Exosomes in cancer: small vesicular transporters for cancer progression and metastasis, biomarkers in cancer therapeutics

Introduction

The solid tumors are complicated structures that including the surrounding tumor stroma and cancer cells, which composed of endothelial cells, fibroblasts, and immune cells (Sund & Kalluri, 2009). The surrounding cells are permanently extracting factors that alter the tumor microenvironment (TME) directly or indirectly (Dvorak et al., 2011). A persistent cross-talk among tumor cells and the distant tumor microenvironment have applied as the pivotal tumor growth, and significant targets in antitumoral intervention, and systemic diffusion (Kalluri & Zeisberg, 2006; Swartz et al., 2012). Extracellular vesicles (EVs) have appeared as long-distance communicators; their outcomes in primary tumors can display as systemic effects and contribute to procedures within the circulation by many various kinds of cells. The exosomes pretense a special class of EVs, which released via various kinds of cells (Desrochers, Antonyak & Cerione, 2016; Kowal, Tkach & Théry, 2014; Mathivanan, Ji & Simpson, 2010). Newly evidence represents that the release of exosomes has been detected to play a considerable role between human tumor cells and systemic cell-to-cell relevance in cancers. The exosomes, initially defined through several common traits in reticulocytes three decades ago, containing morphology (a classic “dish” or “cup” formed in transfer electron microscopy (SEM)), density (1.13–1.19 g/ml), size (30–100 nm in diameter), and determined increased protein markers (TSG101, HSP70, and tetraspanins) (Harding, Heuser & Stahl, 2013). Recent publications illustrated that exosomes are small membrane nanovesicles shaped in multivesicular bodies of endocytic derivation with a diameter of 40–100 nm. Exosomes were primarily considered as the trash bags for elimination of abandoned membrane segments and unwanted molecular fragments from cells, besides the critical task of exosomes in stimulation of immune response is identified as their effect on antigen presentation in the mid-1990s (Raposo et al., 1996). Interestingly, the scholars detected that noncoding RNAs (miRNAs), messenger RNAs (mRNAs), proteins and DNA fragments could be burdened as “goods” in extracellular vesicles (EVs) (Balaj et al., 2011). Likewise the exosomes as a nanovesicles were detected to function as “communication shuttles” from a donator cells to recipient cells, that could able to re-encode genes of receiver cells, reprogramming of the tumor microenvironment and recruitment to shape a pro-tumorigenic soil, and play a considerable act in the progression, invasion, metastasis, and become insensitive to a drug of cancer (Azmi, Bao & Sarkar, 2013; Balaj et al., 2011; Valadi et al., 2007).

Here we reviewed a new science concerning the function of exosomes as a shuttle in tumorigenesis, emphasizing their biogenesis, component, significant affection, and then considering the potential of exosomes as a novel biomarkers for clinical remedial target diagnosis and prognosis.

Survey Methodology

PubMed was mostly utilized to search for relevant articles published utilizing the keyword “exosome”, “cancer” and “therapy.” Afterward, screened articles were utilized as references for this review. Additional keywords, such as “microenvironment,” “nanovesicles” and “tumor,” were also utilized.

