Nt EMT-related pathways within a miRNA-dependent manner [118,125,126]. Within this context, it was reported that the miR-665 identified in hepatocellular carcinomaderived exosomes can downregulate Hippo Carbazochrome Technical Information signaling through directly targeting tyrosine phosphatase receptor sort B (PTPRB) [127], serving as a novel invasive biomarker for this malignancy [128]. This is because the Hippo tumor suppressor signaling pathway is essential to controlling cell proliferation and apoptosis by inhibiting the oncogenic coactivators Yes-associated protein (YAP)/transcriptional coactivator using the PDZ-binding motif (TAZ) [129,130]. Nonetheless, thinking of the plethora of biomolecules, especially miRNAs, delivered by cancer-derived exosomes, the mechanism of action of those vesicles on EMT could not be limited only for the Hippo signaling pathways.Cells 2021, ten,9 ofIn this sense, Yue et al. [131] showed that exosomal miR-301a, secreted by hypoxic glioblastoma cells, targets transcription elongation aspect A like 7 (TCEAL7), top to the activation in the Wnt/-catenin signaling pathway, resulting within the expression with the EMT-related transcription aspects Snail, Slug, and Twist. Similar outcomes were verified by Nam et al. [132], who demonstrated that miR-301a functions as an oncogene in prostate cancer by directly targeting the p63 tumor suppressor, top to loss of E-cadherin and EMT. As a result, it is actually not surprising that cancer-derived exosomes can regulate different measures of your EMT, like cancer progression [133], dissemination [134,135], ECM remodeling [136,137], stemness [138], and metastasis [139], though various miRNAs. Interestingly, studies have demonstrated that exosomes derived from cancer-associated macrophages can also regulate stem cells’ dormancy [140] and cell migration and invasion [141], delivering proof that exosomes are also implicated in metastasis. Within this sense, lung cancer cell-derived exosomes (from the A59 and H358 cell lines) alter the transcriptional and bioenergetic signature of M0 macrophages, leading them to an M2 phenotype [142]. Nevertheless, the M2 macrophage-derived exosomes can transfer miR-21-5p and miR-155-5p to cancer cells, advertising the downregulation of transcription factor Brahma-related gene-1 (BRG1), leading to cell migration and invasion in colon cancer cells [141,143]. Gastric cancer showed comparable outcomes; M2 macrophage-derived exosomemediated apolipoprotein E (ApoE) transfer was found to improve the cancer cell migration within a PI3K/Akt signaling pathway activation-dependent manner [144]. Altogether, these information reinforce the view that exosomes promote crosstalk among cancer and non-cancer cells inside the TME, regulating the EMT and metastasis. 4.three.2. Exosomes in Angiogenesis Tumor vascularization is critical to guaranteeing the support of nutrients and meeting oxygen demands to sustain cancer growth. For this reason, the activation of HIF-1 also serves as a signal to induce sustained angiogenesis [100,145]. Once phosphorylated, HIF-1 induces the expression of vascular endothelial development factor (VEGF) [14548]. VEGF binds to VEGF receptors (VEGFRs)-1, -2, and -3, that are expressed on vascular endothelial cells, regulating vessel formation via endothelial cell migration [149,150]. Within this context, research have demonstrated that cancer-derived exosomes act as a crucial regulator of angiogenesis [151,152]. That is because exosomes derived from cancer cells can stimulate endothelial cell migration and tube formation independe.
