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 Gamma-glutamylcysteine web exosomes can downregulate Hippo signaling by means of directly targeting tyrosine phosphatase receptor type B (PTPRB) [127], serving as a novel invasive biomarker for this malignancy [128]. That is because 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]. L-Palmitoylcarnitine Formula Nevertheless, thinking of the plethora of biomolecules, in particular miRNAs, delivered by cancer-derived exosomes, the mechanism of action of those vesicles on EMT couldn’t be limited 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), top towards the activation on the Wnt/-catenin signaling pathway, resulting inside the expression of your EMT-related transcription factors Snail, Slug, and Twist. Related outcomes had 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, leading to loss of E-cadherin and EMT. As a result, it is actually not surprising that cancer-derived exosomes can regulate various methods of your EMT, including cancer progression [133], dissemination [134,135], ECM remodeling [136,137], stemness [138], and metastasis [139], though unique 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], offering 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]. Nonetheless, 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), major to cell migration and invasion in colon cancer cells [141,143]. Gastric cancer showed comparable benefits; M2 macrophage-derived exosomemediated apolipoprotein E (ApoE) transfer was found 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 between cancer and non-cancer cells within the TME, regulating the EMT and metastasis. 4.3.two. Exosomes in Angiogenesis Tumor vascularization is important to guaranteeing the support of nutrients and meeting oxygen requirements to sustain cancer growth. For this reason, 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 aspect (VEGF) [14548]. VEGF binds to VEGF receptors (VEGFRs)-1, -2, and -3, which 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 crucial regulator of angiogenesis [151,152]. This can be because exosomes derived from cancer cells can stimulate endothelial cell migration and tube formation independe.