Exosomes Biogenesis, Release, and Uptake

Contrary to the larger microvesicles (MVs), that straightly shed from the cell membrane, the exosomes forming is a specific process that contains four steps: beginning, endocytosis, multivesicular bodies (MVBs) creation, and finally the exosome secretion (Théry, Zitvogel & Amigorena, 2002). Exosomes primarily can shape through the ceramide-induced procedures of inside budding from the late endosome restricted membranes (Trajkovic et al., 2008). The encapsulation of RNA molecules and functional proteins occur through this process. The Multivesicular bodies (MVBs) within the endocytic systems shaped via the budding of an endosome limited membrane into the extracellular milieu of the section by the junction and merge of the MVBs with the cell membrane. The MVBs are either classified as the destroying of cargo in the lysosome or leading to secretion within the extracellular space as exosomes after vesicular cumulation (Février & Raposo, 2004; Trams et al., 1981). The procedures based on the classified of exosomal cargo within the intraluminal vesicles (ILVs) are still not completely understood. Although it has been offered to characterize the exosomes formation and releasing by both endosomal tethering complexes necessitated for transport (ESCRT)-dependent and independent symptoms, however, alternative ways may also exist (Trajkovic et al., 2008). The ESCRT pathway discerns ubiquitination of membrane proteins and promotes their internalization within the multivesicular endosome (Wollert & Hurley, 2010). The mechanism for the microvesicles formation has been illustrated to regulate through the Syndecan heparan sulfate proteoglycans and their cytoplasmic adaptor syntenin (Baietti et al., 2012). The MVB trafficking and the secretion procedure of exosomes may be performed through the outside of exosomes and the microvesicles budding procedure or through multiple compositions of the endocytic machinery, containing the members of the Rab guanosine triphosphatase (GTPase) family (Rab11, Rab 27a, Rab 27b, Rab 35), elevated expression of heparanase, SNARES (soluble NSF attachment receptor), and cytoskeleton regulatory proteins (Azmi, Bao & Sarkar, 2013; Beach et al., 2014; Ostrowski et al., 2010; Pant, Hilton & Burczynski, 2012). A promoted dissemination of exosomes is critically was detected to be triggered via multiple kinds of stress, including alters in PH membrane, oxidative stress, shear stress, hypoxia, thermal alters, and radiation, besides through formation of ceramide, stimulation of sphingomyelinase and following the p53- adjusted protein tumor-suppressor-activated pathway 6 (TSAP6) (Andaloussi et al., 2013; Azmi, Bao & Sarkar, 2013; Hannafon & Ding, 2013; Joanne et al., 2005; Kucharzewska & Belting, 2013; Lespagnol et al., 2008; Parolini et al., 2009; Yu, Harris & Levine, 2006). Exosomes shuttle information to the recipient cells via three major pathways: (1) interaction between receptor-ligand; (2) straight merge with cell membrane; (3) endocytosis through phagocytosis (Fig. 1). Also, there are multiple proteins that can function as specific receptors to activate the uptake of the exosome, containing ICAM-1 for APCs, and Tim 1/4 for B-cells (Miyanishi et al., 2007; Segura et al., 2005).

Exosomes Structure and Composition

Exosomes are commonly cup-shaped extracellular small nanovesicles ranging in size from 30 to 100 nm diameter, consist of a phospholipid bilayer comprising membrane proteins that encircles a lumen containing an extensive range of biomolecules including carbohydrates, lipids, small fragments of DNA, mRNAs, proteins, and miRNAs inward to keep them from destruction (De Veirman et al., 2016; Hwang, 2013; Raimondo et al., 2011; Vlassov et al., 2012; Wang et al., 2016).

Exosome Function

As a communicator, exosomes can directly shuttle the bioactive molecules among multiple kinds of recipient cells, with results in targeted cellular phenotyping, contained messenger-RNA (mRNA) and microRNA (miRNA) dependent on the shuttle of genetics, and also epigenetic information and lipid trafficking among cells (Azmi, Bao & Sarkar, 2013; Xiang et al., 2009). The existence of exosomes in the circulating body fluids reveals their role in various pathological situations, the instance of infection disease, cardiovascular disease, and progression of neurodegenerative disease (Bang & Thum, 2012; Fleming et al., 2014). The more substantial role of exosomes has been figured out in cancer which leads to tumor growth, angiogenesis, escaping from the immune response, causing tumor cell migration, stimulating normal cells to an invasion, and leading to metastatic colonization into distal tissues (Azmi, Bao & Sarkar, 2013).

Methods for the Isolation and Analysis of Biomarkers from Exosomes in Cancer Cells and Body Fluids

