Data Availability StatementNot applicable, please make reference to the original reference. as therapeutic strategies targeting extracellular vesicles production for the treatment of malignancy. translation and/or post-translational modifications of target mRNAs [5, 8] or by activating various signaling pathways [8, 22]. Given the lack of standardized nomenclature and isolation protocols for extracellular vesicles, we PF 573228 will commonly refer to exosomes, microvesicles, oncosomes, or microparticles as extracellular vesicles. Extracellular vesicles as modulators of the tumor microenvironment A critical biological feature that contributes significantly to cancer progression, invasion and metastasis is the tumor microenvironment The tumor microenvironment (TME) is an interactive cellular environment surrounding the PF 573228 tumor whose main function is usually to establish cellular communication pathways supporting PF 573228 tumorigenesis . The cellular component of the TME mainly comprises immune and inflammatory cells, stromal fibroblasts, and endothelial cells forming the blood vessels that secrete a series of extracellular/angiogenesis signaling molecules, which in turn lead to a functional modulation of TME The PF 573228 TME then converts into a pathological entity that continually evolves to aid cancer progression and invasion The extracellular vesicles (EVs) secreted by tumors, commonly known as tumor-derived EVs, have been well PF 573228 documented to modulate the tumor microenvironment (Fig.?1) EVs are highly specialized entities of communication carrying several surface markers and signaling molecules, oncogenic proteins and nucleic acids that may be transferred horizontally towards the stromal focus on cells and condition the tumor microenvironment for a better tumor development, invasion, and metastasis [26C28]. The role of EVs in cancer metastasis and progression is referred to at length below. Open in another window Fig. 1 Function from the extracellular vesicles-mediated intercommunication in tumor development and advancement. Tumor and stromal cells discharge extracellular vesicles being BST1 a mean of conversation adding to the intricacy and heterogeneity from the tumor microenvironment. Extracellular vesicles-mediated transportation of bioactive components can induce a tumor microenvironment favorable for tumor growth and resistance to anti-cancer drugs Extracellular vesicles and stromal activation Stromal cells, together with extracellular matrix components are critical components of the tumor microenvironment, playing crucial functions in tumor initiation, progression, and metastasis . One of the main stromal changes within the TME is the appearance of cancer-associated fibroblasts (CAFs) . CAFs constitute a major portion of the reactive tumor stroma and play a crucial role in tumor progression. Tumor-derived EVs are essential mediators of the intercommunication between tumor and stromal cells, contributing to stromal support of tumor growth. Tumor-associated EVs have been reported to play a significant role in the differentiation of fibroblasts into CAFs, inducing a tumor-promoting stroma In addition to fibroblasts activation, tumor-derived EVs can also induce the differentiation of mesenchymal stem cells, and other bone marrow-derived cells to become tumor-supportive cells by delivering growth factors, such as transforming growth factor-beta (TGF-) and various miRNAs [1, 31]. For instance, breast malignancy and glioma cells are capable of conferring malignancy transformed characteristics to normal fibroblasts and epithelial cells through the transfer of malignancy cell-derived EVs transporting the cross-linking enzyme tissue transglutaminase (tTG)-crosslinked fibronectin . More recently, it was reported that ovarian malignancy cells secrete EVs capable of modulating fibroblasts behavior towards a CAF-like state. The secretome of the CAFs is usually, in turn, able to promote the proliferation, motility, and invasion of the tumor and endothelial cells . Furthermore, in a prostate malignancy cell model, the release of TGF-1-associated EVs triggers fibroblast differentiation into a myofibroblast phenotype supporting angiogenesis in vitro and accelerating tumor growth in vivo . Similarly, EVs derived from osteosarcoma cells carry a high level of surface-associated TGF-1, which induces mesenchymal stem cells to secrete interleukin-6 and is associated with increased metastatic dissemination . Breast malignancy cells-derived EVs have also been reported to promote the acquisition of myofibroblast-like features in.