Adipocyte-derived extracellular vesicles: bridging the communications between obesity and tumor microenvironment

Figures

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  Fig. 1. The pleiotropic roles of obese adipocyte secretome in cancer cell. In an obese state, adipocytes emit more leptin, increase the expression of IGF-1 in target cells, and release more ADEVs. Leptin increases P13K, STAT pathway signaling [48, 193]. IGF-1 is responsible for activating the RAS/RAF signaling network [194]. ADEV includes proteins, RNAs, and lipocalin that stimulate JNK/AP-1, IKK, and NF-KB signaling. These signaling mechanisms are triggered and promotes-the progression of cancer [34, 195]

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  Fig. 2. Obesity-leptin signaling and Hypoxia regulate cargo of the ADEV. Hypoxia activates HIF1α-mediated transcriptional upregulation of circRNAs, miRNAs, and mRNAs that, along with the proteins they encode, enter EVs [196]. Leptin signaling activates transcription of HSP90 [48, 50], which stabilizes ESCRT-I subunit TSG101 and increases endosomes and the number of EVs [50]. In contrast, AMPKα1 would negatively regulate TSG101 protein levels [197]

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  Fig. 3. Extracellular vesicles: the cross-talk in obese ATME and TME. EVs play important roles in both obesity and TME. Obesity can lead to chronic inflammation, activate inflammatory cells in the TME, and the ADEV secreted by ObAs can induce and maintain the TME [198]. Meanwhile, tumor cells activate healthy AT by releasing EVs, leading to decreased lipid content and decreased adipocyte markers, which are referred to as CAAs [199]. CAAs are one of the main energy-supplying cells of tumor cells [161, 200]. In addition, EVs can also regulate metabolic pathways and signaling pathways of tumor cells in the pathological state of obesity, promoting tumor formation and progression. The special metabolic state of obesity also affects the composition and production mode of EVs, which reshapes TME and affects the death or survival of tumor cells while regulating metabolic networks. As an important signaling molecule or regulator, EVs play an important role in regulating tumor development. ADSC adipose-derived stem cells, ECM extracellular matrix, ObAs obese adipocytes, ADEVs adipocyte-derived extracellular vesicles, TEVs tumor cell-derived extracellular vesicles, CAAs cancer-associated…

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  Fig. 4. ADEV and the hallmarks of cancer under obesity. ADEV have been shown to play a crucial role linking obesity to the hallmarks of cancer, including but not limited to the tumor cell cycle, proliferation, migration, and metastasis, and thus promoting tumor formation and progression. ADEV can increase cancer cell proliferation through the activation of cAMP response element-binding (CREB) and extracellular signal-regulated kinase (ERK) signaling pathways [201], as well as induce tumorigenesis by regulating SOX-9 [202]. ADEV can stimulate cancer cell migration and metastasis by activating JAK/STAT-3 and TGF-β/SMAD signaling pathways [135]. Additionally, ADEV can regulate FAO and EMT processes to facilitate cancer cell metastasis by increasing the expression of matrix metalloproteinases (MMPs) and integrins to promote cell migration and invasion [32]. ADEV can also reduce apoptosis rates, promote malignant transformation, and advance malignancy progression cancer cells. Moreover, ADEV can alter cell transcriptomes and metabolomes, affecting cell survival and internal environment. Considering the crucial role of ADEVs in cancer cell growth, evolution, and metastasis, ADEV has become a…