Recently, different methods are available for the isolation and discern of exosomes from the distinguished cells under normal and stressed situations, containing nucleic acid (DNA) sequencing, qRT-PCR analysis, western blotting assay, or Enzyme-linked immunosorbent assay (ELISA), which can identify RNA and protein of exosomes, also ultracentrifugation, source gradient ultracentrifugation combined with ultrafiltration centrifugation (SGUUC), commercial kits, magnetic activated cell sorting (MACS) can utilize as another method. To date, the international society for extracellular vesicles (ISEV) can apply for the detection of extracellular vesicles and their functions. Also, western blot and flow cytometry (FCM) are commonly utilized for recognizing of exosomes through discovering particular tetraspanins (for example CD9, CD63, and HSP70). Further, the transmission electron microscopy (TEM) can use for size and shape analysis (Lötvall et al., 2014). The common technique for the isolation of exosomes contains ultracentrifugation, which is often in combination with sucrose density gradients or sucrose cushions to float the relatively low-density exosomes. The ultracentrifugation procedure has multiple disadvantages: The manner is extremely labor-intensive and time-consuming; due to the restrictions of the design of ultracentrifuge rotors one cannot evaluate more than six specimens at a time; the procedure needs a major amount of raw materials; exosome productions are usually low; and vast training of staff is required (Théry et al., 2006; Zeringer et al., 2015). Isolation of exosomes based on size, by the prosperous isolation of exosomes through applying the ultrafiltration methods which are less time-consuming than ultracentrifugation and do not need the usage of the particular tool (Cheruvanky et al., 2007). HPLC (high-performance liquid chromatography)-based protocols could effectively permit the preparation of extremely pure exosomes. However, these methods need appropriative material and are not negligible to scale-up (Lai et al., 2010). Besides, the intricacy is that both body fluids and cell-culture media include an extensive amount of nanoparticles in the identical size range as exosomes. For instance, many miRNAs are included within extracellular protein complexes rather than exosomes (Wang et al., 2010). In addition, volume-excluding polymers such as polyethylene glycols (PEGs) could be used to precipitate exosomes from empirical specimens. The precipitate can be separated applying either low-speed centrifugation or filtration. System Biosciences presents an appropriative reagent called ExoQuick, which can be added to conditioned cell media, urine or serum, which precipitates these nanovesicles (Adams, 1973; Lewis & Metcalf, 1988; Yamamoto et al., 1970). In principle, a preferable resource for special purification of exosomes should be affinity isolation with antibodies to Alix, annexin, CD63, CD81, CD82, CD9, EpCAM, and Rab5. These antibodies could be collected on multiple media, containing microfluidic devices, plates, magnetic beads and chromatography matrices (Chen et al., 2010; Théry et al., 2006).

Exosomes and Cancer

Role of exosomes in cancerogenesis

As mentioned earlier, the exosomes revealed important roles in cancer progression. The exosomes released by human cancer cells are known as tumor-derived (TD) exosomes. The TD exosomes through autocrine signals can modulate the local growth progression of human cancer cells. The exosomal autocrine signaling pathway is related to kinds of cells and cellular traits, for instance, exosomes separated from gastric cancer cells with high CD97 (epidermal growth factor seven-transmembrane subfamily) expression enhanced cancer cell proliferation and invasion via exosome-mediated MAPK signaling pathway, and exosomal miRNAs may be contributing to induction of the CD97-associated pathway (Li et al., 2015). A mutant epidermal growth factor receptor (EGFRVIII), exists on the membrane of these nanovesicles originated from glioblastoma cells, can trigger cells loss of this mutant form. The integration of EGFRVIII within these cells caused by promotion of anti-apoptotic procedures and an augment in capacity for anchorage-independent growth (Al-Nedawi et al., 2008). On the other hand, the exosomes originated from pancreatic cancer cells enhance Bax expression, however, reduce Bcl-2 expression, cause the leading to cancer cells of the mitochondrial apoptotic pathway (Ristorcelli et al., 2008). This process illustrated that TD exosomes might act pivotal anti-cancer role through triggering apoptosis in several tumors. Accordingly, the determined or beneficial TD exosomes in vivo to their own survival relies on the cellular traits and kinds of the cells, which more research needs to be clarified. Moreover, the bone marrow mesenchymal stromal cells (BM-MSCs)-derived exosomes can support the multiple tumor cell expansion and development in various human cancer cells (Fig. 2).

