Nt EMT-related pathways in 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 through straight targeting tyrosine phosphatase receptor form B (PTPRB) [127], serving as a novel invasive biomarker for this malignancy [128]. That is since the Hippo tumor suppressor signaling pathway is important to controlling cell proliferation and apoptosis by inhibiting the oncogenic coactivators Yes-associated protein (YAP)/Okadaic acid ammonium salt Autophagy transcriptional coactivator using the PDZ-binding motif (TAZ) [129,130]. Even so, taking into consideration the plethora of biomolecules, particularly miRNAs, delivered by cancer-derived exosomes, the mechanism of action of those vesicles on EMT couldn’t be restricted 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 issue A like 7 (TCEAL7), leading towards the activation in the Wnt/-catenin signaling pathway, resulting in the expression with the EMT-related transcription components Snail, Slug, and Twist. Similar final results 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, leading to loss of E-cadherin and EMT. Hence, it is actually not surprising that cancer-derived exosomes can regulate distinct actions of your EMT, including cancer BMY-14802 supplier progression [133], dissemination [134,135], ECM remodeling [136,137], stemness [138], and metastasis [139], although distinctive miRNAs. Interestingly, studies have demonstrated that exosomes derived from cancer-associated macrophages also can regulate stem cells’ dormancy [140] and cell migration and invasion [141], supplying proof 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, major them to an M2 phenotype [142]. On the other hand, the M2 macrophage-derived exosomes can transfer miR-21-5p and miR-155-5p to cancer cells, promoting the downregulation of transcription issue Brahma-related gene-1 (BRG1), leading to cell migration and invasion in colon cancer cells [141,143]. Gastric cancer showed related results; M2 macrophage-derived exosomemediated apolipoprotein E (ApoE) transfer was discovered to improve the cancer cell migration inside 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.three.two. Exosomes in Angiogenesis Tumor vascularization is essential to guaranteeing the assistance of nutrients and meeting oxygen requires to sustain cancer growth. For this reason, the activation of HIF-1 also serves as a signal to induce sustained angiogenesis [100,145]. When phosphorylated, HIF-1 induces the expression of vascular endothelial growth factor (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]. Within this context, studies have demonstrated that cancer-derived exosomes act as a crucial regulator of angiogenesis [151,152]. That is because exosomes derived from cancer cells can stimulate endothelial cell migration and tube formation independe.