*3.2.3 Endothelial cells and vascular barriers*

Angiogenesis within the primary tumor is also influenced by tumor MVs and TDE. Normal endothelial cells (ECs) were shown to endocytose tumor EVs, which triggered PI3K/Akt signaling and increased EC motility and tube formation ability [32]. Tumor MVs and TDE also release VEGF, a pro-angiogenic substance that stimulates ECs [33]. Similarly, MVs produced from multiple myeloma cells have been demonstrated to transfer CD138, a myeloma cell marker, to ECs, promoting their proliferation, invasion, and production of the angiogenic mediators IL-6 and VEGF, resulting in tube formation [50] (**Figure 2**). MVs change the environment around the main tumor and create pre-metastatic niches from afar. This was originally attributed to their procoagulant activity, which encouraged the production of microthrombi and facilitated the extravasation of trapped circulating tumor cells. ECs are important components of the tumor microenvironment because they provide a pathway for nutrients and trophic substances [34].