Role of exosomes in tumor metastasis

A major pathway in the metastatic cascade are tumor cell invasion and migration, missing the epithelial traits towards a more mesenchymal phenotype and the ability of the cell to attain a motile phenotype via changes in the cell to matrix interaction, disseminating tumor cells extravasate into remote sites and finally colonize secondary tissues and organs. There is an emerging report that shows tumor-derived exosomes are accomplished by tumor invasion and metastasis through regulating stromal cells, creating a pre-metastatic niche (Fig. 3), remodeling the extracellular matrix (ECM) and inducing angiogenesis (Alderton, 2012; Jung et al., 2009). Metastatic tumor cells dissemination enhanced level of miRNA by tumor-suppressor mechanism, that can indicate another procedure for the function of these nanovesicles in metastasis (Ostenfeld et al., 2014). The recent study illustrated that the exosomal proteins originated from tumor hypoxia of prostate cancer cells are associated with the process of adherens junctions in epithelial cells and cytoskeleton remodeling, including the enhanced metastasis and invasiveness in prostate cancer cells, is modulated through exosomes (Ramteke et al., 2015). Also, by recent investigate gastrointestinal stromal tumor cells (GISTs) secrete exosomes including protein tyrosine kinase to transform progenitor cell-derived smooth muscle cells to a premetastatic phenotype (Atay et al., 2014). Another report indicated that the Colorectal cancer cells with high invasive potential were detected to be significantly dependent on the concentration of exosomes including the signaling competent epidermal growth factor receptor (EGFR) ligand, inferring that exosome-mediated ligand shuttle causes cancer invasiveness and metastasis (Higginbotham et al., 2011). Exosome-modulated transferring of microRNA-221/222 from mesenchymal stem cells (MSCS) to gastric tumor cells significantly promotes migration and metastasis of these tumoral cells (Wang et al., 2014b).

Role of exosomes in tumor immune escape

The current researches represented that tumor-derived microvesicles may function as immunosuppressive effects. Exosome-mediated communication among cancer cells and the immune system is triggered recruiting pro-cancerogenic immune cells (Fig. 4). Also, tumor-derived exosomes are being utilized as an effective source of tumor antigen to induce dendritic cells (DCS), causing a shuttle of tumor antigens to DCs and including CD8+ T cell-related anti-tumor outcomes. The exosomal tumor-carried TGF-β1 deviated IL-2 modulates in favor of regulatory T cells and away from cytotoxic cells (Bu et al., 2011; Clayton et al., 2007). Also, tumor-derived exosomes can activate myeloid-derived suppressor cells (MDSC). The MDSCs by inhibiting the T cell reaction can apply immunosuppressive functions in cancer. tumor-derived microvesicles from several tumor cell lines modulate synthesis of interleukin-6 (IL-6) in MDSCs via the activation of Toll-like receptor 2 through the membrane-associated heat shock protein 72 (HSP 72). Making of IL-6 outcomes in an autocrine phosphorylation of stat3 in MDSCs can enhance their immunosuppressive function (Chalmin et al., 2010; Nagaraj & Gabrilovich, 2012). The miRNA shuttled via cancer cell-derived exosomes may function as ligands through attaching to the Toll-like receptors and activate the inflammation. Indeed, it was cleared that oncogenic miR-21 and miR-29a released from the exosomes derived from highly metastatic lung carcinoma cells can bind to the human and murine TLRs (Fabbri et al., 2012).

Role of exosomes in mediating Insensitivity to a drug in cancer

Exosomes via several mechanisms may play pivotal role in the progression of therapy resistance in cancer cells. Tumor-derived microvesicles can shuttle multi-drug resistance (MDR)-associated miRNAs and proteins to target cells. These illustrated that several major classes of anticancer drugs and their metabolites can be encapsulated and exported through exosomes outside of the cells, and shedding of these extracellular vesicles (EVs) is intimately associated with insensitivity to a drug (Fig. 5) in various human cancer cells (Corcoran et al., 2012; Safaei et al., 2005; Shedden et al., 2003; Wei et al., 2014). Recently, emerging evidence illustrated that miR-21 was shuttled from cancer-associated adipocytes of fibroblasts to the various tumor cells, where it can inhibit ovarian cancer apoptosis and induce the Paclitaxel resistance through binding to its new direct target, apoptotic protease activating factor-1 (APAF1) (Yeung et al., 2016). Besides, there is plenty of interest in insensitivity to a drug through exosome-mediated shuttle of miRNAs. Several studies suggested that breast cancer cells resistant to various drugs (Docetaxel-Adriamycin-Tamoxifen) may shuttle the resistance to sensitive cells in part via exosomal miRNA exchange (Chen et al., 2014). Moreover, PTEN is reduced in exosomes therefore applying biological acts in target cells. The loss of function of PTEN enhances resistance to sensitivity and chemotherapeutic of mTOR, which inhibits in breast cancer cells and, afterwards, PTEN exosomal shuttle, could be drew out as a shuttle mechanism or drug resistance changes (Steelman et al., 2008). Besides exosomes through regulating their binding to tumor cells may counteract the efficacy of antibody drugs. The exosomes-originated lymphoma carry CD20 can bind to the anti CD-20 antibody therapeutics and induce the preserving of target cells from antibody attack (Aung et al., 2011). Thus, the exosomes-derived cancer cells can be utilized as a procedure of cancer chemotherapy resistance of special cancer cells to characteristic drugs.

