerides and release of free fatty acids (
In the context of obesity, the secretory profile of adipocytes is altered. In breast adipose tissue specifically, mRNA expression of aromatase correlated positively with BMI (
Adipose stem cells (ASCs) are subsets of mesenchymal stem cells with the multipotent capability to differentiate into many different cell types including osteocytes, chondrocytes, vascular endothelial cells, and adipocytes (
The breast cancer tumor microenvironment is a complex system and shares many components with healthy breast tissue. It is composed of several specialized cell types, including adipocytes, ASCs, immune cells, cancer-associated fibroblasts, neoplastic cells, and the extracellular matrix (ECM) scaffold and stroma. Complex signaling events and interactions between different cell types in the tumor microenvironment contribute to the hallmarks of cancer, providing a supportive environment during the transformation of normal tissues into high-grade malignancies (
Breast cancer grows in close proximity to adipose tissue, and cancer-associated adipocytes (CAAs) have been found to be a key player in breast cancer progression (
Adipocytes and ASCs in the obese tumor microenvironment. Adipocytes and ASCs contribute to the obese tumor microenvironment through increased secretion of cytokines and adipokines, as well as through increased fatty acid buildup.
The tumorigenic effects of adipocytes are further exacerbated by obesity. When adipocytes are dysfunctional, metabolic substrates, adipokines, and cytokines are released, leading to the promotion of proliferation, progression, invasion, and migration of breast cancer cells (
ASCs are a key component in the breast cancer tumor microenvironment and, through their interactions with the immune system and secretion of trophic factors, play integral roles in tumorigenesis, tumor growth, and distal metastasis. ASCs exhibit an immunomodulatory capacity and promote wound healing and regeneration in inflammatory environments (
ASCs secrete a variety of interleukins, including IL-6, IL-7, IL-8, IL-11, and IL-12 (
When ASCs were co-cultured with breast cancer cell lines, there was a robust increase in cancer cell proliferation that was CXCL5-dependent (
Programmed cell death protein 4 (PDCD4) is a tumor suppressor gene, typically upregulated during apoptosis. Overexpression of PDCD4 in carcinoid cells has been linked to reduced proliferation of cancer cells (
The capacity of ASCs to secrete pro-tumorigenic factors is increased in the context of obesity. ASCs harvested from obese individuals demonstrate increased expression of leptin, IL-1, IL-6, IL-12, PDGF-A, TNF-alpha, leukemia inhibitory factor, intercellular adhesion molecule 1, and granulocyte-colony stimulating factor compared to those harvested from lean individuals (
Leptin, an adipokine expressed proportionally to fat mass, has a profound effect on prognosis (
Leptin signaling has been shown to have immunomodulatory effects in the context of obesity: Malnutrition is associated with hypoleptinemia and increased susceptibility to infection, whereas obesity leads to hyperleptinemia, which is associated with an increase in autoimmune disorders and inflammation (
Leptin is both an anorexigenic and pro-inflammatory factor and exists as a link between the neuroendocrine and immune systems. Leptin plays a role in both innate and adaptive immunity: It polarizes T helper cells toward a pro-inflammatory Th1 phenotype, which secretes IFN-γ, rather than the anti-inflammatory Th2 phenotype, which secretes IL-4 (
In the context of the immune system and breast cancer, leptin is hypothesized to induce IL-18 expression both in TAMs (tumor-associated macrophages) and breast cancer cells. Leptin-induced IL-18 expression was regulated
There is also evidence that obesity contributes to activation of cancer stem cell signaling in breast cancer.
Another instance in which obesity contributes to a tumor microenvironment that favors metastasis is through the increased capacity of ASCs from obese patients to differentiate into cancer/carcinoma-associated fibroblasts, or CAFs. CAFs display myofibroblast-like traits; they have been found in higher numbers in invasive tumors and enhance cancer cell proliferation, invasion, and metastasis (
Obesity further promotes breast cancer tumorigenic potential by remodeling the extracellular matrix (ECM). Tumor-associated ASCs increase the expression and stiffness of fibronectin
In cancer research,
Adipose-derived stem cells in translational research models. Adipocytes and ASCs have many applications in 3D laboratory models of breast cancer.
