**5. Adipocytes**

Adipocytes are specialised cells in the body that synthesise and store excess energy as fat thus regulating energy balance. Adipocytes are divided into lipid storing white adipocytes and thermogenic brown adipocytes [7, 23]. These cells secrete and release metabolites, enzymes, hormones, growth factors and cytokines through which they exert their effects on the tumour microenvironment. Adipocytes become activated when located near a growing tumour thus supplying pro-tumorigenic factors that will stimulate cancer cell invasion [7, 23]. These adipocytes are termed cancer-associated adipocytes (CAA).

In cancer progression and metastasis, these CAA form a crucial yet reciprocal relationship with the tumour cells. For example, in tumour microenvironment, adipocytes play very important role as the breast tissue is largely composed of white adipose tissue [7, 23]. This white adipose tissue enhances metastasis of breast cancer cells to the liver and lungs via paracrine signalling. Under the stimulation of breast cancer cells, adipocytes undergo lipolysis to breakdown lipid stores and make free fatty acids available for cellular uptake by cancer cells in response to local ECM remodelling [7, 23, 28, 32]. Cancer cells then use up these free fatty acids for respiration (energy production), formation of cell membrane, lipid bioactive molecules and/ or package them into extracellular vesicles such as exosomes [7].

Adipose tissues play a vital role in the formation of mammary duct and vasculature by providing growth factors such as VEGF [23]. Therefore, adipocytes regulate angiogenesis and epithelium function. White adipocytes are also important in the production and secretion of hormones, especially leptin, oestrogen, and IGF-1 [6, 7, 23]. As a result, adipocytes directly promote tumour progression by releasing leptin that regulates food intake thus helping the body to maintain its weight. In breast cancer, leptin signalling enhances breast cancer cells by increasing receptor expression levels and activating different signalling pathways such as Notch, Wnt, HER2, AKT and NF-κB that have been implicated in tumorigenesis and tumour invasion [6]. Elevated levels of leptin in the BM microenvironment supports the proliferation and migration of cancer cells and protects them from cellular damage by suppressing caspase-3 activity [7, 23]. Most cancer patients are overweight making obesity a major risk factor for different types of cancer such as breast, pancreatic and ovarian. In addition, obesity-associated fatty acid binding protein (FABP4) is elevated in patients with breast cancer [6]. FABP4 increases tumour volume, tumour-initiating frequency and stemness markers via IL-6/STAT3/ALDH1 signalling pathway [7]. Breast cancer cells also interact with adipocytes via secretion of inflammatory factor IL-6 that plays a key role in maintaining cancer stemness. Adipocyte-secreted IL-6 also play important roles in Notch/Wnt/TGF-β signalling pathways by upregulating ALDH1A1 and LEF1 and AXIN2 gene expression in the Wnt pathways to promote invasion, angiogenesis, and metastasis of breast cancer [6]. Adipocytes also increases the metastasis of breast cancer cells via upregulation of PLOD2 expression. Elevated levels of IL-6 in the tumour microenvironment also regulates Bcl-xl and OCT4 expression in ovarian cancer through the regulation of STAT3, which contributes to chemoresistance [6]. Tumour-secreted soluble factors such as IL-6 and parathyroid hormone-related peptide (PHRP) stimulate browning (trans-differentiation of white to brown adipocytes) thereby resulting in an increase in energy expenditure of adipose tissues that contribute to cancer-associated cachexia [23]. Cancer-associated cachexia is a muscle wasting condition that negatively impacts patient quality life and as a result, is associated with poor prognosis.

Adipocytes also promote tumour progression indirectly, by activating macrophages. These tumour-associated macrophages (TAM) release growth factors, cytokines, inflammatory mediators, and proteolytic enzymes that mediate tumour growth, tumour cell migration and invasion [22]. Finally, adipocytes secrete metalloproteases such as MMP1, MMP7, MMP10, MMP11 and MMP14 that are important in modifying and degrading ECM [22, 34, 35]. These MMPs and serine proteases (such as urokinase plasminogen activator; uPA) are the major enzymes responsible for ECM degradation [29, 36, 37]. Both MMPs and serine proteases are involved in all stages of tumour progression such as angiogenesis, stroma invasion, intravasation, regulation of inflammation and metastasis [22, 29, 36, 37].
