Once internalized into recipient cells, exosomes cargo can regulate fate, function, and phenotype of recipient cells [
71,
85]. Exosomes docking on cell surface may activate/inhibit the signaling pathway in ECs through receptor-ligand interaction [
86]. Therefore, exosomes can engage different signaling pathways of recipient cells to affect recipient cells function [
87]. The exact signaling pathways behind angiogenesis driven by exosomes are poorly known. The pivotal roles of protein cargo of the cancer derived-exosomes in cancer progression and angiogenesis have been documented [
88,
89]. The proteomic content, even angiogenic profile of exosomes from different tumor cells widely differ in various tumor cells (Table
1). However, these differences may arise from the bias of researchers in targeting proteins of interest. Analysis of exosomes from GMB cells showed that these exosomes are enriched with pro-angiogenic factors including VEGF, angiogenin, TGFβ, IL-8, IL-6, MMP2, MMP9, TIMP-1, TIMP-2, and CXCR4 chemokine receptor [
73,
90,
91]. MM-derived exosomes abundantly contain bFGF, VEGF, HGF, Serpin E1, and MMP-9 [
69]. Exosomes from nasopharyngeal carcinoma cells contain a high level of pro-angiogenic proteins including CD44 isoform 5 (CD44v5), ICAM-1, and MMP13, while contain a low level of antiangiogenic protein, thrombospondin-1 [
74,
92].
Table 1
Angiogenic cargo of tumor cell-derived exosomes
Breast cancer | Annexin II, Heparanase, TGFβ, miR-126a |
Bladder cancer | EDIL-3 |
Colorectal cancer | Plexin B2, Tetraspanin-8 |
Glioblastoma | Angiogenin, CXCR4, FGFa, IL-6, IL-8, MMP2, MMP9, TGFβ, TIMP-1, TIMP-2, VEGF |
Lung cancer | Sortilin, miRNA-21, miRNA-23a, miRNA-210 |
Glioma | IGFBP1, IGFBP3, IGFBP5, IL-8, LOXL2, VEGF |
Ovarian cancer | miRNA-21 |
Leukemia | Heparanase |
Nasopharyngeal cancer | CD44v5, HAX-1, ICAM-1, MMP13 |
Malignant melanoma | VEGF, MMP2, IL-6 |
Multiple myeloma | Angiogenin, Heparanase, HGF, MMP9, Serpin E1, Serpin F1, VEGF |
You et al. found that these exosomes contain HAX-1 protein that induces migration ability and angiogenesis in ECs [
92]. Analyzing exosomes from the colorectal carcinoma ascites showed that these exosomes carry angiogenic proteins like Plexin B2 and tetraspanin-8 [
93]. Melanoma cancer released-exosomes bear VEGF, IL-6, and MMP2 [
94]. Exosomes from lung adenocarcinoma are enriched with sortilin, which increases the expression of angiogenic genes including IL-8, VEGF, endothelin-1, thrombospondin-1, and uPA in ECs [
95]. Breast cancer derived-exosomes transfer proangiogenic Annexin II to ECs and induce angiogenesis via the tPA-dependent manner in vitro and in vivo [
76]. Beckham et al. declared that exosomes from bladder cancer patients contain EDIL-3 proteins that facilitate migration and angiogenesis [
96]. Heparanase, an enzyme involved in exosomes biogenesis and loading, is present in tumor cell derived-exosomes and contributes to migration and tube formation of ECs [
97,
98]. Prostate cancer released exosomes contain TGF-β1 proteins that mediate differentiation of fibroblast into myofibroblast, promoting angiogenesis in vitro [
99]. Exosomes produced by pancreatic adenocarcinoma have a high level of Tspan8 that promote proliferation, migration, and sprouting in ECs. Furthermore, these exosomes mediate maturation of endothelial progenitor cells [
100]. Tumor derived-exosome can induce epithelial-mesenchymal transition (EMT) in different cancer cells. EMT cells produce exosomes with angiogenic Rac-1 and PAK-2 proteins that induce angiogenesis in ECs [
101]. In GBM cells, Zeng et al. showed that EMT cells derived-exosomes induced cell migration, invasion, and angiogenesis [
