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Review  |  Open Access  |  22 Jul 2024

Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia

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Extracell Vesicles Circ Nucleic Acids 2024;5:471-96.
10.20517/evcna.2024.36 |  © The Author(s) 2024.
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Abstract

Cancer cachexia is a complex metabolic syndrome characterized by unintentional loss of skeletal muscle and body fat. This syndrome is frequently associated with different types of cancer and negatively affects the prognosis and outcome of these patients. It involves a dynamic interplay between tumor cells and adipose tissue, where tumor-derived extracellular vesicles (EVs) play a crucial role in mediating intercellular communication. Tumor cells release EVs containing bioactive molecules such as hormones (adrenomedullin, PTHrP), pro-inflammatory cytokines (IL-6), and miRNAs (miR-1304-3p, miR-204-5p, miR-155, miR-425-3p, miR-146b-5p, miR-92a-3p), which can trigger lipolysis and induce the browning of white adipocytes contributing to a cancer cachexia phenotype. On the other hand, adipocyte-derived EVs can reprogram the metabolism of tumor cells by transporting fatty acids and enzymes involved in fatty acid oxidation, resulting in tumor growth and progression. These vesicles also carry leptin and key miRNAs (miR-155-5p, miR-10a-3p, miR-30a-3p, miR-32a/b, miR-21), thereby supporting tumor cell proliferation, metastasis formation, and therapy resistance. Understanding the intricate network underlying EV-mediated communication between tumor cells and adipocytes can provide critical insights into the mechanisms driving cancer cachexia. This review consolidates current knowledge on the crosstalk between tumor cells and adipose tissue mediated by EVs and offers valuable insights for future research. It also addresses controversial topics in the field and possible therapeutic approaches to manage cancer cachexia and ultimately improve patient outcomes and quality of life.

Keywords

Cancer cachexia, extracellular vesicles, cancer, adipose tissue transdifferentiation, metabolism, exosome

INTRODUCTION

Patients with cancer cachexia often experience unintentional weight loss mainly due to the progressive loss of body fat and skeletal muscle[1,2]. This metabolic disorder severely impacts patients’ quality of life, treatments, and survival[3,4]. Although nutritional supplementation is recommended in cancer cachexia patients, this solution is not capable of reversing cachexia symptoms[5]. Therefore, a better understanding of the mechanisms underlying cancer cachexia is essential to identify important players driving this syndrome to further improve patient’s clinical outcomes.

In cancer cachexia, the dysregulation between muscle protein synthesis and breakdown leads to substantial protein depletion within the skeletal muscle[6,7]. Recent research has highlighted the pivotal role of extracellular vesicles (EVs) derived from tumor cells in mediating communication between tumor cells, skeletal muscle, and adipose tissue (AT). By transporting key miRNAs, pro-inflammatory cytokines, and proteins, EVs can induce muscle wasting by modulating muscle physiology (as reviewed in refs[8,9]). This modulation includes myofibrillar protein degradation[10-14], myoblast apoptosis[15-17], insulin resistance[18], and impaired mitochondrial function in muscle cells[19,20].

As cancer progresses, tumor cells also establish a metabolic engagement with AT[21,22]. Tumor-derived EVs can induce the transdifferentiation of the white adipose tissue (WAT) into beige adipose tissue, resulting in global body weight loss[21,23]. As a feedback mechanism, mature adipocytes provide adipokines, lipids, and EVs [transporting proteins, fatty acids (FA), and lipid metabolism-related enzymes] to tumor cells, which consequently remodel their metabolism[21,24].

Although skeletal muscle wasting is a major concern for cancer cachexia patients, this review focuses on the interaction between tumor cells and adipose tissue. We discuss and highlight the recent developments involving the role of EVs in mediating the tumor-adipose tissue (tumor-AT) crosstalk in a cancer-associated cachexia context. Furthermore, we provide valuable insights into the potential of EVs as emerging therapeutic targets, highlighting strategies to inhibit either the release or uptake of these nanovesicles and how this could delay the progression of cancer cachexia. In addition, we also provide promising findings regarding the use of engineered EVs to induce tumor cell apoptosis, reduce tumor progression, and enhance the response to therapy.

CANCER CACHEXIA

More than half of all advanced cancer patients will experience cachexia at any point in their disease[1-4]. Moreover, cachexia is already considered to be the primary cause of death in 20%-30% of all cancer patients[5,25,26]. The incidence of this metabolic syndrome is most prevalent in gastric, pancreatic, lung, oesophageal, hepatic, and colorectal cancer patients[3,27,28]. Cachectic patients may experience asthenia, fatigue, anorexia, intestinal malabsorption, nausea, anemia, and a severe disorder in the metabolism of proteins, lipids, and carbohydrates[29,30]. In addition, these patients become more vulnerable to the toxic effects of treatments[31].

Despite the severity of this condition, cancer cachexia remains an underdiagnosed condition due to the lack of standardized diagnostic criteria or biomarkers[32]. Indeed, biomarkers can provide important insights into the metabolic changes associated with cachexia, enabling early detection and personalized interventions[5,33,34]. Regular clinical follow-up and monitoring of cachexia parameters are essential for early detection, intervention, and management of this syndrome to optimize patient outcomes and quality of life. Despite the potential of biomarkers, there are currently no definitive biomarkers available for the diagnosis and management of cancer cachexia (as reviewed in ref[33]). Clinical monitoring of cachexia requires regular assessments of several parameters, including body weight loss and composition, inflammation [such as increased interleukin-6 (IL-6) or C-reactive protein], metabolic disturbances (such as anemia or low serum albumin), immunosuppression (such as low absolute lymphocyte number), decreased muscle strength and physical performance, fatigue, and anorexia[5,32,35]. Upon diagnosis, interventions may include nutritional supplementation, exercise programs, pharmacological therapies, symptom management, and multidisciplinary care[5,36-38]. Currently, the available recommendations for the management of cancer cachexia include a variety of drugs and hormones to (1) improve appetite and reduce nausea (including megestrol acetate, corticosteroids, and ghrelin hormone) (as reviewed in ref[5]); (2) increase lean body mass (including selective androgen receptor modulators and omega-3 FA); and (3) decrease inflammation (such as non-steroidal anti-inflammatory drugs)[29,30]. Unfortunately, the benefits and effectiveness of these strategies are limited and insufficient. Recent research has been focused on GDF15, a circulating growth factor associated with several types of cancer including prostate, gastric, colon, pancreas, and breast[39,40]. It is reported that high levels of GDF15 could promote tumor cell proliferation and metastasis[40]. Additionally, some studies have shown that high levels of GDF15 are associated with weight loss in animal models[41,42] and poor survival rates for cancer patients[43]. Interestingly, treating mice with monoclonal antibodies targeting GDF15 could reverse the tumor-induced metabolic changes and promote weight gain in these animals, even with caloric restrictions[44,45]. Currently, several clinical trials are ongoing to evaluate the therapeutic potential of using GDF15 as a target for cancer cachexia. So far, these treatments have been well-tolerated by cancer patients and have resulted in a reduction in the circulating levels of GDF15[46,47]. These findings suggest that targeting the GDF15 growth factor may represent a promising therapeutic strategy for treating cancer cachexia.

In cancer cachexia, the skeletal muscle undergoes significant metabolic and inflammatory changes (as reviewed in refs[38,48]). Tumor cells release pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), IL-1β, and IL-6, which promote muscle protein degradation and increase oxidative stress[49-51]. Moreover, during this crosstalk, there is also evidence of (mTOR) signaling pathway inhibition[52], insulin and insulin-like growth factor-1 (IGF-1) resistance[53,54], and mitochondria dysfunction[55]. These combined effects result in muscle weakness, fatigue, and reduced response to cancer treatments, which severely impacts patient’s quality of life. Apart from the impact on skeletal muscle, cachexia can also affect the AT, heart, liver, brain, and immune system (as reviewed in refs[1,56]). Over the past decade, the communication between tumor cells and adipocytes has attracted researchers’ attention as it might provide new targets for addressing cancer cachexia. In particular, the changes occurring in AT morphology and function during cancer progression are associated with the development and progression of this metabolic syndrome.

ADIPOSE TISSUE

AT is a complex connective tissue composed of adipocytes and a stromal vascular fraction, which includes various cell types such as fibroblasts, pre-adipocytes, endothelial cells, and immune cells (as reviewed in refs[57,58]). In healthy individuals, the AT comprises around 25% of the total body weight[59]. Adipocytes are lipid-rich cells that contain globules of fat (lipid droplets) surrounded by a structural network of fibers[59,60]. Based on their morphological features, location, and function, adipocytes can be classified as white, brown, and beige adipocytes. The progenitors of white, beige, and brown adipocytes are mesenchymal stem cells derived from the AT, commonly known as adipose-derived mesenchymal stem cells (AMSCs). The importance of these AMSCs has only recently been studied, as many of their mechanisms remain unknown. In physiological conditions, this cell population can give rise to many different lineages[61], including adipocytes, osteoblasts, or chondroblasts [Figure 1]. The differentiation process occurs in a synchronized manner through the regulation of a set of lineage-specific transcription factors. These include the peroxisome proliferator-activated receptor-gamma (PPARγ) for adipogenic lineage[62], runt-related transcription factor 2 (RUNX2) for osteogenic lineage[63], and SRY-Box Transcription Factor 9 (Sox9) for chondrogenic lineage[64]. Adipocyte cell lineage begins with AMSC differentiation. AMSCs can either be positive or negative for the myogenic factor 5 (Myf5). Myf5- AMSCs differentiate in the presence of PPARγ and CCAAT/enhancer binding protein (C/EBP) in white pre-adipocytes, which, upon cell cycle exit, can accumulate and form fat deposits as mature adipocytes[65]. Moreover, white adipocytes can also transdifferentiate into beige adipocytes in the presence of the PR domain containing 16 (PRDM16), PPARγ, and PPARgamma-coactivator-1 (PGC-1α). On the other hand, Myf5+ AMSCs give rise to precursors of the myogenic lineage[66], which, upon the available transcription factors, differentiate in either brown pre-adipocytes, in the presence of PPARy[65], or skeletal muscle cells, in the presence of myoblast determination protein 1 (myoD) and myogenin[67].

Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia

Figure 1. The differentiation process of adipocytes.AMSCs are mesenchymal stem cells that can differentiate into a variety of lineages depending on specific transcription factors. When the Myf-5 factor is absent and the PPARγ and C/EBP proteins are present, AMSCs differentiate into white pre-adipocytes. Upon fat uptake and deposit formation, these adipocytes further differentiate into mature white adipocytes. White adipocytes can also transdifferentiate into beige adipocytes, in a process called white adipocytes browning, in the presence of PRDM16, PPARγ, and PGC-1α. On the other hand, the presence of Myf-5 leads AMSCs to commit to a myogenic lineage. In this lineage, the PRDM16 transcription factor potentiates the AMSC differentiation into brown pre-adipocytes and prevents AMSC differentiation into myoblasts, and further skeletal muscle cells (due to myoD protein and myogenin). In the presence of PPARγ, brown pre-adipocytes mature into brown adipocytes. Other transcription factors, like RUNX2 and Sox9 factors, lead to osteogenic and chondrogenic lineages, respectively. There are also reports that TGF-β released by tumor cells also allows AMSCs to differentiate into myofibroblasts. Created with Biorender.com. AMSCs: Adipose-derived mesenchymal stem cells; Myf-5: myogenic factor 5; PPARγ: peroxisome proliferator-activated receptor-gamma; C/EBP: CCAAT/enhancer binding protein; PRDM16: PR domain containing 16; PGC-1α: PPARgamma-coactivator-1; RUNX2: runt-related transcription factor 2; Sox9: SRY-Box Transcription Factor 9; TGF-β: transforming growth factor-beta.

