The Role of Cancer-Associated Fibroblasts and Extracellular Vesicles in Tumorigenesis

Abstract

Extracellular vesicles (EVs) play a key role in the communication between cancer cells and stromal components of the tumor microenvironment (TME). In this context, cancer cell-derived EVs can regulate the activation of a CAF phenotype in TME cells, which can be mediated by several EV cargos (e.g., miRNA, proteins, mRNA and lncRNAs). On the other hand, CAF-derived EVs can mediate several processes during tumorigenesis, including tumor growth, invasion, metastasis, and therapy resistance. This review aimed to discuss the molecular aspects of EV-based cross-talk between CAFs and cancer cells during tumorigenesis, in addition to assessing the roles of EV cargo in therapy resistance and pre-metastatic niche formation.

Keywords: cancer-associated fibroblasts; extracellular vesicles; neoplasms; tumor microenvironment.

Figure 1

Schematic representation of microvesicles (MVs) and exosomes’ biogenesis and release by eukaryotic cells. MVs are formed after an outward blebbing of the plasma membrane (PM) and are usually sized between 150 and 1000 nm. Exosome (30–150 nm) formation begins in late endosomes that maturate into multivesicular bodies (MVB), including the formation of intervesicular bodies (ILVs) through the inward budding of the MVs limiting membrane. MVB can fuse with the plasma membrane and release the ILVs into the extracellular space as exosomes. Alternatively, MVB can suffer degradation by fusing with lysosomes. EVs can contain numerous biomolecules, including protein, lipids, DNA, and RNA.

Figure 2

Summary of the extra-cellular vesicle (EVs)-mediated cross-talk between cancer cells and cancer-associated fibroblasts (CAFs). Cancer cells can influence stromal cells to activate a CAF phenotype through the release of EVs, which carry several cargos, including proteins, micro-RNAs (miRNA), and long noncoding-RNA (lncRNA). Specific cancer cells-derived EV cargos can also influence a pro-angiogenic or pro-inflammatory phenotype in CAF, and the induction of therapy resistance and pre-metastatic niche formation. At the same time, CAF-derived EVs cargos can influence cancer cells to increase epithelial-to-mesenchymal transition (EMT), growth, invasion, metastasis, motility, stemness, colony formation, apoptosis inhibition, glycolysis, and therapy resistance.