Nt EMT-related pathways in 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 signaling by means of directly targeting tyrosine phosphatase receptor sort B (PTPRB) [127], serving as a novel invasive biomarker for this malignancy [128]. That is because the Hippo tumor suppressor signaling pathway is critical to controlling cell proliferation and apoptosis by inhibiting the oncogenic coactivators Yes-associated AS-0141 Epigenetics protein (YAP)/transcriptional coactivator with the PDZ-binding motif (TAZ) [129,130]. On the other hand, thinking of the plethora of biomolecules, particularly miRNAs, delivered by cancer-derived exosomes, the mechanism of action of these vesicles on EMT could not be restricted only towards the Hippo signaling pathways.Cells 2021, 10,9 ofIn this sense, Yue et al. [131] Almonertinib medchemexpress showed that exosomal miR-301a, secreted by hypoxic glioblastoma cells, targets transcription elongation element A like 7 (TCEAL7), leading towards the activation with the Wnt/-catenin signaling pathway, resulting within the expression of your EMT-related transcription things Snail, Slug, and Twist. Similar final results had been verified by Nam et al. [132], who demonstrated that miR-301a functions as an oncogene in prostate cancer by straight targeting the p63 tumor suppressor, leading to loss of E-cadherin and EMT. As a result, it really is not surprising that cancer-derived exosomes can regulate unique steps on the EMT, like cancer progression [133], dissemination [134,135], ECM remodeling [136,137], stemness [138], and metastasis [139], even though diverse miRNAs. Interestingly, studies have demonstrated that exosomes derived from cancer-associated macrophages may also regulate stem cells’ dormancy [140] and cell migration and invasion [141], supplying evidence 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, 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), major 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 discovered to improve the cancer cell migration within a PI3K/Akt signaling pathway activation-dependent manner [144]. Altogether, these data reinforce the view that exosomes market crosstalk among cancer and non-cancer cells within the TME, regulating the EMT and metastasis. 4.three.2. Exosomes in Angiogenesis Tumor vascularization is essential to guaranteeing the assistance of nutrients and meeting oxygen desires 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 aspect (VEGF) [14548]. VEGF binds to VEGF receptors (VEGFRs)-1, -2, and -3, that are expressed on vascular endothelial cells, regulating vessel formation by way of endothelial cell migration [149,150]. In this context, studies have demonstrated that cancer-derived exosomes act as a important regulator of angiogenesis [151,152]. This is simply because exosomes derived from cancer cells can stimulate endothelial cell migration and tube formation independe.