Nt EMT-related pathways within 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 via directly targeting tyrosine phosphatase receptor kind B (PTPRB) [127], serving as a novel invasive biomarker for this malignancy [128]. This can be since the Hippo tumor suppressor signaling pathway is important to controlling cell proliferation and apoptosis by inhibiting the oncogenic coactivators Yes-associated protein (YAP)/transcriptional coactivator with all the PDZ-binding motif (TAZ) [129,130]. Nevertheless, contemplating the plethora of biomolecules, specially 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] showed that exosomal miR-301a, secreted by hypoxic glioblastoma cells, targets transcription elongation aspect A like 7 (TCEAL7), major for the activation in the Wnt/-catenin signaling pathway, resulting within the expression with the EMT-related transcription aspects Snail, Slug, and Twist. Equivalent outcomes have been 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. Thus, it really is not surprising that cancer-derived exosomes can regulate various measures from the EMT, which includes cancer progression [133], dissemination [134,135], ECM remodeling [136,137], stemness [138], and metastasis [139], although diverse miRNAs. Interestingly, research have demonstrated that exosomes derived from cancer-associated macrophages may also regulate stem cells’ dormancy [140] and cell migration and invasion [141], giving evidence that exosomes are also implicated in metastasis. In this sense, lung cancer cell-derived exosomes (in the A59 and H358 cell lines) alter the transcriptional and bioenergetic signature of M0 macrophages, top them to an M2 phenotype [142]. Having said that, the M2 macrophage-derived exosomes can transfer miR-21-5p and miR-155-5p to cancer cells, promoting 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 related outcomes; M2 macrophage-derived exosomemediated apolipoprotein E (ApoE) transfer was identified to raise the cancer cell migration in a PI3K/Akt signaling pathway activation-dependent manner [144]. Altogether, these information reinforce the view that exosomes promote crosstalk in between cancer and p38�� inhibitor 2 supplier non-cancer cells within the TME, regulating the EMT and metastasis. 4.3.2. 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 AZD4573 web signal to induce sustained angiogenesis [100,145]. When phosphorylated, HIF-1 induces the expression of vascular endothelial growth aspect (VEGF) [14548]. VEGF binds to VEGF receptors (VEGFRs)-1, -2, and -3, which are expressed on vascular endothelial cells, regulating vessel formation by means of endothelial cell migration [149,150]. In this context, research have demonstrated that cancer-derived exosomes act as a essential regulator of angiogenesis [151,152]. This can be simply because exosomes derived from cancer cells can stimulate endothelial cell migration and tube formation independe.