96]. Nucleic acids content of tumor-derived exosomes mediate angiogenesis in ECs upon exosome internalization. For example, colorectal cancer cells release exosomes transferring proliferation-related mRNAs such as RAD21, CDK8, and ERH to ECs and increase proliferation of ECs and subsequently support angiogenesis [
102]. Lang et al. found that GBM-derived exosomes contain lncRNA POU3F3 that promote angiogenesis in ECs [
71]. In addition, in another study, it was demonstrated that these exosomes transfer lncRNA-CCAT2 to ECs, which subsequently inhibits apoptosis and enhances angiogenesis [
71]. Enriched in exosomes, miRNAs can deliver into target cell cytoplasm and control different mRNAs expression and cell function of target cell [
103]. Obviously, exosomal miRNAs fascinated attentions have key roles in increasing the adversarial effects of tumors [
104]. For example, in human nasopharynx cancer, tumor-derived exosomes actively transfer miRNAs including miRNA-106a-5p, miRNA-891a, miRNA-24-3p, and miRNA-20a-5p that promote cell proliferation and survival through suppression of MARK1 protein signaling pathway [
105]. miRNAs cargo of tumor-derived exosomes are also involved in angiogenesis through regulating ECs function and morphology [
106,
107]. Exosomes protect miRNAs from enzymatic degradation, thus increases the stability of exosomal miRNAs compared to circulating ones. In Table
2 a list of angiogenic exosomal miRNAs is presented. Lung cancer cells release exosomes enriched with miRNA-21. This miRNA is an oncogenic and angiogenic molecule that enhances expression and secretion of VEGF, inducing angiogenesis in ECs [
108]. Other miRNAs such as miRNA23a and miRNA-210 which are present in exosomes of lung cancer cells and are implicated in inducing angiogenesis in ECs [
78,
109]. Besides, exosomal miRNA-192 has been shown to inhibit angiogenesis [
110]. Umezu et al. demonstrated that hypoxia-resistant multiple myeloma (HR-MM) cells release exosomes containing miR-135b that enhance angiogenesis in ECs through targeting HIF-1 [
111]. Lung cancer cells secrete exosomes enriched with miR-23a, which facilitate the angiogenesis by targeting tight junction protein ZO-1 and prolyl hydroxylase [
78]. Mao et al. found that hypoxia increased miR-494 loading into exosomes of non-small cell lung cancer (NSCLC) through the HIF-1α-mediated mechanism. In keeping, they showed that these exosomes down-regulated PTEN and activated Akt/eNOS pathway in ECs and consequently promoted angiogenesis [
112]. In addition, miR-210 cargo of exosomes purified from leukemia cells induced the tubulogenesis in human endothelial cells [
113]. The possible mechanisms that tumor-derived exosome cargos promote angiogenesis have been presented in Fig.
3b. The biomarker potential of exosomal miRNAs has frequently been reviewed in literature [
114,
115]. As miRNAs bearing exosomes can be distributed to bio-fluids, therefore, liquid-biopsy from urine, plasma, and CSF is a non-invasive method for obtain exact information about tumor environment/status [
116]. For example, it was demonstrated that miRNAs such as miRNA-205, miRNA-214, miRNA-141, miRNA-203, miRNA-200 a,-b,-c, and miRNA-21 are present in exosomes isolated from patients suffering from ovarian tumors and they could be serve as biomarkers [
117].
Table 2
Hypoxia-induced angiogenic cargo of tumor cell-derived exosomes
Breast cancer | TGFβ |
Leukemia | miR-18b, -20a, -24, -106b, -130b, -185, -210, 224, -379, -652 |
Glioma | IGFBP1, IGFBP3, IGFBP5, IL-8, LOXL2, VEGF |
Multiple myeloma | miR-135b, -200c, -210, -223, -328, -335, -425 |
Lung cancer | miR-23a |