**2. The role of MVs/TDE regional preconditioning**

Tumor development is a multistep process that starts by cellular reprogramming of cells to acquire the hallmarks of cancer cells to gain and maintain abnormal growth and invasive capacity [8]. The complex process of tumor formation and spreading additionally requires a rewiring of the surrounding stromal cells. This can be induced by intrinsic cell events such as genetic or epigenetic aberrations or by external factors from direct or indirect cell communication [9]. In cancer, EVs especially Exo, have been shown to be essential for various steps during tumor initiation and progression. EVs disrupt signaling and gene expression regulation in the recipient cell by horizontally transferring bioactive chemicals between cancer cells and the surrounding stroma. As a result, malignant cells can change the phenotype of surrounding benign cells to one that supports tumor growth and metastasis, creating a favorable environment for cancer progression and spread. EVs play several roles in priming the surrounding environment preparing it for metastasis and invasion. The role of EVs in promoting tumor progression has been elucidated in studies on mixed populations of EVs. The function of EVs largely depends on their bioactive cargo, in particular the shuttling of tumor-specific proteins to the surrounding cells. While researchers have mainly studied the RNA content of EVs, however, the focus is starting to shift towards the EVs proteome [10].

The protein content of MVs within mixed populations of EVs was discovered to be significantly diverse from that of the Exo proteome, and is supplemented in proteins involved in microtubule, actin, and cytoskeleton networks, ARF6, its effector phospholipase D2, and parts of the endosomal sorting complex required for transport family (ESCRT-I) [11]. By transporting these molecules, MVs can impact nearby tumor cells and stromal cells.

### **2.1 MVs mediated tumor-invasion**

One example in which MVs shed by the cancer cells were shown to enhance tumor cell proliferation is in multiple myeloma. This effect was shown to be related to the amelioration of the Extracellular Matrix Metalloproteinase Inducer (EMMPRIN/CD147)

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

on the tumor MVs. This protein is known to be overexpressed in solid tumors, some lymphomas, and leukemias [12]. Another study in breast cancer cells found that the highly glycosylated version of EMMPRIN exists in high quantities in breast cancer cellderived MVs and enhances tumor invasion through activation of p38/MAPK signaling [11]. Interestingly, it was found that MVs from patient Blood with metastatic breast cancer had a similar high-EMMPRIN expression, along with the tumor marker Mucin-1 (MUC1/CA 15-3) [11]. Additionally, the truncated oncogenic form of the epidermal growth factor receptor (EGFR), EGFRvIII, commonly expressed in aggressive brain tumor cells, is associated with pro-tumorigenic tumor–tumor crosstalk via MVs. It was discovered that EGFRvIII was present in MVs released by U373 glioma cells, allowing them to transfer malignant features from highly aggressive tumor cells to the more benign tumor cells, EGFRvIII-negative, thereby facilitating their oncogenic transformation [11]. Hence, MVs are convenient communicators within the TME, as they can either mediate the horizontal transfer of oncogenic material or activate oncogenic signaling pathways in neighboring cancer cells, enhancing their survival, proliferative, and angiogenic potential and triggering their transformation into an aggressive phenotype.