Figure 2 represents the three types of adipocytes, their location, and their main function. White adipocytes comprise the majority of the body fat and function mainly to store energy. They are composed of a large lipid droplet and contain very few cellular organelles[59]. Therefore, their metabolic activity is very low. During lipogenesis, glucose is transported to the white adipocytes to be catabolized and transformed into FA[1,68]. FA are esterified with glycerol, giving rise to triglycerides, which are then stored in the lipid droplets of white adipocytes. These adipocytes are also capable of incorporating FA through the activity of lipoprotein lipase (LPL), the enzyme responsible for the degradation of triglycerides present in circulating lipoproteins. These FA can also be further esterified to triglycerides[1,68]. White adipocytes secrete key factors (hormones, growth factors, and cytokines) that play an important role in endocrine and metabolic regulation[69]. These adipocytes are located under the skin and around internal organs. On the other hand, brown adipocytes are very metabolically active cells containing many small lipid droplets, due to the β-oxidation of FA. Therefore, they are characterized by high mitochondria density, and positivity to the uncoupling protein 1 (UCP1)[70,71]. Their main function is to generate heat[70] and are located in the upper back, above the clavicles, and along the spine[72]. During cold exposure, brown adipocytes are activated and white adipocytes can be transdifferentiated to acquire a brown fat-like phenotype, a process commonly known as white adipose tissue browning (WAT browning), giving rise to beige adipocytes[73]. As a consequence, an increase in the lipolysis activity[74,75], and thermogenesis[76,77] of white adipocytes, together with impaired adipogenesis and lipogenesis[78,79], takes place. During WAT transdifferentiation, individuals may experience profound white adipocyte atrophy characterized by a series of morphological and structural modifications (as reviewed in ref[80]).

Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia

Figure 2. The three types of adipocytes. White adipocytes are characterized by a large lipid droplet and low mitochondria density and UCP1 expression. These adipocytes are responsible for energy storage, being capable of incorporating FA. They are mainly located under the skin and around the visceral organs. Due to a variety of stimuli, white adipocytes can transdifferentiate into beige adipocytes. Beige adipocytes have medium size lipid droplets and mitochondria density. Brown adipocytes are very metabolically active, being characterized by a high β-oxidation activity, sustained by a high mitochondria density. Due to this metabolic signature, they contain several small lipid droplets and very high UCP1 levels. These adipocytes are responsible for generating heat. Brown adipocytes are located above the clavicles, along the spine, in the armpits, and cervical area. Created with Biorender.com. UCP1: Uncoupling protein 1; FA: fatty acids.

THE TUMOR-ADIPOSE TISSUE CROSSTALK

Tumor cells can engage and induce WAT transdifferentiation into beige AT to stimulate lipolysis in adipocytes, in order to sustain their accelerated energy expenditure. Increased activity of adipocyte triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL) enzymes[81,82] results in the activation of lipolysis in white adipocytes. These enzymes are responsible for the hydrolysis of triglycerides. The resulting FA and glycerol are further released into the bloodstream and can be uptake by tumor cells[83]. As a result, tumor cells can adapt their metabolism toward FA β-oxidation (FAO) for energy production[84]. In addition, the high levels of ATGL and MGL have also been correlated with increased tumor aggressiveness in different types of cancer[85-88]. Furthermore, when tumor cells induce the WAT transdifferentiation into beige adipocytes, an increase in UCP1 levels can be observed[89]. By disrupting the mitochondrial ATP synthesis favoring thermogenesis, UCP1 leads to inefficient energy expenditure. This process culminates in involuntary body fat and weight loss, commonly found in cancer cachexia syndrome[89]. The synthesis of UCP1 protein is highly regulated by the PRDM16 protein[90], PPARγ and PPARα proteins[91], C/EBP-α[91], CREB-binding protein[92], and PGC-1α[93,94]. Subcutaneous cell implantation of cells displaying the lipid mobilizing factor zinc-α2-glycoprotein (ZAG) in mouse models stimulated the lipolysis and transdifferentiation of WAT[95]. The authors reported that the ZAG factor, highly expressed in several types of cancers[96-98], could induce the activation of PPARγ and early B cell factor 2 (EBF2) and the recruitment of these factors to the PRDM16 promoter and consequently increase the levels of UCP1 protein[95]. Moreover, it was observed that the weight loss of colon-26 tumor-bearing mice, by adipose tissue wasting, begins in the early stages of cancer cachexia[75]. Notably, a positive correlation was found between the levels of UCP1 protein and basal lipolysis rate in the interscapular brown AT (BAT) of these mice[75]. In addition, the intravenous injection of mice with a lipid-mobilizing factor isolated from the urine of cachectic adenocarcinoma patients led to a marked decrease in their weight, together with a decrease in the plasma leptin levels and an increased UCP1, UCP2, and UCP3 levels in BAT[99].

Tumor cells can secrete numerous pro-inflammatory factors such as TNF-α, interferon-gamma (IFN-γ), IL-1 and IL-6, and parathyroid hormone-related protein (PTHrP) that can trigger cancer cachexia[77,100,101]. Notably, a positive correlation between the serum levels of IL-6 and free fatty acids (FFA) was found in gastric and colorectal cancer patients with cachexia[102]. Moreover, an increase in WAT lipolysis and browning in both early- and late-stage cachexia was observed in these patients. In addition, elevated levels of UCP1 and PGC1α were detected in the subcutaneous AT of gastrointestinal cancer patients[103]. These findings highlight the complex interplay between cancer-related inflammation and metabolic reprogramming in AT, contributing to the development and progression of cancer cachexia. Importantly, it is also known that tumor cells release EVs that can regulate tumor progression, metastasis formation, and chemoresistance by promoting intercellular communication (as reviewed in ref[104]). Recently, the role of these nanovesicles in mediating cancer cachexia has also been explored [Figure 3].

Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia

Figure 3. The tumor-adipose tissue crosstalk. Tumor cells are capable of remodeling adipocyte metabolism, locally and at a distance. Cancer cells secrete EVs containing a vast content of proteins and miRNAs that can promote the transdifferentiation of white adipocytes into beige adipocytes. In turn, the transdifferentiated white adipocytes fuel tumor growth and metastasis formation by engaging in a metabolic crosstalk with tumor cells. These adipocytes can secrete EVs enriched in specific metabolites, epithelial and mesenchymal markers, and/or miRNAs. As a consequence, tumor-AT crosstalk favors cancer progression and metastization of tumor cells to distant organs and induces cachexia in cancer patients. Created with Biorender.com. EVs: Extracellular vesicles; tumor-AT: tumor-adipose tissue.

Recent research has provided important insights into the contribution of EVs to the development of cancer cachexia and tumor progression (as reviewed in refs[9,105]). Tumor-derived EVs carry several bioactive molecules like hormones, proteins, and miRNAs, which may induce lipolysis in AT, contributing to cancer cachexia[106-109]. Moreover, EVs can promote WAT browning by delivering pro-inflammatory cytokines and other signaling molecules to adipocytes, leading to increased expression of browning markers and enhanced thermogenesis[11,110]. On the other hand, EVs derived from adipocytes carry fatty acids, proteins, enzymes, and miRNAs that influence the behavior of recipient cells (as reviewed in ref[111]). These EVs can promote an inflammatory microenvironment favorable to tumor growth, invasion, and metastasis formation[112-115]. In addition, adipocyte EVs deliver lipids and lipid metabolic enzymes, thereby altering the metabolic state of tumor cells and promoting their proliferation and resistance to apoptosis[116,117]. Furthermore, adipocyte-derived EVs carry miRNAs capable of regulating gene expression in recipient tumor cells, often favoring tumor progression by inducing cell proliferation, invasion, and resistance to chemotherapy[118-120]. In summary, the role of EVs in tumor-AT crosstalk highlights their pivotal function in fostering tumor progression and ultimately leading to a cancer cachexia phenotype. Although further studies on different cancer types are still missing to strongly support the role of EVs in driving cancer cachexia, the existing findings already emphasize the potential use of EV-targeted therapies to tackle cancer cachexia.

Cancer extracellular vesicles promote white adipocyte transdifferentiation and metabolism remodeling

EVs are a highly heterogeneous group of nano-sized particles that are essentially secreted by all types of cells as an intercellular communication mechanism. They travel in different body fluids, such as blood, saliva, tears, and breast milk, transporting proteins, enzymes, nucleic acids, lipids, and glycans to recipient cells (as reviewed in refs[121-123]). These vesicles can be classified by size as either small or large EVs, or by their biogenesis mechanism as exosomes, microvesicles, and apoptotic bodies[124]. Exosomes are produced by the inward budding of the cell membrane, whereas microvesicles are shed directly from the cell membrane[125,126]. Regarding apoptotic bodies, they are released during the process of cell apoptosis[125,126]. More recently, a subset of smaller nanoparticles called exomeres have also been described as secreted by cells with a differential cargo and function compared to small and large EVs[127]. EVs membrane consists of a phospholipid bilayer that confers protection to their cargo against proteases and nucleases present in the outside environment[128,129]. The small size of EVs[127,130] facilitates their interaction and uptake by local cells and by cells in distant organs, where they can influence the behavior of the recipient cells[104].

As previously mentioned, cancer cachexia is a multifactorial syndrome driven by several tumor-derived factors, including soluble cytokines and EVs. Tumor cells can release large amounts of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, into the bloodstream[131]. These cytokines induce systemic inflammation and catabolic processes in multiple tissues, leading to muscle wasting and fat loss[131,132]. In addition to cytokines, EVs have emerged as key players during cancer cachexia. Namely, it has been demonstrated the presence of miRNAs, hormones, proteins, and cytokines in cancer EVs that could induce a metabolic remodeling of white adipocytes after internalization. These vesicles can stimulate WAT lipolysis and browning, inhibit adipogenesis, and consequently lead to weight loss in animal models, as detailed in Table 1.

Table 1

Effects of cancer extracellular vesicles in white adipocyte transdifferentiation and metabolism remodeling

Cancer typeCancer EV cargoBiological impactRef.
BreastmiR-1304-3p↑ Adipocyte “browning”[133]
BreastmiR-204-5p↑ Adipocyte lipolysis
↓ Mouse weight
[106]
BreastmiR-155↓ Adipocyte lipogenesis
↓ Mouse weight
[134]
PancreaticLinc-ROR↑ Dedifferentiation of white adipocytes[135]
PancreaticAdrenomedullin↑ Adipocyte lipolysis[136]
Pancreatic-↓ Triglyceride content
↑ Glycerol release
↓ Mouse abdominal adipocyte size
[137]
GastricmiR-410-3p↓ Adipocyte adipogenesis[138]
GastricmiR-155↓ AMSC adipogenesis
↑ Adipocyte “browning”
↓ Mouse weight
[110]
Gastric/LungmiR-425-3p↓ Pre-adipocytes differentiation and proliferation
↑ Adipocyte “browning”
↑ Adipocyte lipolysis
[139]
ColorectalmiR-146b-5p↑ Adipocyte “browning”
↑ Adipocyte lipolysis
↓ Mouse weight
[107]
LungPTHrP↑ HSL levels
↑ Adipocyte “browning”
↑ Glycerol release
↑ Mouse WAT lipolysis
[108]
LungIL-6↑ Adipocyte lipolysis[11]
LungEIF5A↑ Adipocyte lipolysis[109]
Lung-↑ Adipocyte “browning”
↑ Glycerol release
↑ Mouse WAT lipolysis
[140]
Lung/ Colon-↑ Adipocyte lipolysis
↓ Mouse iWAT and eWAT size
[141]
LeukemiamiR-92a-3p↓ Adipocyte adipogenesis
↓ Mouse weight
[142]
Lung-↓ AMSCs adipogenesis[143]
Prostate-EMT transition in AMSCs[144]
Gastric-↑ AMSCs migration and invasion[145]

