Role of cell-free network communication in alcohol-associated disorders and liver metastasis

Abstract

The aberrant use of alcohol is a major factor in cancer progression and metastasis. Contributing mechanisms include the systemic effects of alcohol and the exchange of bioactive molecules between cancerous and non-cancerous cells along the brain-gut-liver axis. Such interplay leads to changes in molecular, cellular, and biological functions resulting in cancer progression. Recent investigations have examined the role of extracellular vesicles (EVs) in cancer mechanisms in addition to their contribution as diagnostic biomarkers. Also, EVs are emerging as novel cell-free mediators in pathophysiological scenarios including alcohol-mediated gut microbiome dysbiosis and the release of nanosized EVs into the circulatory system. Interestingly, EVs in cancer patients are enriched with oncogenes, miRNA, lipids, and glycoproteins whose delivery into the hepatic microenvironment may be enhanced by the detrimental effects of alcohol. Proof-of-concept studies indicate that alcohol-associated liver disease is impacted by the effects of exosomes, including altered immune responses, reprogramming of stromal cells, and remodeling of the extracellular matrix. Moreover, the culmination of alcohol-related changes in the liver likely contributes to enhanced hepatic metastases and poor outcomes for cancer patients. This review summarizes the numerous aspects of exosome communications between organs with emphasis on the relationship of EVs in alcohol-associated diseases and cancer metastasis. The potential impact of EV cargo and release along a multi-organ axis is highly relevant to the promotion of tumorigenic mechanisms and metastatic disease. It is hypothesized that EVs target recipient tissues to initiate the formation of prometastatic niches and cancer progression. The study of alcohol-associated mechanisms in metastatic cancers is expected to reveal a better understanding of factors involved in the growth of secondary malignancies as well as novel approaches for therapeutic interventions.

Keywords: Alcohol-associated liver disease; Colorectal cancer; Exosomes; Extracellular vesicles; Interorgan communication; Liver metastasis.

Figure 1

Extracellular vesicle biogenesis. Pathways involved in extracellular vesicle (EV) generation from the endocytosis of cargo components to release of targeting exosomes. EV biogenesis is achieved by endosomal sorting complex required for transport (ESCRT)-dependent or ESCRT-independent pathways. Several cytoplasmic and nuclear molecules can be sorted in the EVs such as ubiquitin-related proteins, heat shock proteins, miRNAs, and cytoskeleton proteins. ESCRT: Endosomal sorting complex required for transport; sER: Smooth endoplasmic reticulum; rER: Rough endoplasmic reticulum.

Figure 2

Exosome network analysis. Based on Ingenuity Pathway Analysis, distinct molecules from different tissues and cells can be involved in exosome secretion during cancer progression as well as in diagnostic functions. CRYAB: Chaperone alphaB-crystallin; CTTN: Cortactin; EXPH5: Exophilin 5; HGS: Hepatocyte growth factor; HPSE: Heparinase; HTT: Huntingtin protein; PLEC: Plectin; RAB27A: Ras-related protein Rab-27A; RAB27B: Ras-related protein Rab-27B; RAB2B: Ras-related protein Rab-2B; RAB5A: Ras-related protein Rab-5A; RAB7: Ras-related protein Rab-7; RAB9A: Ras-related protein Rab-9A; SDCBP: Syndecan binding protein; SYTL4: Synaptotagmin like 4; TGFA: Transforming growth factor alpha; ZFP36: Zinc finger protein 36; ADARB1: Adenosine deaminase RNA specific B1; AKT1S1: AKT1 Substrate 1.

Figure 3

Exosome-mediated functions in the pre-metastatic niche. The role of tumor-derived exosomes along the establishment and progression of metastatic disease. Extracellular vesicle cargo can be involved in the initiation and regulation of cancer by promoting immune responses, angiogenesis, extracellular matrix modulation, stromal cell changes and metastatic organotropism. EVs: Extracellular vesicles; Tspan8: Tetraspanin-8; MMP2: Matrix metallopeptidase 2; MMP9: Matrix metallopeptidase 9; EGFR VIII: Epidermal growth factor receptor variant III; ZFAS1: ZNFX1 antisense RNA1; ECM: Extracellular matrix.

Figure 4

Model of extracellular vesicle interactions along the gut/liver/lung/brain axis during alcohol disorders and cancer progression. Alcohol exposure leads to enhanced gut microbiome dysbiosis, the development of alcohol-associated liver disease, lung inflammation, and neurological manifestations. The potential role of tumor- and alcohol-derived extracellular vesicles (EVs) in advanced malignancies is a potential consequence of EV organ-organ communication during alcohol disorders. BBB: Blood brain barrier; CRC: Colorectal cancer; AALD: Alcohol-associated liver disease.