Cancer-Associated Adipocytes in Cancer Progression

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1		Melania Lo Iacono	--	3015	2022-06-01 09:12:56	\|
2	format	Jason Zhu	-7 word(s)	3008	2022-06-01 11:28:01	\| \|
3	format	Jason Zhu	-37 word(s)	2971	2022-06-06 03:49:31	\|

This entry is adapted from the peer-reviewed paper 10.3390/biom12050702

The tumor microenvironment (TME) plays a key role in promoting and sustaining cancer growth. Adipose tissue (AT), due to its anatomical distribution, is a prevalent component of TME, and contributes to cancer development and progression. Cancer-associated adipocytes (CAAs), reprogrammed by cancer stem cells (CSCs), drive cancer progression by releasing metabolites and inflammatory adipokines. Several mediators released by cancer-associated adipocytes are considered promising therapeutic targets for anticancer therapy.

tumor microenvironment adipose tissue cancer stem cells

1. Introduction

In the last decade, considerable interest has focused on the contribution of the tumor microenvironment (TME) to cancer progression and chemotherapy resistance. The malignant phenotype is not exclusively driven by a specific cancer cell subset but rather regulated by a complex interplay between cancer stem cells (CSCs) and TME elements ^[1]. This bidirectional crosstalk includes signals that promote tumor growth, foster metastasis dissemination, and limit drug penetration and uptake. In this context, the scientific community’s interest in the role of adipose tissue (AT) in carcinogenesis is constantly increasing. Indeed, it is known that AT is involved in the deregulation of inflammatory and immune responses, leading to aberrant metabolism, and contributing to cancer development and progression ^[2]. The role of AT in cancer progression is supported by its anatomical distribution, such as in breast cancer, where the TME predominantly comprises adipose tissue, with cancer cells growing in contact with adipose cells ^[3]. The tight and prolonged contact between cancer and adipose cells leads to the reprogramming of adipocytes, with the generation of the so-called ‘cancer-associated adipocytes’ (CAAs), which can directly or indirectly facilitate tumor growth and progression by releasing adipokines, growth factors, and metabolites. Understanding the crosstalk between CAAs and CSCs, and how adipokines and metabolites released in TME can regulate different molecular pathways may be essential in the prevention of tumor progression.

2. Obesity and Cancer: The Cause–Effect Relationship

The clinical impact of obesity is still controversial, without clear evidence of its role in cancer progression. Recently, several research groups have investigated the molecular mechanisms underlying the crosstalk between adipocytes and cancer cells.

Obesity is a complex and chronic disease, and is considered as one of the most common diseases in the Western world. It is currently recognized as a global pandemic. According to recently published data by the World Health Organization (WHO), in the last 40 years, a 3-fold increase in obesity in adults has been observed in industrialized countries, and a further increase is expected in the near future ^[4].

Several studies supported by the International Agency for Research on Cancer (IARC) established that the highest BMI (≥30 kg/m²) is correlated with an increased risk of developing different types of solid tumors, including esophageal, meningioma, prostate, ovarian, gallbladder, breast, colorectal, kidney, thyroid, and pancreatic ductal cancer; reduced overall survival; and increased risk of recurrence ^[5]^[6].

Obese post-menopausal women show a 30% higher risk of developing ER-positive breast cancer compared to normal-weight subjects ^[7]^[8], and obesity in men is considered the major risk factor for colon cancer development ^[9]. In this regard, in a large population-based cohort study, Bhaskaran and colleagues observed a decrease in the overall survival in colorectal cancer (CRC) patients with BMI between 25 and 50 kg/m² when compared to CRC patients with a lower BMI ^[10]. Although the obesity–cancer relationship has been widely shared by the scientific community, the molecular mechanisms underlying this biological/clinical phenomenon are still not clear ^[11].