It has been shown that proteins and nucleic acids carried by EVs derived from breast[106,133,134], pancreatic[135-137], gastric[110,138,139,145], colorectal[107,141], lung[11,108,109,140,141,143], and prostate[144] cancers, and leukemia[142] could contribute to WAT transdifferentiation and metabolism remodeling [Table 1]. For instance, in breast cancer, EVs carrying the microRNA1304-3p (miR-1304-3p) could induce the browning of white adipocytes by reducing the expression of the GATA2 transcription factor[133]. Moreover, the proliferation of breast cancer cells could be increased when in co-culture with the transdifferentiated adipocytes. Interestingly, the injection of miR-1304-3p positive breast cancer cells into mice led to an increased accumulation of adipocytes in the primary tumor tissue[133]. Similarly, the injection of miR-204-5p-positive EVs in mice with orthotopic tumors, previously induced by injecting breast cancer cells in the mammary fat pad of these animals, increased the levels of leptin and hypoxia-inducible factor 1α (HIF-1α), concomitant with increased lipolysis in their white fat depots[106]. Furthermore, breast cancer-derived EVs carrying miR-155 induced a decrease in the lipid droplet content and an upregulation of UCP1 protein and HSL and ATGL enzymes in white adipocytes[134]. Notably, in animal models, injecting these miR-155-positive EVs resulted in body weight loss and downregulation of the levels of ubiquilin 1 (UBQLN1) protein in white adipocytes, inducing its browning[134]. In pancreatic cancer, tumor-derived exosomes carrying the long intergenic non-coding ROR (linc-ROR) induced the downregulation of PPARγ, Glut-4, and HSL in adipocytes, resulting in the dedifferentiation of white adipocytes[135]. In addition, exosomes from pancreatic cancer cells, enriched in adrenomedullin hormone, could activate the p38 and the Ras-dependent extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathways in adipocytes. This led to an increase in HSL phosphorylation and lipolysis in white adipocytes[136]. Moreover, lipidomic analysis of adipocytes treated with pancreatic cancer-derived exosomes revealed a significant decrease in the triglyceride content of these adipocytes and an increase in the levels of released glycerol[137]. Additionally, mice injected with these exosomes exhibited smaller abdominal adipocytes, associated with elevated levels of IL-6 in circulation[137]. In gastric cancer, it was found that cachectic patients had high levels of miR-410-3p in their exosomes[138]. In vitro experiments showed that this miR-410-3p inhibited adipogenesis and lipid accumulation and regulated the expression of the insulin receptor substrate-1 (IRS-1), important for adipocyte differentiation. The authors hypothesized that the accentuated weight loss in these patients was correlated with the high levels of miR-410-3p[138]. Similarly, colorectal cancer exosomes enriched in miR-146-5p were able to regulate lipolysis and induce WAT browning, resulting in the weight loss of animal models[107]. It was also found that exosomes from patients with colorectal cancer contained high levels of this miR-146-5p[107]. In the same line of these results, in gastric and lung cancer models, exosomal miR-425-3p negatively impacted pre-adipocyte proliferation and differentiation, inducing a brown fat-like phenotype in fully differentiated white adipocytes through cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway activation[139]. Similar effects were found when studying the impact of EVs released by Lewis lung carcinoma (LLC) and colon cancer cells in increasing adipocyte lipolysis. These EVs led to a decreased inguinal WAT (iWAT) and epididymal WAT (eWAT) size with increased UCP1 and PGC-1α levels in these tissues[141]. In addition, inhibiting the levels of the CXCR2 receptor and nuclear factor-κB (NF-κB) in adipocytes significantly reduced the lipolysis induced by IL-8-positive EVs[141]. Other authors have also reported that the exposure of white adipocytes to LLC-derived exosomes promoted a brown fat-like phenotype in these cells, characterized by high levels of UCP1 and HSL proteins and high glycerol secretion[108,140]. Furthermore, these exosomes stimulated lipolysis in the WAT depots of LLC tumor-bearing mice[108,140]. It was also demonstrated that LLC-derived EVs transporting the PTHrP protein could activate the PKA signaling pathway in adipocytes and consequently increase HSL levels[108]. These EVs also induced adipocyte lipolysis by activating the STAT3 signaling pathway through IL-6 delivery to white adipocytes[11]. In addition, lipolysis in adipocytes could be stimulated by the treatment with LLC-derived EVs enriched in the eukaryotic translation initiation factor 5A (EIF5A) via CREB-binding protein activation[109]. In brief, these reports show that tumor-derived EVs play a crucial role in reprogramming white adipocytes in different types of cancer. They can influence adipogenesis, lipolysis, and WAT browning, affecting overall adipocyte metabolism.

Interestingly, these EVs can also affect adipocytes in their earlier, more primitive form, as adipose-derived mesenchymal stem cells (AMSCs). Indeed, in lung cancer, inhibition of the transforming growth factor-beta (TGF-β) signaling pathway effectively reversed the inhibitory effects of lung cancer exosomes on AMSC adipogenesis[143]. Moreover, the intravenous injection of mice with gastric cancer exosomes carrying miR-155 could lead to an inhibition of AMSC adipogenesis, promoting WAT browning, which resulted in significant weight loss and the development of a cancer cachexia phenotype in these animals[110]. In chronic myeloid leukemia, exosomes transporting miR-92a-3p released by tumor cells were also able to suppress adipogenesis in AMSCs, by inhibiting the levels of the C/EBPα factor, which resulted in a significant weight loss in mice. In another study, prostate cancer-derived exosomes were involved in the neoplastic transformation of AMSCs, promoting the epithelial-mesenchymal transition (EMT) in recipient AMSCs by downregulating the large tumor suppressor homolog 2 (Lats2) and the programmed cell death protein 4 (PDCD4), both in vitro and in vivo[144]. Lastly, it was found that gastric adenocarcinoma-derived exosomes could increase the migration and invasion capacities of AMSCs by upregulating circ_0004303 RNA expression, thereby activating the activated leukocyte cell adhesion molecule (ALCAM) transmembrane protein[145].

Collectively, these results emphasize the pivotal role of EVs in the interplay between tumor cells and adipocytes. Interestingly, inhibiting the production and secretion of exosomes negatively influenced the lipolysis of white adipocytes both in vitro and in vivo. Indeed, the inhibition of LLC-derived exosome biogenesis using GW4869, a pharmaceutical agent that inhibits exosome formation, suppressed the WAT browning in vivo[140]. Moreover, the knockdown of the Rab27A protein in LLC tumor-implanted mice attenuated WAT browning and lipolysis in these animals[108]. It was also found that the loss of adipose tissue in LLC tumor-bearing mice could be attenuated by the administration of omeprazole, an inhibitor of HSP70 and HSP90 positive EVs release by blocking Rab27b synthesis in tumor cells[146]. In addition, the release of EVs and IL-6 from colon cancer cells could be mitigated by treating tumor cells with atractylenolide I (an EV biogenesis inhibitor by regulating the STAT3 pathway in tumor cells), and consequently attenuate weight loss in tumor-bearing mice[147]. Furthermore, white adipocyte lipolysis was reduced by treating these cells with the conditioned medium from colon cancer cells pre-treated with atractylenolide I[147]. These observations suggest that inhibiting the biogenesis and secretion of cancer EVs could be an effective strategy against cancer cachexia.

Altogether, these findings highlight the crucial role of EVs as important mediators of tumor-AT crosstalk. Tumor-derived EVs, carrying specific miRNAs and proteins, can induce a metabolic remodeling of white adipocytes, leading to increased lipolysis and, therefore, to a higher availability of free FA and glucose in the extracellular space. These metabolites become accessible to tumor cells and can be used for energy production and membrane biosynthesis, supporting tumor growth and metastasis formation. Furthermore, these nanovesicles can promote the transdifferentiation/browning of white adipocytes by increasing mitochondrial activity, which in turn supports tumor progression. Notably, inhibitors of EV biogenesis showed to be promising in mitigating WAT browning and weight loss in animal models.

Cancer extracellular vesicles affect adipocyte differentiation and the tumor microenvironment

Tumor cell-derived EVs also play an important role in the formation of an environment propitious to tumor progression. Tumor-derived EVs carry growth factors and enzymes that can stimulate the secretion of pro-inflammatory cytokines by adipocytes, potentially leading to tumor growth and increased angiogenesis. Furthermore, these EVs can promote tumor progression by enhancing the differentiation and motility of adipocytes in their precursor state [Table 2].

Table 2

Effects of cancer extracellular vesicles in adipocyte differentiation and tumor microenvironment

Cancer typeCancer EV cargoBiological functionRef.
Hepatocarcinoma-↑ IL-6, IL-8 and MCP-1 secretion
↑ Tumor growth, angiogenesis, and macrophage recruitment in vivo
[148]
BreastTGFβAMSCs differentiation
↑ VEGF production
[149]
Breast/ovarian-AMSCs differentiation
↑ TGF-β receptors in AMSCs
[150,151]
OvarianpiR-25783Omentum-derived fibroblasts differentiation[152]
LiposarcomaMDM2↑ Proliferation, migration, and MMP2 production in pre-adipocytes[153]

Indeed, exosomes released by hepatocarcinoma cells could activate the NF-κB signaling pathway in adipocytes, thereby inducing an inflammatory phenotype in these cells. The inflammatory state promoted the secretion of pro-inflammatory cytokines, including IL-6, IL-8, and macrophage chemoattractant protein (MCP-1), in a dose-dependent manner[148]. This pro-inflammatory microenvironment fostered tumor growth, enhanced angiogenesis, and promoted macrophage infiltration in mouse models[148]. Interestingly, it has also been shown that breast cancer-derived EVs induced tumor progression through AMSC differentiation into myofibroblasts, which contributed to extracellular matrix remodeling and angiogenesis[149,150]. AMSC differentiation was mediated through the activation of the MAPK signaling pathway by breast cancer EVs carrying the transforming growth factor-beta (TGF-β)[149]. Similar results were reported when investigating the impact of breast and ovarian cancer EVs in AMSC differentiation[150,151]. Increased levels of the TGF-β receptor were found in AMSCs treated with breast and ovarian cancer-derived EVs. These findings indicate that these particles could activate TGF-β receptor-mediated signaling pathways, leading to the differentiation of AMSC into myofibroblast, creating a favorable microenvironment for tumor cell growth[150,151]. The transfer of piR-25783 from ovarian cancer exosomes to omentum-derived fibroblasts also promoted the differentiation of the fibroblasts to myofibroblasts and consequently contributed to the formation of a microenvironment propitious to the establishment and growth of tumor cells in the omentum[152]. Furthermore, it was observed a decrease in p53 tumor suppressor activity and an increase in proliferation, migration, and production of matrix metalloproteinase 2 (MMP2) of pre-adipocytes exposed to EVs secreted from liposarcoma, carrying mouse double minute 2 (MDM2) DNA, thereby contributing to the establishment of a pre-metastatic niche that facilitates tumor growth and colonization[153].

These studies suggest that EVs play a crucial role in establishing a favorable microenvironment for tumor growth by inducing an inflammatory state and promoting the differentiation of AMSCs into myofibroblasts, remodeling the extracellular matrix, and stimulating angiogenesis. These mechanisms could contribute to the formation of a pre-metastatic niche that facilitates tumor progression and metastasis formation. The mentioned studies are not directly correlated with cancer cachexia. Nevertheless, it is important to note that tumor metastasis is usually associated with advanced stages of cancer and closely linked to the development of cancer cachexia.

Adipocyte-derived extracellular vesicles promote tumor progression and metabolic reprogramming

After being transdifferentiated by cancer cells, adipocytes secrete factors, including metabolites, adipokines, and EVs (transporting FAO-related proteins and enzymes, miRNAs, and lncRNAs) that can affect the tumor microenvironment and the biology of tumor cells. The role of adipocyte-derived EVs in AT-cancer crosstalk [Table 3] has been observed in different types of cancer with an impact on tumor progression, metastasis formation, and treatment resistance[167-169]. These observations have been reported in EVs isolated from naïve adipocytes and by EVs isolated from adipocytes in obese or diabetic conditions, highlighting the impact of specific metabolic disorders in cancer progression.

