**7. Tumor-derived extracellular vesicles in ovarian cancer**

Nawaz et al. have recently done an extensive review on the role of EVs in ovarian cancer and concluded that the gaining of new insights into these mechanisms would contribute to the identification of new biomarkers among the ovarian-cancerderived EVs and to the development of efficient EVs-based immunotherapies [126]. Proteomic analysis of exosomes derived from two human ovarian cancer cell lines (i.e., OVCAR-3 and IGROV1) indicated the presence of 2230 proteins, 1017 proteins being common for both cell lines, 380 proteins being newly reported compared to the ExoCarta database, and some of them being associated with tumorigenesis and metastasis and might represent promising biomarkers [127].

Additionally, matrix metalloproteinase-1 (MMP1) might be a very good biomarker for the ovarian cancer due to its overexpression in ascites-derived EVs in correlation with the degree of malignancy and the low prognosis for the ovarian cancer patients [128]. Moreover, the peritoneal dissemination of ovarian cancer is facilitated by malignant EVs containing MMP1 derived from the ascites of patients, and EVs were demonstrated to induce apoptosis in mesothelial cells [128].

**97**

*Extracellular Vesicles in Cancer*

peutic targets in breast cancer.

Hs578T cells [132].

invasiveness [129].

*DOI: http://dx.doi.org/10.5772/intechopen.85117*

**8. Breast-cancer-derived extracellular vesicles**

The mechanisms of drug resistance development also involve the release of EVs from ovarian cancer cells upon exposure to drug (i.e., cisplatin) and induce

In breast cancer, EVs can play two essential roles "diagnosis biomarkers" or "therapeutic targets." Thus, breast cancer induces the release of exosomes from salivary glands, being potential markers for early diagnosis [130]. Interestingly, EVs serve as a cargo not only for nucleic acids and proteins, but also for anticancer drugs. Considering the critical contribution of EVs in facilitating tumorigenesis, metastasis, and drug resistance [130], they could be considered as potential thera-

Moreover, the analysis of EVs can help to distinguish the "degree of aggressiveness" in breast cancer. To detail, EVs derived from the aggressive human breast cancer MDA-MB-231 cell line, but not from the less invasive human breast cancer MCF-7 cell line, were demonstrated to induce platelet activation and aggregation by tissue factor-independent and tissue factor-dependent procoagulant activities [131]. EVs have been demonstrated to be involved in the cross talk between neighboring cancer cells and to transmit phenotypic aggressive traits from one cell to another. To date, EVs released by Hs578Ts(i)8 triple-negative breast cancer cells were able to increase the invasion, proliferation, and migration characteristics of

In different body fluids, especially plasma and serum, EVs biomarkers have been

The protein content of the EVs can be potentially used in the early detection of cancer as suggested in a pilot study by Smalley et al. [151]. The plasma levels of exosomal proteins represents an important biomarker that discriminates between ovarian cancer patients and normal ones, and their values correlate with the stage of the disease [119]. Among exosomal proteins, TGF-β1 and MAGE3/6 can be used as reliable biomarkers to discriminate between benign and malignant ovarian tumors, or to ascertain the efficacy of chemotherapy [119]. Although epithelial cell adhesion molecule (EpCAM) was demonstrated to promote epithelial-mesenchymal transition in advanced stages of endometrial cancer [152], studies indicated that EpCAM is not a robust biomarker to classify exosomes derived from benign and malignant ovarian tumors [134] or to detect early stages of the pathology [153]. Besides EpCAM, several exosomal proteins were identified to be overexpressed in ovarian cancer, including proliferation cell nuclear antigen (PCNA), tubulin beta-3 chain (TUBB3), epidermal growth factor receptor (EGFR), apolipoprotein E (APOE), claudin 3 (CLDN3), fatty acid synthase (FASN), ERBB2, and L1CAM (CD171) [127]. Additionally, claudin-4, but not claudin-3, is a valuable biomarker in the peripheral blood of ovarian cancer patients with almost 98% specificity [133]. Exosomal proteins can also represent important biomarkers for the evaluation of efficacy of therapies. Thus, annexin A3 can be employed for early detection of the resistance to platinum-based therapy in ovarian cancer patients [135, 136]. In breast cancer, several studies identified various exosomal miRNAs as potential biomarkers correlated with tumor malignancy degree and prognosis. Indeed, exosomal miR-21 and miR-1246 had higher levels in plasma of breast cancer

**9. Extracellular vesicles as biomarkers—new diagnostic tools**

detected with great clinical value in various types of cancer, **Table 2**.

*Extracellular Vesicles and Their Importance in Human Health*

**5. Extracellular vesicles and metastatic niches**

the generation of the pre-metastatic niche [121, 122].

**6. Role of extracellular vesicles in metastasis**

contributes to this process by promoting angiogenesis [125].

metastasis and might represent promising biomarkers [127].

**7. Tumor-derived extracellular vesicles in ovarian cancer**

and dormancy [123].

cancers [124].

Tumor microenvironment was described to undergo series of molecular and cellular changes to form the metastatic-designated sites, called pre-metastatic niche [115, 116]. The formation of pre-metastatic niche requires the cross talk between primary tumor-derived components, and the microenvironment of the host stromal components and of the tumor-mobilized bone-marrow-derived cells [117]. Interestingly, the role of EVs in metastatic niches can be exploited in novel therapeutic approaches. Indeed, technologies based on exosomes, separated from the ascitic fluid of ovarian cancer patients, embedded in a 3D scaffold metastatic trap, were successfully tested in murine models of ovarian metastasis in order to improve survival [118]. Numerous studies indicated that tumor-derived exosomes might play a role in promoting angiogenesis and modulation of the immune system [119, 120]. Moreover, exosomes derived from cancerous tumor are capable of remodeling the surrounding parenchyma, thus supporting tumor progression and

EVs have been described to play an essential role in the local and distant communication between cancer cells and their environment and in contributing to the progression of metastasis [123]. Although the function of EVs in metastasis is not completely understood, studies show that miRNAs isolated from EVs are actively involved in complex metastatic processes, including local invasion, angiogenesis, immune modulation, metastatic niche preparation, colonization,

EVs play an essential role in the tumor metastasis by ensuring the cross talk between tumor and the adipose tissue, and obesity was described to influence the metastatic behavior of tumors, especially in melanoma, breast, and ovarian

In breast cancer, metastatic exosomes creating a facilitating local environment for metastasis was demonstrated, and annexin II contained in these exosomes

Nawaz et al. have recently done an extensive review on the role of EVs in ovarian cancer and concluded that the gaining of new insights into these mechanisms would contribute to the identification of new biomarkers among the ovarian-cancerderived EVs and to the development of efficient EVs-based immunotherapies [126]. Proteomic analysis of exosomes derived from two human ovarian cancer cell lines (i.e., OVCAR-3 and IGROV1) indicated the presence of 2230 proteins, 1017 proteins being common for both cell lines, 380 proteins being newly reported compared to the ExoCarta database, and some of them being associated with tumorigenesis and

Additionally, matrix metalloproteinase-1 (MMP1) might be a very good biomarker for the ovarian cancer due to its overexpression in ascites-derived EVs in correlation with the degree of malignancy and the low prognosis for the ovarian cancer patients [128]. Moreover, the peritoneal dissemination of ovarian cancer is facilitated by malignant EVs containing MMP1 derived from the ascites of patients,

and EVs were demonstrated to induce apoptosis in mesothelial cells [128].

**96**

The mechanisms of drug resistance development also involve the release of EVs from ovarian cancer cells upon exposure to drug (i.e., cisplatin) and induce invasiveness [129].
