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: Exosomes, Extracellular vesicles, Alcohol-associated liver disease, Colorectal cancer, Liver metastasis, Interorgan communication

Core Tip: Alcohol consumption is an independent risk factor for cancer development as well as the promotion of metastatic disease, a major cause of morbidity and mortality in cancer patients. The identification of mechanisms and potential therapeutic targets for metastases remains to be determined for many cancers. Interorgan communication involving extracellular vesicles (EVs) is considered a vital process in the promotion of tumorigenic pathways and the spread of disease. Understanding the role of EVs in organ-organ communication networks will likely contribute to the development of future opportunities to combat cancer metastasis.