Table 3

Effects of adipocyte-derived extracellular vesicles in tumor progression and metabolic reprogramming

Cancer typeAdipocyte EV cargoBiological impactRef.
MelanomaFAO‐related proteins↑ FAO on tumor cells
↑ Tumor cell invasion and migration
Mitochondria reorganization
[116,117]
Melanomaβ-catenin↑ Tumor cell progression and aggressiveness[112]
BreastTSP5↑ EMT induction
Changes in tumor cell morphology
[154]
Breast-↑ Tumor cell invasion and migration
↑ EMT induction
[114]
Breast-↑ Tumor cell migration[155]
BreastLeptin and MMP9↑ MMP9 secretion
↑ Tumor cell proliferation and motility
[156]
Breast-↓ Tumor cell apoptosis
↑ Tumor cell proliferation and migration
[157]
BreastmiR-155-5p, miR-10a-3p, and miR-30a-3p↑ Tumor cell proliferation
↑ Mitochondrial density
[113]
Nasopharyngeal↓ miR-433-3p↑ Tumor cell motility
↑ Lipid accumulation
[158]
LungMMP3↑ Tumor cell invasion and metastasis formation in vivo[159]
Liver-↑ Production of liver fibrosis genes, integrins, and MMP9[160]
HepatocellularmiR-32a/b↑ Tumor cell proliferation and migration
5-FluoroUracile resistance
[118]
OvarianmiR-21↓ Tumor cell apoptosis
Paclitaxel resistance
[119]
Ovarian-↑ Tumor cell growth
↑ Metastasis formation in vivo
[161]
ColorectalMTTP↓ Tumor cell ferroptosis
Oxaliplatin resistance
[115]
Colorectal-↑ Tumor cell invasion and migration[162]
Prostate-↑ Tumor cell proliferation and migration
Docetaxel resistance
Tumor cell metabolism switch
[120]
Prostate-EMT transition[163]
MyelomaLncRNAs (LOC606724 and SNHG1)Bortezomib resistance[164]
Pancreatic-↑ Tumor cell proliferation and motility
↑ EMT induction
[135,165]
Osteosarcoma-↑ Tumor cell proliferation, migration, and invasion[166]

Recent studies have shown that adipocyte-derived EVs can reprogram the metabolism of melanoma cells toward FAO by providing FA, proteins, and the necessary enzymes for this metabolic transformation[116,117]. Moreover, these EVs could promote the migration and invasion capacity of melanoma cells[116,117] by stimulating the reorganization of mitochondria in these tumor cells[116]. Interestingly, it was observed that adipocytes from obese mice released higher amounts of EVs compared to those from lean mice[116,117]. This higher secretion of adipocyte-derived EVs in obese mice may lead to a stronger effect on tumorigenesis since the amount of FA delivered to tumor cells increases. Another study revealed that EVs derived from the AT of obese patients could regulate the expression of the TWIST1 transcription factor in prostate cancer cells and thus regulate the EMT transition of these cells[163]. Moreover, it was also shown that adipocyte EVs carrying β-catenin could block the transcription of CDKN2A factor (responsible for cell growth regulation) and decrease p16INK4A levels (associated with cell cycle regulation) in melanoma cells, which resulted in tumor progression[112]. The authors hypothesize that the higher secretion of EVs containing β-catenin in obese patients might amplify the effect of these particles on tumor aggressiveness[112]. Furthermore, EVs isolated from the adipocytes of obese patients, enriched in leptin and MMP9, could promote the release of MMP9 by breast cancer cells[156]. This could enhance the proliferation and mobility of tumor cells by activating the ERK/MAPK and the PI3K/AKT signaling pathways[156]. Remarkably, EVs isolated from obese individuals promoted the proliferation of breast cancer cells by enhancing the mitochondrial function and density of these cells, through the Akt/mTOR/P70S6K signaling pathway[113]. Interestingly, it was found that the enriched miRNAs (miR-155-5p, miR-10a-3p, and miR-30a-3p) in these EVs stimulated oxidative phosphorylation (OXPHOS) in tumor cells[113]. In liver cancer, the TGF-β signaling pathway was dysregulated in hepatocytes by the presence of adipocyte EVs isolated from obese patients[160]. The treatment of hepatocytes with these EVs led to an increased expression of genes involved in the development of liver fibrosis, including the tissue inhibitor of matrix metalloproteinase-1 and -4 (TIMP-1 and -4), the integrins ανβ-5 and ανβ-8, and MMP9, thus evidencing the role of adipocyte EVs in modulating the tumor microenvironment[160]. Similarly, EVs carrying thrombospondin-5 (TSP5) protein, isolated from patients with type 2 diabetes, could increase the expression of genes associated with EMT transition in breast cancer cells, leading to alterations in cellular morphology[154]. Furthermore, it was found that adipocyte-derived EVs could enhance the growth, motility, and invasion of breast cancer cells by stimulating the activity of HIF-1α in tumor cells[114]. Additionally, it was observed that these EVs could facilitate the process of lung metastatic colonization in mice after breast cancer cells were injected into the tail vein of these animals[114]. These studies illustrate the link between obesity, diabetes, and cancer progression. Adipocyte-derived EVs from obese or diabetic individuals could contribute to microenvironment modulation, tumor aggressiveness, and metastasis. Indeed, it has been described that obesity is strongly linked to a higher risk of developing several types of cancer (as reviewed in ref[170]). In obesity, AT produces elevated levels of estrogen, pro-inflammatory cytokines (TNFα, IL-6, IL-1β), adipokines (leptin), and EVs[171], which may contribute to enhanced tumor invasiveness, proliferation, and metastasis[172]. In addition, obesity has been associated with an increased risk of overall mortality and disease recurrence in patients with breast[173], liver[174], colorectal[175,176], prostate[177], and pancreatic[178] cancer. Both obesity and cancer cachexia share common underlying mechanisms that result in profound metabolic alterations. Key factors such as insulin resistance[179], WAT lipolysis[180], muscle atrophy[181], and systemic inflammation[182] play crucial roles in both conditions. Interestingly, a recent study demonstrated that obese and lean LLC-bearing mice experience similar patterns of weight loss[183]. Moreover, obese mice exhibit reduced survival rates and mitochondrial dysfunction, emphasizing the complex interplay between obesity and cancer outcomes[183]. Obesity not only increases the risk of cancer mortality and recurrence but also significantly increases the risk of patients developing type 2 diabetes (as reviewed in ref[184]). In diabetic patients, insulin resistance, elevated levels of glucose, insulin, and IGF-1, as well as pro-inflammatory cytokines, increased leptin, and decreased adiponectin can increase the risk of cancer development[185]. Evidence has shown that diabetes type 2 is linked to a higher incidence and recurrence rates of pancreatic[186,187], liver[186,187], colorectal[187,188], breast[187,189], and endometrial[186] cancer. Importantly, it was found that the pre-existence of type 2 diabetes in patients with pancreatic and colorectal cancer could lead to increased cachexia incidence, resulting in higher weight loss and reduced survival rates[190]. These findings show the complex metabolic interplay between obesity, type 2 diabetes, and cancer cachexia, emphasizing the need for novel and better comprehensive management strategies to address the metabolic unbalance in these patients.

Furthermore, breast cancer cell migration could also be enhanced by AMSCs-derived exosomes through the activation of the tumor Wnt/β-catenin signaling pathway[155]. It was also noted that exosomes secreted from AMSCs reduced apoptosis and promoted the proliferation and migration of breast cancer cells through activation of the Hippo signaling pathway[157]. In the same line with these results, adipocyte-derived exosomes expressing low levels of miR-433-3p promoted lipid accumulation in nasopharyngeal cancer cells by activating the stearoyl-CoA desaturase 1 (SCD1), a key enzyme in FA metabolism[158]. It was also found that adipocyte exosomes enriched in MMP3 could activate MMP9 in lung tumor cells and promote their invasiveness and metastasis in vivo[159]. Studies have also shown that adipocytes could regulate insulin resistance in hepatocytes by secreting EVs carrying miR-141-3p[191], monocyte chemoattractant protein-1 (MCP-1), IL-6, and macrophage migration inhibitory factor (MIF)[192]. The weak response of cells to insulin translated into increased levels of extracellular glucose that could be taken up by tumor cells and used as an energy source[193]. Moreover, exosomes from AMSCs were able to promote ovarian cancer cell growth and motility in vitro and metastasis formation in mouse models by regulating the levels of the forkhead box protein M1 (FOXM1) protein[161]. The increased presence of this protein could induce the expression of Cyclin F and kinesin family member 20A (KIF20A) proteins as well as the activation of the ERK1/2 and c-Jun N-terminal kinases (JNK)-MAPK signaling pathways in tumor cells[161]. Furthermore, exosomes from colon cancer cells could induce the differentiation of AMSCs into cancer-associated fibroblasts (CAFs) by activating the NF-κB signaling pathway through the transient receptor potential cation channel subfamily C member 3 (TRPC3)[162]. These activated CAFs could further promote the migration and invasion of colon cancer cells. Moreover, high levels of TRPC3 in mesenchymal cells were associated with a worse clinical outcome in colon cancer patients[162]. Additionally, pancreatic tumor cells could induce morphological and metabolic alterations in adipocytes, which in turn led to increased motility and proliferation of tumor cells[135,165]. The treatment of osteosarcoma cells with AMSC-derived exosomes could induce their proliferation, migration, and invasion by upregulating the collagen beta(1-O)galactosyltransferase 2 levels in tumor cells, a gene responsible for the collagen glycosylation in the endoplasmic reticulum[166]. In the case of ovarian cancer, adipocytes could promote a metabolic switch of tumor cells favoring β-oxidation by direct transfer of lipids, which contributed to tumor growth[168]. Similar results were reported when EVs secreted by white adipocytes could enhance the migration, invasion, and proliferation of prostate cancer cells[120]. Interestingly, after exposing prostate cancer cells to adipocyte-derived EVs, the authors observed a switch in tumor cell metabolism characterized by increased glucose consumption and lactate and ATP production[120]. Briefly, this evidence shows that adipocyte-derived EVs have a significant impact on cancer progression by modulating the metabolism of tumor cells and enhancing their malignancy.

It has also been shown that adipocyte-derived exosomes can contribute to therapy resistance in different types of cancer. For instance, adipocyte-derived exosomes containing miR-32a and miR-32b could activate the von Hippel-Lindau-HIF-1α (VHL-HIF-1α) pathway in hepatocellular cancer cells, leading to increased resistance to 5-FluoroUracile[118]. Interestingly, high levels of these exosomes were found in hepatocellular carcinoma patients, and a low survival rate was associated with low VHL presence and high HIF-1α[118]. In another study, the downregulation of apoptotic protease activating factor 1 (APAF1) by adipocyte-derived exosomes carrying miR-21 suppressed ovarian cancer cell apoptosis and conferred resistance to paclitaxel treatment[119]. In colorectal cancer, ferroptosis of tumor cells could be inhibited by adipocyte-derived exosomes carrying the microsomal triglyceride transfer protein (MTTP)[115]. Additionally, the exposure of colorectal cancer cells to adipocyte-derived exosomes was able to induce the resistance of tumor cells to oxaliplatin treatment[115]. Moreover, increased levels of adipocyte exosomal long non-coding RNAs (lncRNAs) LOC606724 and SNHG1 were associated with a poor prognosis in multiple myeloma patients[164]. It was also observed that these lncRNAs induced bortezomib resistance in tumor cells[164]. Similarly, EVs released by white adipocytes could negatively impact the sensitivity of prostate cancer cells to docetaxel treatments[120].

Altogether, these findings suggest that adipocyte-derived EVs are key players in the metabolic and phenotypic reprogramming of tumor cells, namely by affecting tumor biology, drug resistance, cancer progression, and metastasis formation. Importantly, metastatic tumors can contribute to systemic inflammation and metabolic dysfunctions, exacerbating cancer cachexia[194]. Furthermore, it has been reported that obesity may lead to an increased secretion of adipocyte-derived EVs, thereby enhancing the effects of these nanoparticles in tumor progression.

Adipose tissue-derived extracellular vesicles as inhibitors of cancer progression

So far, we discussed the role of adipocyte-derived EVs in remodeling the metabolism and acquired aggressiveness of tumor cells. However, it is worth mentioning that some studies have also reported that these EVs could inhibit the growth and progression of tumor cells by transporting and delivering specific miRNAs into the recipient cell [Table 4].

Table 4

Adipocyte-derived extracellular vesicles as inhibitors of cancer progression

Cancer typeAdipocytes EV cargoBiological functionRef.
ProstatemiR-145↓ Tumor cell proliferation and invasion
↓ Metastasis formation in vivo
[195]
OvarianAnticancer miRNAs↓ Tumor cell proliferation
↑ Tumor cell apoptosis
[196]
LungmiR-99a-5p↓ Tumor cell proliferation and migration[197]
NeuroblastomaLncRNAs LINC00622↓ Tumor cell proliferation, migration, and invasion[198]
Glioblastoma-↓ Tumor cell proliferation
↓ Tumor invasion in vivo
[199]
Colorectal-↓ EGFR and aquaporin 5 levels[200]

In prostate cancer, AMSC cells carrying the tumor suppressor miR-145 could inhibit the growth and invasion of tumor cells in vitro through direct contact or mediated by EVs[195]. In addition, the metastasis of these cells could be mitigated by treating mouse models with miR-145-positive AMSCs[195]. In lung cancer, adipocyte-derived exosomes enriched in miR-99a-5p from obese mice could mitigate the proliferation and migration of tumor cells[197]. In another cell model, AMSCs-derived exosomes carrying the lncRNA LINC00622 inhibited the proliferation, migration, and invasion of tumor cells by regulating the expression of the transcriptional factor androgen receptor and consequently promoted the activation of the gamma-aminobutyric acid type B receptor subunit 1 (GABBR1)[198]. In glioblastoma, it was also observed that the treatment of tumor cells with EVs derived from AMSCs led to a decrease in the proliferation capacity of these cells in vitro and negatively impacted their invasion capacity in vivo[199]. In colorectal cancer, it was found that AMSCs-derived exosomes could significantly reduce the mRNA levels of epidermal growth factor receptor (EGFR) and aquaporin 5, which plays an important role in cancer progression by promoting tumor cell motility[200]. Thus, the authors defend that a good strategy against tumor progression may involve inhibiting the levels of this transmembrane protein using these AMSCs-derived exosomes[200]. In ovarian cancer, it was also reported the impact of AMSCs-derived adipocytes on the inhibition of tumor cell proliferation and induction of apoptosis by promoting the activation of the p53, Bcl-2-associated X protein (BAX), and caspase 3 and 9 via anticancer miRNAs[196].

