*3.2.3.1 Neovascularization*

TDE enriched in vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 has been demonstrated to regulate the process of

#### **Figure 2.**

*Possible mechanisms of pre-metastatic niche formation. The figure delineates how TDEs can modulate its surroundings of ECM, cancer-CAFs, immune cells, ECs, and MSCs all in favor of tumor support and progression. TDE can carry integrins to distant sites and create a pre-metastatic niche.*

*Roles of Extracellular Vesicles in Cancer Metastasis DOI: http://dx.doi.org/10.5772/intechopen.103798*

neovascularization in myeloid leukemia [35]. Furthermore, enhanced vascularization has been linked to the packaging of miR-92a in Exo derived from leukemia[36] and CO-029/D6.1A Tetraspanin in Exo produced from pancreatic cancer [37]. Upregulation of Heparanase in tumor cells, such as myeloma and breast malignancies, has also been linked to increased exosome production and exosomal packing of Syndecan-1, VEGF, and hepatocyte growth factor, resulting in enhanced endothelial invasion through the ECM [38]. Exo produced from skin cancer can also enhance angiogenesis by transferring the EGFR [39] and miR-9 to ECs [26]. Furthermore, melanoma-derived Exo have been found to condition sentinel lymph nodes prior to the installation of melanoma cells and subsequent metastasis by upregulating Collagen 18 and Laminin 5, as well as producing angiogenic growth factors [26].

Another significant component in altering tumor-EC communication is hypoxia. Hypoxic glioblastoma cells, for example, release Exo that interact with ECs, promoting proliferation and angiogenesis both in vitro and in vivo [40], and also prompting tissue factor/Factor VIIa dependent activation of hypoxic ECs [26].

#### *3.2.3.2 Vascular leakage*

Exo from melanoma cause pulmonary vascular leakiness and upregulate tumor cell recruitment genes such Stabilin 1, Vitronectin, Integrins, and Ephrin receptor b4 in lymph nodes, forming pre-metastatic niches [41]. Furthermore, breast cancerderived Exo enriched in miR-105 alter the expression of Claudin 5, Zonula Occludens protein 1, and Occludin, which promotes metastasis by disrupting vascular endothelial barriers [42]. Exo produced from brain tumors include miR-181c, which regulates EC actin dynamics and promotes the breakdown of the blood-brain barrier by three times. Protein Kinase-1 Degradation Requires Phosphoinositol [43]. Similarly, glioblastoma cells release Exo with high quantities of VEGF-A, which promote EC permeability and angiogenesis in vitro [44].

#### *3.2.4 Tumor-stem/progenitor-non-transformed cell communication*

TDE can promote pro-tumorigenic microenvironments via promoting tumorstem/progenitor cell contact, in addition to its well-known actions in differentiated cells. Melanoma-derived Exo, for example, stimulate BMDCs by transferring the oncoprotein MET, resulting in the mobilization of vasculogenic and hematopoietic bone marrow progenitor cells to ensure vascular proliferation and immunosuppression at pre-metastatic niches [45]. Communication between tumor stem/progenitor cells is also critical in bone metastasis. Exo from bone metastatic prostate cancer PC3 cells were found to influence the process of bone metastasis by modulating both osteoclast genesis and osteoblast proliferation. Exo generated from osteoblasts, on the other hand, have been demonstrated to stimulate PC3 prostate cancer cell proliferation [46].

TDE was also demonstrated to influence the development of myeloid precursor cells into myeloid-derived suppressor cells (MDSCs), which are known to aid tumor progression by permitting immune escape [47]. Exo produced from breast carcinomas have been found to be taken up by bone marrow cells and to convert these cells' development pathways toward MDSCs via Prostaglandin E2 and TGF-β, boosting COX2, IL6, VEGF, and Arginase1 accumulation by MDSCs [48].

TDE can also cause alterations in mesenchymal stem cells (MSCs), which help to promote and maintain tumor-promoting inflammatory environments. For example, HSP70+ lung tumor-derived exosomes (TDEs) activate NF-kB and cause MSCs to

secrete IL-6, IL-8, and MCP1 via TLR2-mediated signaling, causing MSCs to become more inflammatory and tumor supportive [49]. According to De Veirman et al. [50], myeloma-derived Exo transfer miR-146a to mesenchymal cells, stimulating them to secrete numerous cytokines and chemokines including CXCL1, IL6, IL-8, IP-10, MCP-1, and CCL-5 (**Figure 2**). Another example is Exo produced by KMBC cholangiocarcinoma cells, which cause MSCs to upregulate IL-6, and hence KMBC cell proliferation [51].