3D cancer models can provide more accurate results for drug responses and identification of biomarkers (
Biotechnology and fabrication have recently emerged as a superior approach to creating microphysiological systems in order to study different diseases in the human body, especially cancer. Because human tissues are organized in a complex 3D structure with cellular-ECM cross talk, 3D bioprinting allows for the design of a complex architecture with placement of the cellular components in physiological spatial micro-arrangements (
Tissue-engineered constructs, which utilizes a biocompatible or biodegradable material to engineer a scaffold, is another novel technique used to recreate the breast mound post-mastectomy. In this technique, the ASCs are seeded on scaffold-based tissue-engineered constructs in which the ASCs will differentiate into adipocytes and form ECM, creating sheets which can be formed into thicker adipose constructs. The design and scaffold material used is important in order to overcome issues related to volume retention and vascularization (
Decellularized extracellular matrix (ECM) is another commonly used technique when designing tissue-engineered scaffolds. These decellularized ECM scaffolds when re-cellularized with the recipient patient’s ASCs (commonly used in cellular therapy due to their capability to differentiate into MSCs and ESCs) can be advantageous for personalized medicine in autologous applications (
White adipose tissue (WAT) inflammation has been found to have a positive relationship with breast cancer. Thus, WAT has become increasingly common for use when researching novel targets in breast cancer. Zhao et.al investigated the relationship between breast WAT inflammation, obesity, and breast cancer. Previous studies show that WAT inflammation, defined by the presence of CLS-B, is formed by dying or dead adipocytes surrounded by macrophages. It was found that WAT inflammation usually occurs in overweight and obese breast cancer patients (
Organ-on-a-chip models have recently become a promising alternative to non-human animal models. By adding microfluidics into microphysiological systems, a more physiologically relevant human microenvironment is created because the human tissue is supplied by a vasculature-like microfluidic perfusion (
Adipose-derived stem cells have emerged as key players in developing novel tissue engineering techniques, even more so in the field of breast reconstruction. However, a main concern is the oncological safety of ASC therapies or surgical implantation of the engineered constructs. ASCs have the potential to influence the behavior of breast cancer cells due to secreted adipokines and their effect on the tumor microenvironment (
ASC-enhanced fat grafting is a novel alternative to prosthetic implants for breast reconstruction for patients who have undergone a mastectomy. This method utilizes tissue engineering strategies by using ASCs to generate adipose tissue in the breast to reaugment the breast post-mastectomy (
In this review, we have delineated adipocytes’ and ASCs’ many physiological and pathological roles, including breast cancer. They are a key component of the breast tumor microenvironment and provide both proliferative cues and drive carcinogenesis, especially in the context of obesity. Future directions into this area of research include using pharmacological or molecular inhibitors of downstream targets of ASCs to test their direct effects on cancer development and progression. We have described adipocytes and ASCs in novel laboratory models of breast cancer. Novel microphysiological systems enable more translational research of complicated cell-to-cell and cell-to-tissue interactions that occur in the human body. These 3D models can range from spheroids, 3D printed scaffolds or constructs, microphysiological systems to organ-on-a-chip systems, which are useful for studying the mechanisms behind cancer invasion and migration with implications for pharmaceutical discovery and targeted cancer therapy. Adipocytes and ASCs are also promising tools in cancer therapeutics and regenerative medicine, due to their plastic nature. Further investigation is required to ensure the safety of ASC use in tissue-engineered constructs and/or autologous grafting.
CB and KH wrote this manuscript with help of MA, MW, and TC. KH and GW created figures. KN and MSA contributed to the final revision of this manuscript. BC-B, BB, and MB contributed financially to the manuscript. All authors contributed to the article and approved the submitted version.
This project received funding from the National Institutes of Health 1R01CA174785-01A1 (BC-B) and 1R41CA257425-01 (MB). The project was also supported by Award Number TL1TR003106 from the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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