Overall, these studies demonstrate the potential of EVs derived from AMSCs as therapeutic strategies for inhibiting the growth and progression of various types of cancer. By carrying specific miRNAs and lncRNAs, these EVs could inhibit the proliferation, migration, and invasion of tumor cells. These findings suggest that AMSCs-derived EVs could be a valuable tool for the development of new anticancer therapies.

Adipose tissue-derived extracellular vesicles as potential therapeutic delivery strategies

As previously mentioned, AMSCs-derived EVs hold great promise as a novel anticancer strategy. Recent evidence demonstrates the use of targeted manipulation of these nanoparticles to inhibit tumor progression and enhance chemosensitivity in tumor cells. After being loaded with specific miRNAs, EVs showed the potential to trigger tumor cell apoptosis, decrease tumor growth, and metastasis formation, and enhance the sensitivity of tumor cells to anticancer treatments [Table 5].

Table 5

Adipocyte-derived extracellular vesicles as potential therapeutic delivery strategies

Cancer typeManipulated EV cargoBiological functionRef.
BreastmiR-145↓ Metastasis formation in vivo[201]
Breast↓ CD90 and
miR-16-5p
↓Tumor cell growth
↑ Tumor cell apoptosis
↓ Tumor mass in vivo
[202]
BreastmiR-424-5p↑ Anti-inflammatory cytokines secretion
↓ Tumor cell growth
↑ Tumor cell apoptosis
[203]
BreastmiR-381-3p↓ Tumor cell proliferation, migration, and invasion
↑ Tumor cell apoptosis
[204]
BreastmiR-140↓ Tumor cell migration, stemness, and differentiation
↓Tumor growth in vivo
[205]
BreastmiR-1236↑ Cisplatin sensitivity[206]
HepatocellularmiR-199a↑ Doxorubicin sensitivity
↓ Tumor cell viability
[207]
HepatocellularmiR-122↑ 5-FluoroUracile and sorafenib sensitivity[208]
BladermiR-138-5p↓ Tumor cell proliferation, migration, and invasion
↓ Tumor growth in vivo
[209]

In breast cancer, lentivirus transfection was used to load miR-145 into AMSCs[201]. These manipulated AMSCs were able to transfer miR-145 via EVs into breast cancer cells, which negatively impacted the expression of genes related to cell apoptosis and metastasis in tumor cells. These included MMP9, Erb-B2 receptor tyrosine kinase 2 (ERBB2), tumor suppressor p53, and Rho-associated coiled-coil containing protein kinase 1 (ROCK1)[201]. Furthermore, the injection of AMSCs-derived EVs containing low levels of CD90 in mice bearing breast cancer cell xenografts, slower tumor growth and reduced tumor mass formation in these animals[202]. In addition, loading the miR-16-5p into AMSC EVs via liposomes enhanced the effect of these CD90 low-EVs in inducing tumor cell apoptosis in vitro and reduced tumor mass in vivo[202]. Similar results were observed in a triple-negative breast cancer cell model. AMSCs were transfected with miR-424-5p using lipofectamine reagents[203]. The miR-424-5p transfer via EVs led to the suppression of programmed death-ligand 1 (PD-L1) levels, consequently slowing tumor growth and promoting apoptosis of breast cancer cells. Additionally, miR-424-5p transfer via EVs induced the secretion of anti-inflammatory cytokines and diminished the release of pro-inflammatory cytokines[203]. Moreover, the treatment of triple-negative breast cancer cells with AMSCs-derived exosomes loaded with miR-381-3p, by electroporation, inhibited the proliferation, migration, and invasion of the breast cancer cells and promoted their apoptosis[204]. It was found that these exosomes could decrease the levels of the Wnt pathway and EMT-related genes (Snail, CTNNB1, and N-cadherin)[204]. In bladder cancer, exosomes derived from AMSCs previously transfected with a lentivirus carrying the miR-138-5p gene, have shown promising results in reducing tumor cell proliferation, migration, and invasion[209]. Notably, the growth and spread of tumor cells both in vitro and in vivo were reduced by AMSCs-derived exosomes carrying the miR-138-5p[209]. Interestingly, the invasion capacity and viability of skin cancer cells were reduced upon treating these cells with AMSCs-derived exosomes carrying the miR-199a-5p[210]. It was found that these miR-199-5p-positive EVs control the expression of the SOX4 transcription factor[210]. It was further suggested that exosomes secreted from pre-adipocytes could regulate early-stage breast cancer cells. The treatment of white pre-adipocytes with anti-tumor component shikonin (SK), led to the secretion of exosomes with high levels of miR-140. These exosomes further inhibited the migration, stemness, and differentiation of tumor cells by decreasing the levels of SOX9 protein[205], an important transcription factor of pre-adipocyte differentiation[211]. Notably, the injection of SK-treated adipocyte exosomes reduced breast tumor volume compared to mice injected with untreated exosomes[205]. This finding suggests that the manipulation of EVs derived from AMSCs has therapeutic potential against different cancer types, effectively suppressing tumor growth and metastasis formation. In particular, the incorporation of specific miRNAs into these EVs seems to enhance their anti-tumor effects.

It was also proposed that these manipulated EVs could play a significant role in enhancing the sensitivity of tumor cells to chemotherapeutic drugs. Indeed, the sensitivity of breast cancer cells to cisplatin could be increased by treating these cells with AMSC-derived exosomes enriched in miR-1236[206]. This miR-1236 regulated the levels of SLC9A1 in breast cancer cells, thereby affecting the Wnt/β-catenin pathway[206]. Furthermore, AMSCs-derived exosomes carrying miR-199a[207] and miR-122[208] increased the sensitivity of hepatocellular cancer cells to chemotherapeutic agents (doxorubicin, 5-FluoroUracile, and sorafenib) in vitro and in vivo. The transfer of miR-199a via exosomes inhibited the mTOR signaling pathway, leading to a decrease in tumor cell viability. AMSCs were transfected with a lentivirus or a plasmid containing pre-miR-199a-3p[207] or miR-122[208], respectively.

Currently, a clinical trial is ongoing where manipulated EVs derived from mesenchymal stromal cells are being used to treat patients with pancreatic cancer[212]. In this phase I clinical trial, metastatic pancreatic ductal adenocarcinoma patients with the KRASG12D mutation were treated with mesenchymal stromal cell-derived exosomes loaded with KRASG12D siRNA. Initial results from the trial indicate that the treatment is being well-tolerated at lower doses, leading to reduced levels of circulating KrasG12D DNA and phosphorylated ERK in the tumor[213].

In summary, these findings highlight the potential of adipocyte-derived EVs, carrying specific miRNAs, as innovative therapeutic strategies against cancer. The engineered EVs have exhibited success in inducing tumor cell apoptosis, slowing tumor progression and metastasis formation, and enhancing the response to therapy in animal models. Further research is essential to fully understand the potential of EV-based therapies in clinical settings.

CONCLUSION

Cancer cachexia is a complex syndrome involving skeletal muscle and body fat loss, that has been intricately linked to elevated morbidity and mortality rates[3]. Despite nutritional interventions, a complete reversal of cachexia remains elusive, and effective therapies for cancer cachexia patients are currently lacking[3]. Consequently, unraveling the intricate molecular mechanisms underlying the development and progression of cancer cachexia will potentiate the development of innovative therapeutic approaches. This review explores the latest insights into the role of EVs in modulating the dynamic interplay between tumor cells and adipose tissue in the context of cancer cachexia.

Recent studies have highlighted that tumor cells release EVs capable of influencing adipocyte recipient cell behavior, thus establishing a crucial link in the tumor-AT crosstalk. Tumor-derived EVs can induce a brown fat-like phenotype by stimulating adipocyte lipolysis and the secretion of metabolites, such as FA. Additionally, these adipocytes reciprocate by releasing EVs carrying lipids, proteins, and miRNAs that can trigger metabolic reprogramming of tumor cells, favoring fatty acid β-oxidation.

Compelling evidence suggests that manipulating EVs could serve as a therapeutic strategy for cancer cachexia. In animal models, inhibiting the production and secretion of tumor-derived EVs[108,140,147] or modifying the cargo carried by adipocyte-derived EVs[207-209] effectively mitigated cachexia effects. In addition, these alterations were also capable of inhibiting tumor progression and enhancing tumor cells’ sensitivity to therapy. Given their capacity to transport vital information between cells and their presence in various biological fluids[121], EVs emerge as a promising drug delivery system. Therefore, comprehending the pathways that regulate EV biogenesis, secretion, and cargo selection and packaging holds significant promise as a therapeutic strategy against cachexia.

In conclusion, EVs are pivotal players in the intricate communication network between tumor cells and adipocytes during cancer cachexia. However, numerous questions persist regarding the role of EVs as modulators of cancer cachexia. Future research should focus on disclosing the mechanisms and EV cargo that facilitate tumor-AT communication and modulation. It is worth noting that the current research on EV-mediated communication between tumor cells and adipose tissue relies mostly on in vitro observations. Therefore, there is a need for further studies using animal models and clinical samples to validate the in vitro findings and effectively translate the knowledge into the clinical setting. We believe that this knowledge will be instrumental in the development of novel targeted therapeutic strategies for cancer cachexia management, ultimately enhancing the quality of life and survival of cancer patients.

DECLARATIONS

Acknowledgments

All the figures in this manuscript were created with Biorender.com.

Authors’ contributions

Conceived the idea for the manuscript: Freitas D

Writing - original draft preparation: Ramos CC, Freitas D

Writing, review, and editing: Ramos CC, Pires J, Gonzalez E, Garcia-Vallicrosa C, Reis CA, Falcon-Perez JM, Freitas D

Image preparation: Ramos CC, Pires J

All authors have read and agreed to the published version of the manuscript.

Availability of data and materials

Not applicable.

Financial support and sponsorship

This work was funded by the project EXPL/MED-ONC/1001/2021 from FCT and by the BIAL Foundation, in the scope of the Maria de Sousa Award 2/2021. This work was partially funded by Programa Operacional Regional do Norte and co-funded by European Regional Development Fund under the project “The Porto Comprehensive Cancer Center” with the reference NORTE-01-0145-FEDER-072678 - Consórcio PORTO.CCC - Porto.Comprehensive Cancer Center. Freitas D acknowledges FCT under the stimulus of Scientific Employment, Individual Support (2020.04384.CEECIND). Ramos CC acknowledges the financial support of the FCT and i3S for the Ph.D. research scholarship (UI/BD/152090/2021).

Conflicts of interest

All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Copyright

© The Author(s) 2024.

REFERENCES

1. Argilés JM, Busquets S, Stemmler B, López-Soriano FJ. Cancer cachexia: understanding the molecular basis. Nat Rev Cancer 2014;14:754-62.

2. Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer 2002;2:862-71.

3. Baracos VE, Martin L, Korc M, Guttridge DC, Fearon KCH. Cancer-associated cachexia. Nat Rev Dis Primers 2018;4:17105.

4. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011;12:489-95.

5. Roeland EJ, Bohlke K, Baracos VE, et al. Management of cancer cachexia: ASCO guideline. J Clin Oncol 2020;38:2438-53.

6. Neshan M, Tsilimigras DI, Han X, Zhu H, Pawlik TM. Molecular mechanisms of cachexia: a review. Cells 2024;13:252.

7. Armstrong VS, Fitzgerald LW, Bathe OF. Cancer-associated muscle wasting-candidate mechanisms and molecular pathways. Int J Mol Sci 2020;21:9268.

8. Wang Y, Ding S. Extracellular vesicles in cancer cachexia: deciphering pathogenic roles and exploring therapeutic horizons. J Transl Med 2024;22:506.

9. Marzan AL, Chitti SV. Unravelling the role of cancer cell-derived extracellular vesicles in muscle atrophy, lipolysis, and cancer-associated cachexia. Cells 2023;12:2598.

10. Zhang G, Liu Z, Ding H, et al. Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90. Nat Commun 2017;8:589.

11. Hu W, Ru Z, Zhou Y, et al. Lung cancer-derived extracellular vesicles induced myotube atrophy and adipocyte lipolysis via the extracellular IL-6-mediated STAT3 pathway. Biochim Biophys Acta Mol Cell Biol Lipids 2019;1864:1091-102.