One of the possible obesity-driven mechanisms supporting cancer disease concerns the onset of a chronic inflammatory state and increased cellular oxidative stress. This biological process affects the genome stability of cells in a direct and indirect way by driving the accumulation of mutations due to the increased presence of oxygen reactive species (ROS), and increasing lysine homocysteinylation in DNA damage repair systems’ proteins through post-translational modification ^[12]. The enhanced induction of unrepaired mutations plays a crucial role in both the initiation and progression of the tumor by contributing to cancer cells’ heterogeneity, with a direct impact on cell survival ^[13]. However, some studies have reported a better prognosis in obese patients with premenopausal breast cancer, non-small cell lung cancer (NSCLC), and head/neck cancers, a phenomenon called ‘the obesity paradox’, which is likely driven by the inadequacy/inconsistency of data collection/analysis, and the selection and stratification of patients ^[14]^[15].

It has been highlighted that there is continuous and dynamic crosstalk between adipose and tumor cells, which is mainly sustained by the altered production of steroid hormones, adipokines, and cytokines, which affects cancer cells during all steps of tumor progression ^[16]^[17]^[18]. Among the different types of adipokines, leptin and adiponectin are considered the main regulators of the dynamic control of appetite and energy expenditure ^[19]^[20]^[21]. In obesity, higher leptin levels and reduced adiponectin levels were observed compared to normal weight individuals. Moreover, WAT secretes a plethora of proinflammatory and protumorigenic factors that recruit different types of immune and stromal cells, thus creating a tumor-permissive microenvironment ^[22]^[23]^[24]^[25]. In the context of the adipose tissue of breast cancer patients, it has been observed that macrophages recalled by inflammation phenomena (such as pyroptosis and necrosis of adipocytes) can form crown-like structures (CLSs), which is highly correlated with relapse and mortality ^[26]^[27].

Recently, visceral AT stromal cells (V-ASCs), through the release of IL-6 and HGF, induce transcriptional reprogramming of CRC cells toward the acquisition of a mesenchymal-like phenotype ^[28]. Moreover, V-ASCs’ released factors lead to an increase in CD44v6⁺ cells, which in turn attract ASCs within the tumor bulk due to their release of neurotrophins. The recruited ASCs, following the release of VEGF by CD44v6⁺ cancer cells, actively participate in tumor progression processes by transdifferentiating into endothelial-like cells ^[28].

The clinical impact of obesity is still controversial, without clear evidence of its role in cancer progression. Obese cancer patients are refractory to standard chemotherapy. This phenomenon could be driven by a direct effect of adipose tissue on cancer cell behavior, and the failure of clinicians to provide adequate treatment doses due to possible toxicity ^[29]. In this regard, the ASCO 2012 guidelines recommend the patient’s current weight as the best method for assessing the amount of chemotherapy to prescribe. However, in obese cancer patients, given the high amount of treatment provided, pharmacodynamics and pharmacokinetics studies should be performed to increase the efficacy of therapeutic options, and limit associated side effects ^[29]^[30]^[31]. In 2021, new updates about the treatment of obese adult patients were provided by ASCO, in which immunotherapies and new targeted anticancer therapies were included ^[32].

3. Cancer-Associated Adipocytes (CAAs): Origin and Role in Cancer Progression

Numerous pieces of evidence support the active contribution of TME, with its cellular and acellular elements, to cancer cell proliferation, invasion, epithelial to mesenchymal transition (EMT), and response to therapies. TME includes a wide variety of cell types, such as endothelial cells, fibroblasts, pericytes, immune cells, mesenchymal stromal cells (MSCs), and mature adipocytes ^[33]^[34].

Adipocytes, through the release of growth factors, exosomes, and metabolic symbiosis, promote tumor development. On the other hand, CSCs can reprogram the phenotype of neighboring adipocytes, characterized by an increase in lipolysis and overexpression of proinflammatory adipokines (such as growth factors and chemokines) and proteases ^[35]. These reactive adipocytes, known as CAAs, contribute to acquisition of the hallmark traits of cancer, such as increased angiogenesis, invasion, metastatic potential, and therapy resistance ^[36]. The presence of CAAs has been demonstrated in multiple cancers, including breast, ovarian, colon, prostate, and pancreatic tumors ^[34]^[37]. The scientific interest in these cell populations is justified by the fact that they could represent an alternative therapeutic target in the treatment of tumors.

