The Role of Exosomes in the Crosstalk between Adipocytes and Liver Cancer Cells

Abstract

Exosomes are membrane-bound extracellular vesicles (EVs) that transport bioactive materials between cells and organs. The cargo delivered by exosomes can alter a wide range of cellular responses in recipient cells and play an important pathophysiological role in human cancers. In hepatocellular carcinoma (HCC), for example, adipocyte- and tumor-secreted factors contained in exosomes contribute to the creation of a chronic inflammatory state, which contributes to disease progression. The exosome-mediated crosstalk between adipocytes and liver cancer cells is a key aspect of a dynamic tumor microenvironment. In this review, we summarize the role of increased adiposity and the role of adipocyte-derived exosomes (AdExos) and HCC-derived exosomes (HCCExos) in the modulation of HCC progression. We also discuss recent advances regarding how malignant cells interact with the surrounding adipose tissue and employ exosomes to promote a more aggressive phenotype.

Keywords: adipocyte exosomes; adipocytes; cell signaling; exosomal cargo; exosomes; hepatocellular carcinoma; obesity.

Figure 1

Adipogenesis and different types of adipose tissue. Adipocytes can be divided into three different types depending on their origin, metabolic activity and morphological features. These are brown (BAT), white (WAT) and beige adipocytes. Mesenchymal precursors are committed and differentiate into pre-adipocytes, then further mature into adipocytes of a particular lineage influenced by various transcription factors, cell to cell communication, and extracellular signaling. WATs can also be transformed into beige adipocytes and vice versa, influenced by energy availability, temperature and extracellular signaling.

Figure 2

Exosome biogenesis and release. Exosomes are generated by the endocytic pathway activated by local signaling that culminates in its exocytosis into the extracellular microenvironment. Inward budding and complete invagination results in the formation of MVBs and the encapsulation of RNAs, cytosolic proteins, metabolites, hormones and bioactive lipids. After further processing, a fusion of the membrane facilitates the release of mature exosomes into extracellular space. Alternatively, they may also form lysosomes that are slated for degradation.

Figure 3

Adipocyte and HCC exosomes crosstalk leading to increased tumor progression. Exosomes released by both adipocytes (AdExos) and HCC (HCCExos) have unique intracellular components, including a wide variety of mRNAs, microRNAs, lncRNAs, circRNAs, lipids, metabolites and proteins. These intracellular components are utilized as autocrine or paracrine communicators to induce pathways that result in increased cell proliferation, angiogenesis, invasion, and other hallmarks of malignancy.