**4.1 Tumor cell proliferation and anti-apoptotic effect**

One of the proposed mechanisms of tumorigenicity of TDE is the induction of tumor cell proliferation. Studies involving various cancer cells such as, chronic myeloid leukemia and in human gastric cancer, showed that this proliferative potential is via an autocrine induction through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and MAPK/ERK signaling pathways. Additionally, through the transference of lncRNAs (reviewed in [49]).

In addition, glioblastoma-derived Exo were shown to induce proliferation of the human glioma U87 cell line [40] in a mechanism dependent on the chloride intracellular channel protein 1 (CLIC1) [52]. In a more specific context linked to prostate cancer treatment, prostate cancer LNCaP cells grown in the presence of androgens generate Exo high in CD9, which enhance the growth of androgen-depleted LNCaP cells. Another example involves the promotion of in vivo growth of murine melanomas by systemic treatment of mice with melanoma-derived Exo, which accelerated growth and inhibited apoptosis of melanoma tumors in vivo [26].

### **4.2 Invasiveness and motility**

TDE can alter the migratory behavior of recipient malignant cells. Exo produced from nasopharyngeal cancer-bearing EMT-inducing signals such as TGF-β and hypoxia-inducible factor 1 alpha (HIF1a) [53], matrix metalloproteinases (MMPs) Notch1, LMP1 Casein Kinase II and Annexin A2, were shown to enhance the migratory capacity of the tumor recipient cells. Another example involves Exo derived from hypoxic prostate cancer cells, which prompted invasiveness and motility of naïve human prostate cancer cells (reviewed in [26]) through the neighboring stroma and to nearby cells.

## **4.3 Chemoresistance**

Exo have been found to have a role in tumor-tumor communication by transferring chemoresistance. Exo have been linked to the transfer of Docetaxel resistance in prostate cancer since Corcoran and colleagues first discovered it [54]. The transfer of cisplatin resistance in lung cancer is achieved by donor resistant cells producing Exo with low levels of miR-100-5p, which leads to enhanced expression of the mammalian target of rapamycin (mTOR) protein and chemoresistance in recipient cells [55].

MiRNA packed in Exo from drug-resistant cells can modulate the expression of specific target genes in breast cancer, such as miR-23a targeting Sprouty2, miR-222 targeting PTEN, miR-452 targeting APC4, and miR-24 targeting p27, thereby *Roles of Extracellular Vesicles in Cancer Metastasis DOI: http://dx.doi.org/10.5772/intechopen.103798*

modulating chemoresistance in recipient cells that integrate these Exo. In fact, exosomal miR-222 plays a key role in this process, as the silencing of miR-221/222 prevents the transmission of resistance [56].

In addition to miRNAs, the transfer of exosomal mRNAs that encode drugresistant proteins may result in chemoresistance in the receiving cell. GSTP1 exosomal mRNA from Adriamycin-resistant breast cancer cells, for example, confers resistance to previously susceptible cells. The presence of GSTP1 in circulating Exo from patients' peripheral blood was linked to a worse outcome in breast cancer patients receiving Adriamycin [57]. A supporting stroma is required for an optimum metabolic and physiological environment for tumor growth. Fibroblasts are the most abundant cells in most solid tissues, participating in environmental cue responses and being a common target of tumor-derived signals [58].

#### **4.4 Integrins in metastasis**

Integrins are a wide family of cell adhesion receptor proteins such as alpha3beta1, alpha6beta1, alpha6beta4, and alpha7beta1. Their roles have been implicated in tumor metastasis and mesenchymal transformation. TDE carry these integrins from primary tumor sites to distant sites such as lung, lymph nodes, brain, and bone creating premetastatic niches (**Figure 2**) [59].