CAAs can be distinguished from mature adipocytes according to their morphology and phenotype during the dedifferentiation process. The fibroblast-like morphology, typical of CAAs, is due to de-lipidation and alteration of the fat storage capacity, as found in patients with colorectal cancer ^[34]. In addition, compared to mature adipocytes, CAAs are smaller, have an increased number of mitochondria, show lower expression of differentiation markers, and exhibit a proinflammatory phenotype ^[3]. Among the adipokines secreted by CAAs, leptin, matrix metalloproteinase (MMP)-11, CCL2, chemokine ligand 5 (CCL5), IL-6, IL-1β, and TNF-α have been identified^[38]^[39]^[40].

These reactive adipocytes not only contribute to energy storage, thanks to the uptake of lipids, such as triacylglycerols (TAGs), which can be released in the microenvironment in the form of free fatty acids (FFAs), but also represent a source of a plethora of factors that induce both local and systemic effects ^[41].

CAAs adopt a dedifferentiation phenotype following tight crosstalk with CSCs. In particular, the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein β (c/EBPα) is markedly inhibited, with a subsequent reduction in the mRNA levels of two markers of mature adipocytes, such as fatty-acid-binding protein 4 (FABP4) and hormone-sensitive lipase (HSL) ^[42]^[43]. The decrease in lipid droplets and cell size leads to the release of FFAs and ketone bodies, crucial factors for CSC metabolism in the promotion of tumor progression ^[40]. Another distinctive trait of CAAs is the increased production of ECM-related molecules, such as MMP-11, PAI-1, MMP1, fibroblast-activating protein (FAP), and collagen VI, which are involved in ECM remodeling, thus representing a crucial step in tumor progression ^[44]. In CAAs, the production and release of leptin and resistin is increased while the expression of adiponectin and adipokines with antitumorigenic functions is reduced ^[36].

3.1. Mechanisms and Regulation of CAA Activation

The acquisition of an activated phenotype by mature adipocytes is attributed to molecules that are released by tumor cells. However, the mechanisms underlying CAAs’ activation remain to be fully elucidated. Few studies have highlighted the role of molecules and pathways involved in the arrest of the adipogenesis process as a possible outcome of CAA development. In this context, the Wnt signaling pathway plays a key role as an inhibitor of adipogenesis and, therefore, has also been evaluated in adipocyte dedifferentiation. WNT3A ^[45] and WNT5A ^[46]^[47] have been identified as crucial players in the induction of an adipocyte dedifferentiation phenotype. Interestingly, the inhibition of Wnt signaling reduced the dedifferentiation rate and re-accumulation of lipids in fat cells ^[48]. Consistent with these results, exogenous administration of WNT3A was sufficient to restore the CAAs’ phenotype ^[47]. Other potential modulators released by CSCs that may trigger the reprogramming of mature adipocytes toward CAAs are represented by exosomes. Recent studies have shown that hepatocarcinoma cells (HepG2) release exosomes that, when internalized by adipocytes, can induce a proinflammatory cytokine expression profile similar to that of CAAs ^[49]. Some researchers suggested that IL-6, miRNA-144, and mir-126, which are released by breast cancer cells, are possible inducers of the CAA phenotype by reducing PPARγ expression and promoting adipocyte dedifferentiation ^[50]. Hu and colleagues showed that IL-6 contained within exosomes and released by Lewis lung carcinoma (LLC) cells activates the Jak/Stat3 pathway in adipocytes, inducing lipolysis ^[51].

Another two potential signaling pathways involved in adipocytes’ dedifferentiation are the Notch ^[52] and TGF-β pathways ^[53]. TGF- β is known to have a key role in adipose tissue remodeling via the activation of extracellular matrix molecules, such as collagen I and VI ^[54], and is probably involved in the activation of MMP11, a negative regulator of adipogenesis and inducer of dedifferentiation ^[55].