12. Zhang W, Sun W, Gu X, et al. GDF-15 in tumor-derived exosomes promotes muscle atrophy via Bcl-2/caspase-3 pathway. Cell Death Discov 2022;8:162.

13. Gao X, Wang Y, Lu F, et al. Extracellular vesicles derived from oesophageal cancer containing P4HB promote muscle wasting via regulating PHGDH/Bcl-2/caspase-3 pathway. J Extracell Vesicles 2021;10:e12060.

14. Yang J, Zhang Z, Zhang Y, et al. ZIP4 promotes muscle wasting and cachexia in mice with orthotopic pancreatic tumors by stimulating RAB27B-regulated release of extracellular vesicles from cancer cells. Gastroenterology 2019;156:722-34.e6.

15. Qiu L, Chen W, Wu C, Yuan Y, Li Y. Exosomes of oral squamous cell carcinoma cells containing miR-181a-3p induce muscle cell atrophy and apoptosis by transmissible endoplasmic reticulum stress signaling. Biochem Biophys Res Commun 2020;533:831-7.

16. Miao C, Zhang W, Feng L, et al. Cancer-derived exosome miRNAs induce skeletal muscle wasting by Bcl-2-mediated apoptosis in colon cancer cachexia. Mol Ther Nucleic Acids 2021;24:923-38.

17. He WA, Calore F, Londhe P, Canella A, Guttridge DC, Croce CM. Microvesicles containing miRNAs promote muscle cell death in cancer cachexia via TLR7. Proc Natl Acad Sci U S A 2014;111:4525-9.

18. Wang L, Zhang B, Zheng W, et al. Exosomes derived from pancreatic cancer cells induce insulin resistance in C2C12 myotube cells through the PI3K/Akt/FoxO1 pathway. Sci Rep 2017;7:5384.

19. Kuang JX, Shen Q, Zhang RQ, et al. Carnosol attenuated atrophy of C2C12 myotubes induced by tumour-derived exosomal miR-183-5p through inhibiting Smad3 pathway activation and keeping mitochondrial respiration. Basic Clin Pharmacol Toxicol 2022;131:500-13.

20. Ruan X, Cao M, Yan W, et al. Cancer-cell-secreted extracellular vesicles target p53 to impair mitochondrial function in muscle. EMBO Rep 2023;24:e56464.

21. Dumas JF, Brisson L. Interaction between adipose tissue and cancer cells: role for cancer progression. Cancer Metastasis Rev 2021;40:31-46.

22. Lengyel E, Makowski L, DiGiovanni J, Kolonin MG. Cancer as a matter of fat: the crosstalk between adipose tissue and tumors. Trends Cancer 2018;4:374-84.

23. Morigny P, Boucher J, Arner P, Langin D. Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics. Nat Rev Endocrinol 2021;17:276-95.

24. Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogenesis 2016;5:e189.

25. Law ML. Cancer cachexia: Pathophysiology and association with cancer-related pain. Front Pain Res 2022;3:971295.

26. Li M, Bu X, Cai B, et al. Biological role of metabolic reprogramming of cancer cells during epithelial-mesenchymal transition (Review). Oncol Rep 2019;41:727-41.

27. Sun L, Quan XQ, Yu S. An epidemiological survey of cachexia in advanced cancer patients and analysis on its diagnostic and treatment status. Nutr Cancer 2015;67:1056-62.

28. Stewart GD, Skipworth RJ, Fearon KC. Cancer cachexia and fatigue. Clin Med 2006;6:140-3.

29. Rogers JB, Syed K, Minteer JF. Cachexia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.

30. Evans WJ, Morley JE, Argilés J, et al. Cachexia: a new definition. Clin Nutr 2008;27:793-9.

31. Chowdhry SM, Chowdhry VK. Cancer cachexia and treatment toxicity. Curr Opin Support Palliat Care 2019;13:292-7.

32. Argilés JM, López-Soriano FJ, Toledo M, Betancourt A, Serpe R, Busquets S. The cachexia score (CASCO): a new tool for staging cachectic cancer patients. J Cachexia Sarcopenia Muscle 2011;2:87-93.

33. Cao Z, Zhao K, Jose I, Hoogenraad NJ, Osellame LD. Biomarkers for cancer cachexia: a mini review. Int J Mol Sci 2021;22:4501.

34. Geppert J, Rohm M. Cancer cachexia: biomarkers and the influence of age. Mol Oncol 2024:Online ahead of print.

35. Argilés JM, Betancourt A, Guàrdia-Olmos J, et al. Validation of the CAchexia SCOre (CASCO). Staging cancer patients: the use of miniCASCO as a simplified tool. Front Physiol 2017;8:92.

36. Watanabe H, Oshima T. The latest treatments for cancer cachexia: an overview. Anticancer Res 2023;43:511-21.

37. Nishikawa H, Goto M, Fukunishi S, Asai A, Nishiguchi S, Higuchi K. Cancer cachexia: its mechanism and clinical significance. Int J Mol Sci 2021;22:8491.

38. Setiawan T, Sari IN, Wijaya YT, et al. Cancer cachexia: molecular mechanisms and treatment strategies. J Hematol Oncol 2023;16:54.

39. Ling T, Zhang J, Ding F, Ma L. Role of growth differentiation factor 15 in cancer cachexia (Review). Oncol Lett 2023;26:462.

40. Siddiqui JA, Pothuraju R, Khan P, et al. Pathophysiological role of growth differentiation factor 15 (GDF15) in obesity, cancer, and cachexia. Cytokine Growth Factor Rev 2022;64:71-83.

41. Mullican SE, Lin-Schmidt X, Chin CN, et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med 2017;23:1150-7.

42. Emmerson PJ, Wang F, Du Y, et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med 2017;23:1215-9.

43. Lerner L, Hayes TG, Tao N, et al. Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients. J Cachexia Sarcopenia Muscle 2015;6:317-24.

44. Suriben R, Chen M, Higbee J, et al. Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice. Nat Med 2020;26:1264-70.

45. Kim-Muller JY, Song L, LaCarubba Paulhus B, et al. GDF15 neutralization restores muscle function and physical performance in a mouse model of cancer cachexia. Cell Rep 2023;42:111947.

46. Hendifar A, Dotan E, Weinberg B, et al. Abstract PR006: initial results of a cohort of advanced pancreatic cancer patients in a phase 1b Study of NGM120, a first-in-class anti-GDNF Family Receptor Alpha Like (GFRAL) antibody. Cancer Res 2022;82:PR006.

47. Crawford J, Calle RA, Collins SM, et al. A phase Ib first-in-patient study assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponsegromab in participants with cancer and cachexia. Clin Cancer Res 2024;30:489-97.

48. Argilés JM, López-Soriano FJ, Busquets S. Mediators of cachexia in cancer patients. Nutrition 2019;66:11-5.

49. Patel HJ, Patel BM. TNF-α and cancer cachexia: molecular insights and clinical implications. Life Sci 2017;170:56-63.

50. Bonetto A, Aydogdu T, Jin X, et al. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. Am J Physiol Endocrinol Metab 2012;303:E410-21.

51. Rupert JE, Narasimhan A, Jengelley DHA, et al. Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia. J Exp Med 2021;218:e20190450.

52. White JP, Puppa MJ, Gao S, Sato S, Welle SL, Carson JA. Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK. Am J Physiol Endocrinol Metab 2013;304:E1042-52.

53. Wang X, Hu Z, Hu J, Du J, Mitch WE. Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology 2006;147:4160-8.

54. Asp ML, Tian M, Wendel AA, Belury MA. Evidence for the contribution of insulin resistance to the development of cachexia in tumor-bearing mice. Int J Cancer 2010;126:756-63.

55. Argilés JM, López-Soriano FJ, Busquets S. Muscle wasting in cancer: the role of mitochondria. Curr Opin Clin Nutr Metab Care 2015;18:221-5.

56. Porporato PE. Understanding cachexia as a cancer metabolism syndrome. Oncogenesis 2016;5:e200.

57. Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci 2013;9:191-200.

58. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89:2548-56.

59. Torres N, Vargas-Castillo AE, Tovar AR. Adipose tissue: white adipose tissue structure and function. In: Caballero B, Finglas PM, Toldrá F, editors. Encyclopedia of food and health. Oxford: Academic Press; 2016. pp. 35-42.

60. Peurichard D, Delebecque F, Lorsignol A, et al. Simple mechanical cues could explain adipose tissue morphology. J Theor Biol 2017;429:61-81.

61. Czerwiec K, Zawrzykraj M, Deptuła M, et al. Adipose-derived mesenchymal stromal cells in basic research and clinical applications. Int J Mol Sci 2023;24:3888.

62. Farmer SR. Regulation of PPARgamma activity during adipogenesis. Int J Obes 2005;29:S13-6.

63. Bruderer M, Richards RG, Alini M, Stoddart MJ. Role and regulation of RUNX2 in osteogenesis. Eur Cell Mater 2014;28:269-86.

64. Yi SW, Kim HJ, Oh HJ, et al. Gene expression profiling of chondrogenic differentiation by dexamethasone-conjugated polyethyleneimine with SOX trio genes in stem cells. Stem Cell Res Ther 2018;9:341.

65. Wu H, Li X, Shen C. Peroxisome proliferator-activated receptor gamma in white and brown adipocyte regulation and differentiation. Physiol Res 2020;69:759-73.

66. Lee JH, Kemp DM. Human adipose-derived stem cells display myogenic potential and perturbed function in hypoxic conditions. Biochem Biophys Res Commun 2006;341:882-8.

67. Liu N, Wang G, Zhen Y, et al. Factors influencing myogenic differentiation of adipose-derived stem cells and their application in muscle regeneration. Chin J Plast Reconstr Surg 2022;4:126-32.

68. Daas SI, Rizeq BR, Nasrallah GK. Adipose tissue dysfunction in cancer cachexia. J Cell Physiol 2018;234:13-22.

69. Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 2001;60:329-39.

70. Cohen P, Spiegelman BM. Brown and beige fat: molecular parts of a thermogenic machine. Diabetes 2015;64:2346-51.

71. Virtanen KA, Lidell ME, Orava J, et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360:1518-25.

72. Sacks H, Symonds ME. Anatomical locations of human brown adipose tissue: functional relevance and implications in obesity and type 2 diabetes. Diabetes 2013;62:1783-90.

73. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med 2013;19:1252-63.

74. Agustsson T, Rydén M, Hoffstedt J, et al. Mechanism of increased lipolysis in cancer cachexia. Cancer Res 2007;67:5531-7.

75. Kliewer KL, Ke JY, Tian M, Cole RM, Andridge RR, Belury MA. Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice. Cancer Biol Ther 2015;16:886-97.

76. Petruzzelli M, Schweiger M, Schreiber R, et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab 2014;20:433-47.

77. Kir S, White JP, Kleiner S, et al. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 2014;513:100-4.

78. Bing C, Russell S, Becket E, et al. Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumour-bearing mice. Br J Cancer 2006;95:1028-37.

79. Batista ML Jr, Neves RX, Peres SB, et al. Heterogeneous time-dependent response of adipose tissue during the development of cancer cachexia. J Endocrinol 2012;215:363-73.

80. Sun X, Feng X, Wu X, Lu Y, Chen K, Ye Y. Fat wasting is damaging: role of adipose tissue in cancer-associated cachexia. Front Cell Dev Biol 2020;8:33.

81. Bezaire V, Mairal A, Ribet C, et al. Contribution of adipose triglyceride lipase and hormone-sensitive lipase to lipolysis in hMADS adipocytes. J Biol Chem 2009;284:18282-91.

82. Schweiger M, Schreiber R, Haemmerle G, et al. Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J Biol Chem 2006;281:40236-41.

83. Nieman KM, Romero IL, Van Houten B, Lengyel E. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim Biophys Acta 2013;1831:1533-41.

84. Koundouros N, Poulogiannis G. Reprogramming of fatty acid metabolism in cancer. Br J Cancer 2020;122:4-22.

85. Wang YY, Attané C, Milhas D, et al. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2017;2:e87489.

86. Nomura DK, Lombardi DP, Chang JW, et al. Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer. Chem Biol 2011;18:846-56.

87. Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 2010;140:49-61.

88. Yin H, Li W, Mo L, et al. Adipose triglyceride lipase promotes the proliferation of colorectal cancer cells via enhancing the lipolytic pathway. J Cell Mol Med 2021;25:3963-75.

