The role of three-dimensional in vitro models in modelling the inflammatory microenvironment associated with obesity in breast cancer

Breast Cancer Research (2023) 25:104 Blyth et al. Breast Cancer Research https://doi.org/10.1186/s13058-023-01700-w Open Access REVIEW The role of three‑dimensional in vitro models in modelling the inflammatory microenvironment associated with obesity in breast cancer Rhianna Rachael Romany Blyth1, Charles N. Birts1,2,3 and Stephen A. Beers1* Abstract Obesity is an established risk factor for breast cancer in postmenopausal women. However, the underlying biological mechanisms of how obesity contributes to breast cancer remains unclear. The inflammatory adipose microenvironment is central to breast cancer progression and has been shown to favour breast cancer cell growth and to reduce efficacy of anti-cancer treatments. Thus, it is imperative to further our understanding of the inflammatory microenvironment seen in breast cancer patients with obesity. Three-dimensional (3D) in vitro models offer a key tool in increasing our understanding of such complex interactions within the adipose microenvironment. This review discusses some of the approaches utilised to recapitulate the breast tumour microenvironment, including various co-culture and 3D in vitro models. We consider how these model systems contribute to the understanding of breast cancer research, with particular focus on the inflammatory tumour microenvironment. This review aims to provide insight and prospective future directions on the utility of such model systems for breast cancer research. Keywords Three-dimensional (3D) models, Breast cancer, Obesity, Adipose, Tumour microenvironment Introduction Breast cancer (BC) is the most common form of cancer among women globally, with an estimated annual 2.3 million cases worldwide [1]. Despite the increase in survival rates, it remains the second most common cause of mortality in women. The introduction of screening programs, improved understanding of disease pathogenesis, and greater utilisation of intervention therapies have all contributed to the continued reduction in BC-related mortality. However, there remains a growing incidence of BC globally, with current projections indicating that by 2030, worldwide cases will reach 2.7 million a year [2]. Thus, a greater understanding of BC development and progression, along with the models required to do this, is needed. *Correspondence: Stephen A. Beers 1 Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK 2 School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK 3 Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK Obesity and breast cancer Approximately 23% of BC cases in the UK are avoidable due to lifestyle factors, with 8% of cases being caused by overweight and obesity [3]. Obesity is associated with an increased BC incidence and poorer survival outcomes. This is most established in postmenopausal women with oestrogen receptor (ER)-positive disease [4]. In the United States, the increased relative risk of breast cancer © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Blyth et al. Breast Cancer Research (2023) 25:104 associated with excess body weight in postmenopausal women is 1.10 (1.08–1.12) per 5-unit increase in BMI [5]. However, there is increasing evidence that a high BMI is associated with poorer prognosis in BC patients of all ages [6, 7]. Conversely, BMI has been demonstrated to exhibit an inverse association with risk of premenopausal BC, though results from previous studies are inconsistent. Therefore, the underlying biological mechanisms of how obesity mediates BC remains unclear. Interestingly, previous studies have shown that women classified as obese were also more likely to exhibit larger tumour sizes, lymph node involvement, higher propensity to distant metastasis, and lower distant disease-free interval, and overall survival [7–9]. However, this may be due to the issue of late-stage presentation, owing to the difficulty in performing clinical examinations (e.g. examination of larger breasts in women with obesity) and identifying tumours in overweight individuals [10]. In obese women, numerous local and systemic factors are hypothesised to support the link between breast cancer and obesity. Recent evidence highlights inflammation as a central mechanism through which obesity promotes cancer progression via effects in the local tumour microenvironment (TME), as well as systemic effects. In obesity, adipose tissue may promote breast cancer progression through the secretion of adipokines and inflammatory mediators [11]. Systemically, increased circulating levels of insulin and glucose, increased levels of oestrogens due to increased aromatase activity [12], insulin resistance [13], and hypercholesterolemia [14] have all been shown to contribute towards breast cancer development. The breast tumour microenvironment The environment surrounding the tumour is referred to as the tumour microenvironment (TME) and can be Page 2 of 11 divided into cellular, soluble, and physical components [15]. The cellular component can be further classified as intratumoral, regional (breast) or metastatic compartments. The intratumoral compartment refers to tumour cells and the tumour infiltrating cells such as lymphocytes, macrophages, and dendritic cells [16]. The regional compartment refers to adjacent stromal cells, including stromal fibroblasts, myoepithelial cells, and adipocytes [17]. The metastatic compartment refers to sites of metastases such as lymph nodes and distant organs [18]. The major cellular components of the breast TME are highlighted in Table 1. The crosstalk between BC cells and stromal cell populations as well as infiltrating immune cells induces phenotypic changes in the cellular components of the TME, resulting in extracellular matrix (ECM) remodelling and angioge (...truncated)