CD26, also known as DDP4 (dipeptidyl peptidase 4), is another molecule that participates in the induction of dedifferentiation of adipocytes. DDP4 is a transmembrane serine peptidase involved in ECM degradation by cleaving collagen, whose role in adipose tissue concerns adipose tissue remodeling and the regulation of cell plasticity by regulating C/EBP expression ^[56].

3.2. CAA-Secreted Molecules: A Key Role in Tumor Progression

In vitro and in vivo studies have shown the role of adipokines/cytokines, hormones, and metabolic substrates released by CAAs in influencing the hallmarks of cancer cells. Interestingly, a better characterization of the molecular events induced by CAAs, underlying the adipocyte–CSCs interplay, could elucidate the multistep process of tumorigenesis, paving the way for the development of new therapeutic strategies ^[41]. Importantly, CAAs exhibit dysregulated production of adipokines, both in terms of the quality and quantity of released factors, compared with mature adipocytes ^[38].

3.2.1. Adipokines

Increased expression of leptin has been found in tumors compared to normal tissue, and its presence has been correlated with poor prognosis and a more invasive phenotype ^[57]. Leptin, a hormone encoded by the obese gene (OB), regulates the energy balance by binding to its receptor (OB-R), which is expressed in the hypothalamic arcuate and paraventricular nucleus ^[58]. Systemic levels of leptin are strictly dependent on the amount of body fat, with its secretion stimulated by insulin ^[59] and tumor necrosis factor-α (TNF-α), and inhibited by catecholamines ^[60]. Mechanistically, leptin binds its receptor OB-R in CSCs by promoting activation of the JAK/STAT3, c-Jun, and Akt pathways, thus inducing the transcription of IL-6, TGF-β, and MMP, which drive cancer cell proliferation and invasion. Consequently, in a mouse model, the absence of OB-R resulted in reduced tumor growth and invasiveness by reducing JAK/STAT3 and ERK1/2 signaling ^[61]. Another interesting role of leptin consists of modulation of the metabolic signature of CSCs. In breast cancer, Park et al. demonstrated that an absence of the leptin receptor led to a decrease in glycolysis and an increase in oxidative mitochondrial processes ^[61]. Moreover, Liu et al. highlighted that in melanoma cells, leptin can contribute to chemotherapy resistance by inhibiting apoptosis through activation of the Akt and MEK/ERK pathways. Leptin increased autophagic proteins in myeloma cells and decreased the apoptotic effect of conventional drugs, such as dexamethasone or doxorubicin, melphalan, and bortezomib, in tumor cells ^[62].

Adiponectin is another adipokine that is known to be a regulator of energy and nutrient homeostasis and an anticancer agent. In hepatocarcinoma, adiponectin can abolish the effects of leptin by inhibiting the proliferation and invasion of cancer cells ^[63]. Interestingly, the imbalance between leptin and adiponectin is a crucial factor in promoting tumor growth. In this regard, obese patients with elevated leptin levels and decreased adiponectin expression are more likely to develop tumors ^[64]. Patients with colorectal cancer have been found to express low levels of adiponectin, which correlates with a better prognosis. Adiponectin can be considered as a promising biomarker of prognosis in colorectal cancer ^[65]. Conversely, a possible role of adiponectin in the promotion of cancer growth has been demonstrated ^[66]. The existence of two adiponectin forms may clarify these opposite roles. The complex and controversial role of leptin and adiponectin in supporting tumor growth needs further investigation to develop innovative therapeutic strategies ^[67].

3.2.2. Cytokines

In addition to leptin and adiponectin, CAAs secrete different cytokines compared to mature adipocytes. Among them, researchers identified IL-6 as a proinflammatory cytokine that mediates the activation of Stat-3 in cancer cells, thus promoting tumorigenesis. In particular, the IL-6/Stat-3 axis has been described as the main mechanism through which adipocytes induce the EMT phenotype in tumor cells ^[68]. Interestingly, IL-6 together with leptin can increase the expression of procollagen-lysin-2-oxoglutarate 5 dioxygenase (PLOD2), a protein involved in ECM remodeling, and therefore has a decisive role in cancer cell invasion and EMT ^[69].