89. Kir S, Spiegelman BM. Cachexia & brown fat: a burning issue in cancer. Trends Cancer 2016;2:461-3.

90. Seale P, Kajimura S, Yang W, et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab 2007;6:38-54.

91. Rosen ED, Hsu CH, Wang X, et al. C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev 2002;16:22-6.

92. Rim JS, Kozak LP. Regulatory motifs for CREB-binding protein and Nfe2l2 transcription factors in the upstream enhancer of the mitochondrial uncoupling protein 1 gene. J Biol Chem 2002;277:34589-600.

93. Shen SH, Singh SP, Raffaele M, et al. Adipocyte-specific expression of PGC1α promotes adipocyte browning and alleviates obesity-induced metabolic dysfunction in an HO-1-dependent fashion. Antioxidants 2022;11:1147.

94. Pettersson-Klein AT, Izadi M, Ferreira DMS, et al. Small molecule PGC-1α1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration. Mol Metab 2018;9:28-42.

95. Elattar S, Dimri M, Satyanarayana A. The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting. FASEB J 2018;32:4727-43.

96. Hale LP, Price DT, Sanchez LM, Demark-Wahnefried W, Madden JF. Zinc alpha-2-glycoprotein is expressed by malignant prostatic epithelium and may serve as a potential serum marker for prostate cancer. Clin Cancer Res 2001;7:846-53.

97. Díez-Itza I, Sánchez LM, Allende MT, Vizoso F, Ruibal A, López-Otín C. Zn-alpha 2-glycoprotein levels in breast cancer cytosols and correlation with clinical, histological and biochemical parameters. Eur J Cancer 1993;29A:1256-60.

98. Mracek T, Stephens NA, Gao D, et al. Enhanced ZAG production by subcutaneous adipose tissue is linked to weight loss in gastrointestinal cancer patients. Br J Cancer 2011;104:441-7.

99. Bing C, Russell ST, Beckett EE, et al. Expression of uncoupling proteins-1, -2 and -3 mRNA is induced by an adenocarcinoma-derived lipid-mobilizing factor. Br J Cancer 2002;86:612-8.

100. Matthys P, Dijkmans R, Proost P, et al. Severe cachexia in mice inoculated with interferon-gamma-producing tumor cells. Int J Cancer 1991;49:77-82.

101. Mantovani G, Macciò A, Mura L, et al. Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites. J Mol Med 2000;78:554-61.

102. Han J, Meng Q, Shen L, Wu G. Interleukin-6 induces fat loss in cancer cachexia by promoting white adipose tissue lipolysis and browning. Lipids Health Dis 2018;17:14.

103. Molfino A, Belli R, Imbimbo G, et al. Evaluation of browning markers in subcutaneous adipose tissue of newly diagnosed gastrointestinal cancer patients with and without cachexia. Cancers 2022;14:1948.

104. Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell 2016;30:836-48.

105. Pitzer CR, Paez HG, Alway SE. The contribution of tumor derived exosomes to cancer cachexia. Cells 2023;12:292.

106. Hu Y, Liu L, Chen Y, et al. Cancer-cell-secreted miR-204-5p induces leptin signalling pathway in white adipose tissue to promote cancer-associated cachexia. Nat Commun 2023;14:5179.

107. Di W, Zhang W, Zhu B, Li X, Tang Q, Zhou Y. Colorectal cancer prompted adipose tissue browning and cancer cachexia through transferring exosomal miR-146b-5p. J Cell Physiol 2021;236:5399-410.

108. Hu W, Xiong H, Ru Z, et al. Extracellular vesicles-released parathyroid hormone-related protein from Lewis lung carcinoma induces lipolysis and adipose tissue browning in cancer cachexia. Cell Death Dis 2021;12:134.

109. Xiong H, Ye J, Luo Q, Li W, Xu N, Yang H. Exosomal EIF5A derived from Lewis lung carcinoma induced adipocyte wasting in cancer cachexia. Cell Signal 2023;112:110901.

110. Liu Y, Wang M, Deng T, et al. Exosomal miR-155 from gastric cancer induces cancer-associated cachexia by suppressing adipogenesis and promoting brown adipose differentiation via C/EPBβ. Cancer Biol Med 2022;19:1301-14.

111. Bouche C, Quail DF. Fueling the tumor microenvironment with cancer-associated adipocytes. Cancer Res 2023;83:1170-2.

112. Lazar I, Clement E, Carrié L, et al. Adipocyte extracellular vesicles decrease p16INK4A in melanoma: an additional link between obesity and cancer. J Invest Dermatol 2022;142:2488-98.e8.

113. Liu S, Benito-Martin A, Pelissier Vatter FA, et al. Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism. EMBO Rep 2023;24:e57339.

114. La Camera G, Gelsomino L, Malivindi R, et al. Adipocyte-derived extracellular vesicles promote breast cancer cell malignancy through HIF-1α activity. Cancer Lett 2021;521:155-68.

115. Zhang Q, Deng T, Zhang H, et al. Adipocyte-derived exosomal MTTP suppresses ferroptosis and promotes chemoresistance in colorectal cancer. Adv Sci 2022;9:e2203357.

116. Clement E, Lazar I, Attané C, et al. Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells. EMBO J 2020;39:e102525.

117. Lazar I, Clement E, Dauvillier S, et al. Adipocyte exosomes promote melanoma aggressiveness through fatty acid oxidation: a novel mechanism linking obesity and cancer. Cancer Res 2016;76:4051-7.

118. Liu Y, Tan J, Ou S, Chen J, Chen L. Adipose-derived exosomes deliver miR-23a/b to regulate tumor growth in hepatocellular cancer by targeting the VHL/HIF axis. J Physiol Biochem 2019;75:391-401.

119. Au Yeung CL, Co NN, Tsuruga T, et al. Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun 2016;7:11150.

120. Fontana F, Anselmi M, Carollo E, et al. Adipocyte-derived extracellular vesicles promote prostate cancer cell aggressiveness by enabling multiple phenotypic and metabolic changes. Cells 2022;11:2388.

121. Yáñez-Mó M, Siljander PRM, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 2015;4:27066.

122. Martins ÁM, Ramos CC, Freitas D, Reis CA. Glycosylation of cancer extracellular vesicles: capture strategies, functional roles and potential clinical applications. Cells 2021;10:109.

123. Rackles E, Lopez PH, Falcon-Perez JM. Extracellular vesicles as source for the identification of minimally invasive molecular signatures in glioblastoma. Semin Cancer Biol 2022;87:148-59.

124. Welsh JA, Goberdhan DCI, O’Driscoll L, et al; MISEV Consortium. Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. J Extracell Vesicles 2024;13:e12404.

125. van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 2018;19:213-28.

126. Bebelman MP, Smit MJ, Pegtel DM, Baglio SR. Biogenesis and function of extracellular vesicles in cancer. Pharmacol Ther 2018;188:1-11.

127. Zhang H, Freitas D, Kim HS, et al. Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat Cell Biol 2018;20:332-43.

128. Kusuma GD, Barabadi M, Tan JL, Morton DAV, Frith JE, Lim R. To protect and to preserve: novel preservation strategies for extracellular vesicles. Front Pharmacol 2018;9:1199.

129. Kalra H, Drummen GP, Mathivanan S. Focus on extracellular vesicles: introducing the next small big thing. Int J Mol Sci 2016;17:170.

130. Doyle LM, Wang MZ. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells 2019;8:727.

131. Argilés JM, Busquets S, Toledo M, López-Soriano FJ. The role of cytokines in cancer cachexia. Curr Opin Support Palliat Care 2009;3:263-8.

132. Argilés JM, Busquets S, López-Soriano FJ. The pivotal role of cytokines in muscle wasting during cancer. Int J Biochem Cell Biol 2005;37:2036-46.

133. Zhao D, Wu K, Sharma S, et al. Exosomal miR-1304-3p promotes breast cancer progression in African Americans by activating cancer-associated adipocytes. Nat Commun 2022;13:7734.

134. Sun S, Wang Z, Yao F, et al. Breast cancer cell-derived exosome-delivered microRNA-155 targets UBQLN1 in adipocytes and facilitates cancer cachexia-related fat loss. Hum Mol Genet 2023;32:2219-28.

135. Sun Z, Sun D, Feng Y, et al. Exosomal linc-ROR mediates crosstalk between cancer cells and adipocytes to promote tumor growth in pancreatic cancer. Mol Ther Nucleic Acids 2021;26:253-68.

136. Sagar G, Sah RP, Javeed N, et al. Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue. Gut 2016;65:1165-74.

137. Wang S, Xu M, Xiao X, et al. Pancreatic cancer cell exosomes induce lipidomics changes in adipocytes. Adipocyte 2022;11:346-55.

138. Sun D, Ding Z, Shen L, Yang F, Han J, Wu G. miR-410-3P inhibits adipocyte differentiation by targeting IRS-1 in cancer-associated cachexia patients. Lipids Health Dis 2021;20:115.

139. Liu A, Pan W, Zhuang S, Tang Y, Zhang H. Cancer cell-derived exosomal miR-425-3p induces white adipocyte atrophy. Adipocyte 2022;11:487-500.

140. Hu W, Ru Z, Xiao W, et al. Adipose tissue browning in cancer-associated cachexia can be attenuated by inhibition of exosome generation. Biochem Biophys Res Commun 2018;506:122-9.

141. Xiong H, Ye J, Xie K, Hu W, Xu N, Yang H. Exosomal IL-8 derived from Lung Cancer and Colon Cancer cells induced adipocyte atrophy via NF-κB signaling pathway. Lipids Health Dis 2022;21:147.

142. Wan Z, Chen X, Gao X, et al. Chronic myeloid leukemia-derived exosomes attenuate adipogenesis of adipose derived mesenchymal stem cells via transporting miR-92a-3p. J Cell Physiol 2019;234:21274-83.

143. Wang S, Li X, Xu M, Wang J, Zhao RC. Reduced adipogenesis after lung tumor exosomes priming in human mesenchymal stem cells via TGFβ signaling pathway. Mol Cell Biochem 2017;435:59-66.

144. Abd Elmageed ZY, Yang Y, Thomas R, et al. Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes. Stem Cells 2014;32:983-97.

145. Ba L, Xue C, Li X, et al. Gastric cancer cell-derived exosomes can regulate the biological functions of mesenchymal stem cells by inducing the expression of circular RNA circ_0004303. Stem Cells Dev 2021;30:830-42.

146. Liu Z, Xiong J, Gao S, et al. Ameliorating cancer cachexia by inhibiting cancer cell release of Hsp70 and Hsp90 with omeprazole. J Cachexia Sarcopenia Muscle 2022;13:636-47.

147. Fan M, Gu X, Zhang W, et al. Atractylenolide I ameliorates cancer cachexia through inhibiting biogenesis of IL-6 and tumour-derived extracellular vesicles. J Cachexia Sarcopenia Muscle 2022;13:2724-39.

148. Wang S, Xu M, Li X, et al. Exosomes released by hepatocarcinoma cells endow adipocytes with tumor-promoting properties. J Hematol Oncol 2018;11:82.

149. Song YH, Warncke C, Choi SJ, et al. Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells. Matrix Biol 2017;60-1:190-205.

150. Cho JA, Park H, Lim EH, Lee KW. Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. Int J Oncol 2012;40:130-8.

151. Cho JA, Park H, Lim EH, et al. Exosomes from ovarian cancer cells induce adipose tissue-derived mesenchymal stem cells to acquire the physical and functional characteristics of tumor-supporting myofibroblasts. Gynecol Oncol 2011;123:379-86.

152. Li G, Yi X, Du S, et al. Tumour-derived exosomal piR-25783 promotes omental metastasis of ovarian carcinoma by inducing the fibroblast to myofibroblast transition. Oncogene 2023;42:421-33.

153. Casadei L, Calore F, Braggio DA, et al. MDM2 derived from dedifferentiated liposarcoma extracellular vesicles induces MMP2 production from preadipocytes. Cancer Res 2019;79:4911-22.

154. Jafari N, Kolla M, Meshulam T, et al. Adipocyte-derived exosomes may promote breast cancer progression in type 2 diabetes. Sci Signal 2021;14:eabj2807.

155. Lin R, Wang S, Zhao RC. Exosomes from human adipose-derived mesenchymal stem cells promote migration through Wnt signaling pathway in a breast cancer cell model. Mol Cell Biochem 2013;383:13-20.

