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 by means of straight targeting tyrosine phosphatase receptor variety B (PTPRB) [127], serving as a novel invasive biomarker for this malignancy [128]. That is because the Hippo tumor suppressor signaling pathway is crucial 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]. Even so, thinking of 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 towards 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 issue A like 7 (TCEAL7), leading for the activation in the Wnt/-catenin signaling pathway, resulting within the expression in the EMT-related transcription aspects Snail, Slug, and Twist. Comparable 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. Thus, it is actually not surprising that cancer-derived exosomes can regulate various actions in the EMT, including cancer progression [133], dissemination [134,135], ECM remodeling [136,137], stemness [138], and metastasis [139], even though various 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], offering evidence 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]. Even so, the M2 macrophage-derived exosomes can transfer miR-21-5p and miR-155-5p to cancer cells, advertising the downregulation of transcription aspect Brahma-related gene-1 (BRG1), top to cell migration and invasion in colon cancer cells [141,143]. Gastric cancer showed similar benefits; M2 macrophage-derived exosomemediated apolipoprotein E (ApoE) transfer was discovered to raise the cancer cell migration in a PI3K/Akt signaling pathway activation-dependent manner [144]. Altogether, these data reinforce the view that exosomes Simotinib Purity promote crosstalk in between 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 support 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, that are expressed on vascular endothelial cells, regulating vessel formation through endothelial cell migration [149,150]. In this context, research have demonstrated that cancer-derived exosomes act as a essential regulator of angiogenesis [151,152]. That is because exosomes derived from cancer cells can stimulate endothelial cell migration and tube formation independe.
