Ntly of uptake [153]. This response is mediated by the 189-amino-acid heparin-bound isoform of VEGF, which, in contrast to other typical isoforms of VEGF, is preferentially enriched around the exosome surface [153]. Nevertheless, cancer-derived exosomes also can market angiogenesis in an uptakedependent manner. In this sense, Li et al. [154] showed that hepatocellular carcinomaderived exosomes transporting lysyl oxidase-like 4 (LOXL4) induce angiogenesis. In one more study, Zhang et al. [155] demonstrated that ovarian cancer-derived exosomes expressing Quisqualic acid In stock prokineticin receptor 1 (PKR1) promote angiogenesis by promoting the migration and tube formation of HUVEC cells. Equivalent final results had been also described by Umezu et al. [156], who demonstrated that hypoxia increases the production of several myeloma cell-derived exosomes transporting miR-135b, which can bind to factor-inhibiting hypoxia-inducible factor 1 (FIH-1) in endothelial cells, enhancing the formation of endothelial tubes. In a further study, Zeng et al. [157] showed that colorectal cancer-derived exosomes drive miR-25-3p to endothelial cells, targeting Kruppel-like aspects 1 and four (KLF2 and KF4, respectively) and promoting vascular permeability and angiogenesis. Altogether, these data strongly suggest that cancer-derived exosomes are involved in angiogenesis. 4.3.3. Cancer-Derived Exosomes Contribute to Pre-Metastatic Niche (PMN) Formation Angiogenesis contributes to each cancer cell and cancer-derived exosome dissemination. Nonetheless, the outcome of cancer metastasis depends upon the interactions betweenCells 2021, 10,ten ofmetastatic cells as well as the host microenvironment [158]. These interactions involving the cancer cells (“seeds”) as well as the host microenvironment (“soils”) have been initially found by the English surgeon Stephen Paget in 1889 [158]. About 40 years later (in 1928), James Ewing postulated that metastasis is determined by a mechanism associated with hemodynamic elements in the vascular technique [159]. Within a complementary hypothesis postulated in the 1970s, Isaiah Fidler demonstrated that, even though the mechanical properties of blood flow are essential, metastatic colonization only happens at certain organ web sites (organotropism) [159]. Fidler’s theory was supported by more discoveries, which revealed that tumors induce the formation of microenvironments in distant organs, facilitating the survival and outgrowth of cancer cells before they arrived at these sites [15962]. These predetermined microenvironments are termed `pre-metastatic niches’ (PMNs) [163]. Inside the context in the “seed and soil” theory (Paget’s theory), the exosomes are equivalent to fertilizers, which could make barren land fertile and facilitate the colonization of cancer cells [16366]. This happens mainly because exosomes exhibit adhesion molecules on their surface, especially Daunorubicin Apoptosis integrins (ITGs), which bind to the ECM and organ-specific PMN receptors [164]. Supporting this theory, inside a study evaluating the biodistribution of exosomes from different cancer cell lines, Hoshino et al. [167] provided evidence that cancer-derived exosomes are preferentially uptaken by tissues frequently recognized as metastatic internet sites. The authors also demonstrated that this site-specific biodistribution is connected with higher expression levels of integrins (ITG6, ITG4, and ITG1 for lung tropism; ITG5 and ITGv for liver tropism; and ITG3 for brain tropism) [167], reinforcing the view that the integrins involved in PMN formation. Cumulative studies have provided evidence t.
