Research progress on the role of adipocyte exosomes in cancer progression

Abstract

Exosomes, minute vesicles ubiquitously released by diverse cell types, serve as critical mediators in intercellular communication. Their pathophysiological relevance, especially in malignancies, has garnered significant attention. A meticulous exploration of the exosomal impact on cancer development has unveiled avenues for innovative and clinically valuable techniques. The cargo conveyed by exosomes exerts transformative effects on both local and distant microenvironments, thereby influencing a broad spectrum of biological responses in recipient cells. These membrane-bound extracellular vesicles (EVs) play a pivotal role in delivering bioactive molecules among cells and organs. Cellular and biological processes in recipient cells, ranging from stromal cell reprogramming to immunological responses, extracellular matrix formation, and modulation of cancer cell activation, expansion, and metastasis, are subject to exosome-mediated cell-to-cell communication. Moreover, exosomes have been implicated in endowing cancer cells with resistance to treatment. Extensive research has explored the potential of exosomes as therapeutic targets and diagnostic indicators. This comprehensive review seeks to provide an in-depth understanding of the pivotal components and roles of exosomes in tumorigenesis, growth, progression, and therapeutic responses. The insights into the multifaceted involvement of exosomes in malignant cancers are essential for the scientific community, fostering the development of novel therapeutic and diagnostic strategies in the relentless pursuit of cancer.

Keywords: Adipose tissue; Exosomes; Extracellular vesicles; Obesity; Tumor microenvironment.

Figure 1. The molecular intricacies governing exosome biogenesis, inclusive of the release and uptake processes, constitute a complex cascade. In essence, the initiation of exosome biogenesis commences with the formation of an endosomal vesicle derived from the plasma membrane through the process of endocytosis. Subsequent stages involve cargo loading and sorting, culminating in the distinctive multivesicular appearance of late endosomes (MVB). The sorting of exosomal content is orchestrated by a range of mechanisms, both ESCRT-dependent and independent. Various exosomal cargoes, such as ceramides and tetraspanins, converge on the MVB membrane for loading into exosomes. The release of exosomes from MVBs into the extracellular space is facilitated either through the Rab and SNARE complex or via lysosomal degradation. These released exosomes are then available for uptake by recipient cells, achieved through either direct fusion with the plasma membrane or engagement in ligand-receptor binding (Key: miRNA—microRNA, ESCRT—endosomal-sorting complex required for transport; MVB—multivesicular body; SNARE—soluble N-ethylmaleimide-sensitive fusion attachment protein receptor; ALIX—apoptosis-linked gene 2-interacting protein X).

Figure 2. Schematic overview illustrating the impact of adipose tissue-derived exosomes (AdExos) on tumor cells, driving cancer cell growth, invasion, progression, chemoresistance, and metastasis. In summary, obesity initiates the expansion of adipose tissue, characterized by adipocyte hyperplasia, hypertrophy, and elevated cytokine-related signaling pathways (IL-6, IL-8, and CCR5 in macrophages), fostering a persistent inflammatory state conducive to the tumor microenvironment (TME). Adipose tissue releases a plethora of extracellular vesicles (EVs), among which AdExos play a crucial role in mediating communication between adipose tissue and cancer cells. The secreted components of AdExos (mRNAs, short RNAs, microRNAs, proteins, enzymes, and other molecules, etc.) significantly contribute to key cancer hallmarks, including the promotion of cancer cell growth, facilitation of cell invasion, advancement of progression, induction of chemoresistance, and orchestration of metastasis, all mediated through various pathways as detailed in this manuscript.