Nt EMT-related pathways inside 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 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 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]. Even so, thinking about the plethora of biomolecules, specifically miRNAs, delivered by cancer-derived exosomes, the mechanism of action of these vesicles on EMT couldn’t 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 element A like 7 (TCEAL7), top for the activation on the Wnt/-catenin signaling pathway, resulting within the expression with the EMT-related transcription things Snail, Slug, and Twist. Equivalent final results 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, major to loss of E-cadherin and EMT. As a result, it’s not surprising that cancer-derived exosomes can regulate unique steps with the EMT, including cancer progression [133], dissemination [134,135], ECM remodeling [136,137], stemness [138], and metastasis [139], although unique miRNAs. Interestingly, Ziritaxestat medchemexpress research have demonstrated that exosomes derived from cancer-associated macrophages may also regulate stem cells’ dormancy [140] and cell migration and invasion [141], supplying proof that exosomes are also Leukotriene D4 Autophagy 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, major them to an M2 phenotype [142]. However, 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), leading to cell migration and invasion in colon cancer cells [141,143]. Gastric cancer showed equivalent final results; M2 macrophage-derived exosomemediated apolipoprotein E (ApoE) transfer was found to increase the cancer cell migration in a PI3K/Akt signaling pathway activation-dependent manner [144]. Altogether, these information reinforce the view that exosomes promote crosstalk involving cancer and non-cancer cells within the TME, regulating the EMT and metastasis. four.three.2. Exosomes in Angiogenesis Tumor vascularization is vital to guaranteeing the support of nutrients and meeting oxygen requires to sustain cancer development. Because of this, the activation of HIF-1 also serves as a signal to induce sustained angiogenesis [100,145]. After phosphorylated, HIF-1 induces the expression of vascular endothelial development element (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 important regulator of angiogenesis [151,152]. This can be mainly because exosomes derived from cancer cells can stimulate endothelial cell migration and tube formation independe.