156. Ramos-Andrade I, Moraes J, Brandão-Costa RM, et al. Obese adipose tissue extracellular vesicles raise breast cancer cell malignancy. Endocr Relat Cancer 2020;27:571-82.

157. Wang S, Su X, Xu M, et al. Exosomes secreted by mesenchymal stromal/stem cell-derived adipocytes promote breast cancer cell growth via activation of Hippo signaling pathway. Stem Cell Res Ther 2019;10:117.

158. Yin H, Qiu X, Shan Y, et al. HIF-1α downregulation of miR-433-3p in adipocyte-derived exosomes contributes to NPC progression via targeting SCD1. Cancer Sci 2021;112:1457-70.

159. Wang J, Wu Y, Guo J, Fei X, Yu L, Ma S. Adipocyte-derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells. Oncotarget 2017;8:81880-91.

160. Koeck ES, Iordanskaia T, Sevilla S, et al. Adipocyte exosomes induce transforming growth factor beta pathway dysregulation in hepatocytes: a novel paradigm for obesity-related liver disease. J Surg Res 2014;192:268-75.

161. Qu Q, Liu L, Cui Y, Chen Y, Wang Y, Wang Y. Exosomes from human omental adipose-derived mesenchymal stem cells secreted into ascites promote peritoneal metastasis of epithelial ovarian cancer. Cells 2022;11:3392.

162. Xue C, Gao Y, Li X, et al. Mesenchymal stem cells derived from adipose accelerate the progression of colon cancer by inducing a MT-CAFs phenotype via TRPC3/NF-KB axis. Stem Cell Res Ther 2022;13:335.

163. Mathiesen A, Haynes B, Huyck R, Brown M, Dobrian A. Adipose tissue-derived extracellular vesicles contribute to phenotypic plasticity of prostate cancer cells. Int J Mol Sci 2023;24:1229.

164. Wang Z, He J, Bach DH, et al. Induction of m6A methylation in adipocyte exosomal LncRNAs mediates myeloma drug resistance. J Exp Clin Cancer Res 2022;41:4.

165. Cai Z, Liang Y, Xing C, et al. Cancer-associated adipocytes exhibit distinct phenotypes and facilitate tumor progression in pancreatic cancer. Oncol Rep 2019;42:2537-49.

166. Wang Y, Chu Y, Li K, et al. Exosomes secreted by adipose-derived mesenchymal stem cells foster metastasis and osteosarcoma proliferation by increasing COLGALT2 expression. Front Cell Dev Biol 2020;8:353.

167. Dirat B, Bochet L, Dabek M, et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res 2011;71:2455-65.

168. Nieman KM, Kenny HA, Penicka CV, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011;17:1498-503.

169. Ye H, Adane B, Khan N, et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell 2016;19:23-37.

170. Pati S, Irfan W, Jameel A, Ahmed S, Shahid RK. Obesity and cancer: a current overview of epidemiology, pathogenesis, outcomes, and management. Cancers 2023;15:485.

171. Kwan HY, Chen M, Xu K, Chen B. The impact of obesity on adipocyte-derived extracellular vesicles. Cell Mol Life Sci 2021;78:7275-88.

172. Annett S, Moore G, Robson T. Obesity and cancer metastasis: molecular and translational perspectives. Cancers 2020;12:3798.

173. Jiralerspong S, Goodwin PJ. Obesity and breast cancer prognosis: evidence, challenges, and opportunities. J Clin Oncol 2016;34:4203-16.

174. Sohn W, Lee HW, Lee S, et al. Obesity and the risk of primary liver cancer: a systematic review and meta-analysis. Clin Mol Hepatol 2021;27:157-74.

175. Parkin E, O’Reilly DA, Sherlock DJ, Manoharan P, Renehan AG. Excess adiposity and survival in patients with colorectal cancer: a systematic review. Obes Rev 2014;15:434-51.

176. Doleman B, Mills KT, Lim S, Zelhart MD, Gagliardi G. Body mass index and colorectal cancer prognosis: a systematic review and meta-analysis. Tech Coloproctol 2016;20:517-35.

177. Rivera-Izquierdo M, Pérez de Rojas J, Martínez-Ruiz V, et al. Obesity as a risk factor for prostate cancer mortality: a systematic review and dose-response meta-analysis of 280,199 patients. Cancers 2021;13:4169.

178. Majumder K, Gupta A, Arora N, Singh PP, Singh S. Premorbid obesity and mortality in patients with pancreatic cancer: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2016;14:355-68.e2.

179. Dev R, Bruera E, Dalal S. Insulin resistance and body composition in cancer patients. Ann Oncol 2018;29:ii18-26.

180. Arner P, Langin D. Lipolysis in lipid turnover, cancer cachexia, and obesity-induced insulin resistance. Trends Endocrinol Metab 2014;25:255-62.

181. Martin L, Birdsell L, Macdonald N, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol 2013;31:1539-47.

182. Divella R, Gadaleta Caldarola G, Mazzocca A. Chronic inflammation in obesity and cancer cachexia. J Clin Med 2022;11:2191.

183. Cardaci TD, VanderVeen BN, Bullard BM, et al. Obesity worsens mitochondrial quality control and does not protect against skeletal muscle wasting in murine cancer cachexia. J Cachexia Sarcopenia Muscle 2024;15:124-37.

184. Chandrasekaran P, Weiskirchen R. The role of obesity in type 2 diabetes mellitus-an overview. Int J Mol Sci 2024;25:1882.

185. Shahid RK, Ahmed S, Le D, Yadav S. Diabetes and cancer: risk, challenges, management and outcomes. Cancers 2021;13:5735.

186. Ling S, Brown K, Miksza JK, et al. Association of type 2 diabetes with cancer: a meta-analysis with bias analysis for unmeasured confounding in 151 cohorts comprising 32 million people. Diabetes Care 2020;43:2313-22.

187. Bjornsdottir HH, Rawshani A, Rawshani A, et al. A national observation study of cancer incidence and mortality risks in type 2 diabetes compared to the background population over time. Sci Rep 2020;10:17376.

188. Bergen ES, Christou N, Le Malicot K, et al. 391MO Impact of diabetes and metformin use on recurrence and outcome in early colon cancer (CC) patients: a pooled analysis of 3 adjuvant trials. Ann Oncol 2021;32:S534.

189. Boyle P, Boniol M, Koechlin A, et al. Diabetes and breast cancer risk: a meta-analysis. Br J Cancer 2012;107:1608-17.

190. Chovsepian A, Prokopchuk O, Petrova G, et al. Diabetes increases mortality in patients with pancreatic and colorectal cancer by promoting cachexia and its associated inflammatory status. Mol Metab 2023;73:101729.

191. Dang SY, Leng Y, Wang ZX, et al. Exosomal transfer of obesity adipose tissue for decreased miR-141-3p mediate insulin resistance of hepatocytes. Int J Biol Sci 2019;15:351-68.

192. Kranendonk MEG, Visseren FLJ, van Herwaarden JA, et al. Effect of extracellular vesicles of human adipose tissue on insulin signaling in liver and muscle cells. Obesity 2014;22:2216-23.

193. Jee SH, Kim HJ, Lee J. Obesity, insulin resistance and cancer risk. Yonsei Med J 2005;46:449-55.

194. Biswas AK, Acharyya S. Understanding cachexia in the context of metastatic progression. Nat Rev Cancer 2020;20:274-84.

195. Takahara K, Ii M, Inamoto T, et al. microRNA-145 mediates the inhibitory effect of adipose tissue-derived stromal cells on prostate cancer. Stem Cells Dev 2016;25:1290-8.

196. Reza AMMT, Choi YJ, Yasuda H, Kim JH. Human adipose mesenchymal stem cell-derived exosomal-miRNAs are critical factors for inducing anti-proliferation signalling to A2780 and SKOV-3 ovarian cancer cells. Sci Rep 2016;6:38498.

197. Zhai S, Li X, Lin T. Obese mouse fat cell-derived extracellular vesicles transport miR-99a-5p to mitigate the proliferation and migration of non-small cell lung cancer cells. Comb Chem High Throughput Screen 2024;27:214-26.

198. Guo M, Li D, Feng Y, Li M, Yang B. Adipose-derived stem cell-derived extracellular vesicles inhibit neuroblastoma growth by regulating GABBR1 activity through LINC00622-mediated transcription factor AR. J Leukoc Biol 2022;111:19-32.

199. Gečys D, Skredėnienė R, Gečytė E, Kazlauskas A, Balnytė I, Jekabsone A. Adipose tissue-derived stem cell extracellular vesicles suppress glioblastoma proliferation, invasiveness and angiogenesis. Cells 2023;12:1247.

200. Mansourabadi AH, Aghamajidi A, Faraji F, et al. Mesenchymal stem cells- derived exosomes inhibit the expression of Aquaporin-5 and EGFR in HCT-116 human colorectal carcinoma cell line. BMC Mol Cell Biol 2022;23:40.

201. Sheykhhasan M, Kalhor N, Sheikholeslami A, Dolati M, Amini E, Fazaeli H. Exosomes of mesenchymal stem cells as a proper vehicle for transfecting mir-145 into the breast cancer cell line and its effect on metastasis. Biomed Res Int 2021;2021:5516078.

202. Li T, Zhou X, Wang J, et al. Adipose-derived mesenchymal stem cells and extracellular vesicles confer antitumor activity in preclinical treatment of breast cancer. Pharmacol Res 2020;157:104843.

203. Zhou Y, Yamamoto Y, Takeshita F, Yamamoto T, Xiao Z, Ochiya T. Delivery of miR-424-5p via extracellular vesicles promotes the apoptosis of MDA-MB-231 TNBC cells in the tumor microenvironment. Int J Mol Sci 2021;22:844.

204. Shojaei S, Hashemi SM, Ghanbarian H, Sharifi K, Salehi M, Mohammadi-Yeganeh S. Delivery of miR-381-3p mimic by mesenchymal stem cell-derived exosomes inhibits triple negative breast cancer aggressiveness; an in vitro study. Stem Cell Rev Rep 2021;17:1027-38.

205. Gernapudi R, Yao Y, Zhang Y, et al. Targeting exosomes from preadipocytes inhibits preadipocyte to cancer stem cell signaling in early-stage breast cancer. Breast Cancer Res Treat 2015;150:685-95.

206. Jia Z, Zhu H, Sun H, et al. Adipose mesenchymal stem cell-derived exosomal microRNA-1236 reduces resistance of breast cancer cells to cisplatin by suppressing SLC9A1 and the Wnt/β-catenin signaling. Cancer Manag Res 2020;12:8733-44.

207. Lou G, Chen L, Xia C, et al. MiR-199a-modified exosomes from adipose tissue-derived mesenchymal stem cells improve hepatocellular carcinoma chemosensitivity through mTOR pathway. J Exp Clin Cancer Res 2020;39:4.

208. Lou G, Song X, Yang F, et al. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol 2015;8:122.

209. Liu T, Li T, Zheng Y, et al. Evaluating adipose-derived stem cell exosomes as miRNA drug delivery systems for the treatment of bladder cancer. Cancer Med 2022;11:3687-99.

210. Liu M, Wang H, Liu Z, Liu G, Wang W, Li X. Exosomes from adipose-derived stem cells inhibits skin cancer progression via miR-199a-5p/SOX4. Biotechnol Genet Eng Rev 2023:1-13.

211. Wang Y, Sul HS. Pref-1 regulates mesenchymal cell commitment and differentiation through Sox9. Cell Metab 2009;9:287-302.

212. Phase I study of mesenchymal stromal cells-derived exosomes with KrasG12D siRNA for metastatic pancreas cancer patients harboring KrasG12D mutation. Available from: https://www.mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2018-0126.html. [Last accessed on 22 Jul 2024].

213. Smaglo BG, LeBleu VS, Lee JJ, et al. Abstract C084: iExplore: a phase I study of mesenchymal stem cell derived exosomes with KrasG12D siRNA for metastatic pancreas cancer patients harboring the KrasG12D mutation. Cancer Res 2024;84:C084.

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Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia
Cátia C. Ramos, ... Daniela FreitasDaniela Freitas

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Ramos, C. C.; Pires J.; Gonzalez E.; Garcia-Vallicrosa C.; Reis C. A.; Falcon-Perez J. M.; Freitas D. Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia. Extracell. Vesicles. Circ. Nucleic. Acids. 2024, 5, 471-96. http://dx.doi.org/10.20517/evcna.2024.36

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Extracellular Vesicles and Circulating Nucleic Acids
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