Exosomes released by hepatocarcinoma cells endow adipocytes with tumor-promoting properties

Abstract

BackgroundThe initiation and progression of hepatocellular carcinoma (HCC) are largely dependent on its local microenvironment. Adipocytes are an important component of hepatic microenvironment in nonalcoholic fatty liver disease (NAFLD), which is a significant risk factor for HCC. Given the global prevalence of NAFLD, a better understanding of the interplay between HCC cells and adipocytes is urgently needed. Exosomes, released by malignant cells, represent a novel way of cell-cell interaction and have been shown to play an important role in cancer cell communication with their microenvironment. Here, we explore the role of HCC-derived exosomes in the cellular and molecular conversion of adipocytes into tumor-promoting cells.MethodsExosomes were isolated from HCC cell line HepG2 and added to adipocytes. Transcriptomic alterations of exosome-stimulated adipocytes were analyzed using gene expression profiling, and secretion of inflammation-associated cytokines was detected by RT-PCR and ELISA. In vivo mouse xenograft model was used to evaluate the growth-promoting and angiogenesis-enhancing effects of exosome-treated adipocytes. Protein content of tumor exosomes was analyzed by mass spectrometry. Activated phospho-kinases involved in exosome-treated adipocytes were detected by phospho-kinase antibody array and Western blot.ResultsOur results demonstrated that HCC cell HepG2-derived exosomes could be actively internalized by adipocytes and caused significant transcriptomic alterations and in particular induced an inflammatory phenotype in adipocytes. The tumor exosome-treated adipocytes, named exo-adipocytes, promoted tumor growth, enhanced angiogenesis, and recruited more macrophages in mouse xenograft model. In vitro, conditioned medium from exo-adipocytes promoted HepG2 cell migration and increased tube formation of human umbilical vein endothelial cells (HUVECs). Mechanistically, we found HepG2 exosomes activated several phopho-kinases and NF-κB signaling pathway in exo-adipocytes. Additionally, a total of 1428 proteins were identified in HepG2 exosomes by mass spectrometry.ConclusionsOur results provide new insights into the concept that tumor cell-derived exosomes can educate surrounding adipocytes to create a favorable microenvironment for tumor progression.

HSP4 triggers epithelial‐mesenchymal transition and promotes motility capacities of hepatocellular carcinoma cells via activating AKT

“…Hep3B, SMMC7721, Huh7 and L02 cell line was purchased from American Type Culture Collection (ATCC). All cell lines were cultured in Dulbecco's modification of Eagle's medium (DMEM; Gibco) supplemented with 10% fetal bovine sera (FBS; Gibco) and 1% penicillin‐streptomycin, and maintained in a humidified atmosphere containing 5% CO 2 at 37°C according to the previous studies 21,22 …”

Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm

“…Exosomes released by malignant cells play an important role in cancer cell communication with their microenvironment. HCC cell HepG2-derived exosomes could be actively internalized by adipocytes and caused significant transcriptomic alterations and in particular induced an inflammatory phenotype in adipocytes [14]. Exosomal miRNAs can affect many aspects of physiological and pathological conditions in HCC and indicates that miRNAs in exosomes can not only serve as sensitive biomarkers for cancer diagnostics and recurrence but can also potentially be used as therapeutics to target HCC progression [15].…”

Macrophage-derived exosomes accelerate wound healing through their anti-inflammation effects in a diabetic rat model

“…Increasing data indicate that macrophages may create an optimal microenvironment for reducing inflammation through a paracrine mechanism [16][17][18], and exosomes secreted by macrophages play an important role in communicating with neighboring cells via regulating levels of cytokines and miRNAs to ameliorate the inflammatory response in recipient cells [19,20]. It has been reported that macrophage-derived exosomes attenuated thermal hyperalgesia in a murine model of inflammatory pain, suggesting their role in dysregulated inflammation [21].…”