3.2.3. Metabolites

According to the Warburg theory, cancer cells were thought to mainly depend on glycolytic metabolism, based on the conversion of glucose into lactate, which occurs independently from the presence of oxygen ^[70]^[71]. Recently, cancer cells, particularly CSCs, have been strongly linked to lipid metabolism ^[72]^[73]. In this scenario, CSCs have been shown to adopt different mechanisms to reprogram their metabolic pathways. Tumor cells require fuel energy to sustain biomass production and to promote migration, invasion, and metastasis. In this context, CSCs use metabolites released by stromal cells as substrates for anabolic metabolism. It is widely recognized that de novo lipogenesis, alteration in fatty acid storage, and β-oxidation are pivotal biological processes that support metabolic reprogramming, which is considered a typical hallmark of CSCs ^[41]. FFAs, released by CAAs in the surrounding microenvironment, are taken up by CSCs through several transporters, such as CD36, also called fatty acid translocase, FATPs (fatty acid transport proteins), and FABPs (fatty-acid-binding protein) ^[74]. Overexpression of CD36 has been found in several tumors, such as breast and ovarian cancers, and has been associated with poor prognosis ^[75]^[76]. The mechanisms by which FAs promote tumor progression are multiple: epigenetic changes, increased reactive oxygen species (ROS) expression, and metabolic remodeling ^[74]. Due to the significant role of FA in contributing to tumor pathogenesis, significant interest has been shown by the medical community in the development of therapeutic strategies that reprogram the metabolic fate of FAs. In this regard, inhibitors of enzymes involved in FA synthesis and the uptake of exogenous lipid have been developed.

Another metabolite that plays a key role in supporting cancer metabolism is glutamine, an amino acid that provides catabolic intermediates for the TCA cycle and has a key role in ATP mitochondrial generation in CSCs ^[77]. Several studies have demonstrated that glutamine promotes tumor growth and contributes to cancer therapy resistance. In pancreatic cancer cells, the secretion of glutamine by adipocytes was correlated with tumor proliferation while in leukemia cells, it was associated with a reduction in cytotoxicity induced by L-asparaginase ^[78]^[79].

Ketone bodies produce more ATP and consume less oxygen compared to glycolysis. Ketone bodies are catabolites produced by FA β-oxidation or aerobic glycolysis. In breast cancer, β-hydroxybutyrate, a ketone body released by adipocytes, has been shown to promote cancer proliferation and growth-inducing expression of its receptor, MCT2. Moreover, β-hydroxybutyrate favors the transcription of some genes, such as Il-1 β and lipocalin-2, through epigenetic regulation. High expression of MCT-2, Il-1 β, and lipocalin-2 is, indeed, correlated with poor prognosis in breast cancer patients ^[80].

3.2.4. Exosomes

Emerging elements involved in adipocytes–cancer cells crosstalk include exosomes and miRNA. Exosomes are microvesicles with a diameter of 30–100 nm that contain mRNA, miRNA, lncRNA, and enzymes. In melanoma, these vesicles have been shown to transport proteins involved in the metabolic reprogramming of CSCs ^[81]. In a lung cancer model, exosomes carry MMP3 to CSCs, promoting tumor progression and metastasis in vivo through the activation of MMP9 ^[82]. Overall, these data highlight that TME is characterized by multiple scenarios of non-mutually exclusive events that arise from crosstalk between CAAs and CSCs. Despite the extrinsic and intrinsic factors elucidated in adipocyte dedifferentiation and CAAs’ involvement in tumor growth, progression, and drug resistance, further studies are needed to understand how CAAs can be targeted to develop an effective therapeutic strategy and identify a tumor cure.

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