Nt EMT-related pathways in a miRNA-dependent manner [118,125,126]. In this context, it was reported that the miR-665 identified in hepatocellular carcinomaderived exosomes can downregulate Hippo signaling by means of straight targeting tyrosine phosphatase receptor form B (PTPRB) [127], serving as a novel invasive biomarker for this malignancy [128]. This can be because the Hippo tumor suppressor signaling pathway is vital to controlling cell proliferation and apoptosis by inhibiting the oncogenic coactivators Yes-associated protein (YAP)/transcriptional coactivator with the PDZ-binding motif (TAZ) [129,130]. Nevertheless, taking into Camostat Autophagy consideration the plethora of biomolecules, particularly miRNAs, delivered by cancer-derived exosomes, the mechanism of action of those vesicles on EMT could not be restricted only for the Hippo signaling pathways.Cells 2021, 10,9 ofIn this sense, Yue et al. [131] showed that exosomal miR-301a, secreted by hypoxic glioblastoma cells, targets transcription elongation element A like 7 (TCEAL7), leading for the activation with the Wnt/-catenin signaling pathway, resulting in the expression in the EMT-related transcription variables Snail, Slug, and Twist. Similar benefits have been verified by Nam et al. [132], who demonstrated that miR-301a functions as an oncogene in prostate Thromboxane B2 site 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 diverse methods of the EMT, including cancer progression [133], dissemination [134,135], ECM remodeling [136,137], stemness [138], and metastasis [139], though diverse miRNAs. Interestingly, research have demonstrated that exosomes derived from cancer-associated macrophages also can regulate stem cells’ dormancy [140] and cell migration and invasion [141], delivering proof that exosomes are also implicated in metastasis. In this sense, lung cancer cell-derived exosomes (from the A59 and H358 cell lines) alter the transcriptional and bioenergetic signature of M0 macrophages, top them to an M2 phenotype [142]. Nevertheless, the M2 macrophage-derived exosomes can transfer miR-21-5p and miR-155-5p to cancer cells, promoting the downregulation of transcription aspect Brahma-related gene-1 (BRG1), major to cell migration and invasion in colon cancer cells [141,143]. Gastric cancer showed related benefits; M2 macrophage-derived exosomemediated apolipoprotein E (ApoE) transfer was identified to increase the cancer cell migration inside a PI3K/Akt signaling pathway activation-dependent manner [144]. Altogether, these data reinforce the view that exosomes promote crosstalk amongst cancer and non-cancer cells inside the TME, regulating the EMT and metastasis. 4.three.two. Exosomes in Angiogenesis Tumor vascularization is crucial to guaranteeing the help of nutrients and meeting oxygen demands to sustain cancer development. For this reason, the activation of HIF-1 also serves as a signal to induce sustained angiogenesis [100,145]. As soon as phosphorylated, HIF-1 induces the expression of vascular endothelial development factor (VEGF) [14548]. VEGF binds to VEGF receptors (VEGFRs)-1, -2, and -3, which are expressed on vascular endothelial cells, regulating vessel formation by way of endothelial cell migration [149,150]. In this context, research have demonstrated that cancer-derived exosomes act as a important regulator of angiogenesis [151,152]. This can be because exosomes derived from cancer cells can stimulate endothelial cell migration and tube formation independe.