Use of exosomes as a cancer therapeutic

Emerging reports indicate that various clinical researches illustrated the role of exosomes as cancer remedies, and a few main adverse effects were identified for applying of these nanovesicles in cancer therapy. Figure 6 indicates the remedies that were proposed for therapy of cancers based on exosomes characteristics.

(1) Trough secretion of exosomes, tumoral cells trigger the alteration of the local and systemic tumor environment to induce tumor growth promotion, metastasis and insensitivity to drugs. Thus, either the destruction of exosome-dissemination pathway through tumor cells or the removal of these nanovesicles from the blood circulatory system may create an effective method for cancer therapy. The Tinzaparin (a low-molecular-weight heparin) can trigger tissue factor pathway inhibitor (TFPI) secretion from cancer cells, and also the recombinant TFPI induce suppression of tumor-derived exosomes causing migration of tumor cells (Gamperl et al., 2016). Lately for the elimination of extracellular vesicles (EVs) from the blood circulatory system, a therapeutic hemofiltration process which is called ADAPT™ (adaptive dialysis-like affinity platform technology) is applied. Whenever the patient’s blood plasma samples transfer via ADAPT™ system, plasma specimens factors by the porous fibers are interacted with the immobilized affinity agents to that target molecules are particularly absorbed while unbound serum factors and blood cells can pass through this system (Logozzi et al., 2009).

(2) As a delivery system, exosomes are considerably utilized as vehicles loaded with multiple anticancer drugs, siRNAs, and miRNAs for several cancer therapeutic cargos. The lipid bilayer membrane of these nanovesicles forms a natural protective shelter, thus enhances the cellular internalization of the encapsulated anti-cancer drugs. Regarding to the exosomes originated from autologous cancer cells, these nanovesicles can cause minimal toxicity when being shuttled into the target cells and can be less immunogenic than artificial delivery vehicles. Also their naturally small size can permit them to elude phagocytosis through the mononuclear phagocyte system (MPS) and simplify their extravasation via tumor blood vessels and their subsequent release in target cancer tissues. The various researches illustrated that prosperous delivery and tumor inhibition utilizing this procedure. The enhancement of colorectal and breast xenograft cancers in vivo by applying the Doxorubicin loaded into exosomes or using exosome-mimetic nanovesicles can be suppressed. Thus, the efficacy of Doxorubicin was widely promoted through targeting the immature dendritic cell exosomes into cancer tissues (Jang et al., 2013; Tian et al., 2014). Also the another greatly utilized antimitotic chemotherapeutic drug is Paclitaxel that can be loaded into microvesicles through sonication, and these loaded microvesicles have 50 times more cytotoxicity than free Paclitaxel for drug resistance tumor cells in vitro. Besides the exosome-encapsulated Paclitaxel can considerably block murine Lewis lung cancer pulmonary metastases and decline size of tumor in the mouse model (Kim et al., 2016).

(3) Exosomes can be utilized to target special tissues or organs because of the having special cell tropism according to their traits. Applying the well-characterized exosomal membrane protein (Lamp2b) for expressing the targeting peptide instantly below the signal peptide sequence including the targeting peptides RVG and iRGD were prosperously inserted within these nanovesicles from immature dendritic cells to target either brain or cancer tissues. This method considerably promoted the cellular uptake of the nanovesicles in the tissue of interest, and enhanced the specificity of the remedy, and also reduced the toxicity of drugs delivered through exosomes (Jang et al., 2013; Tian et al., 2014).

(4) In addition to anticancer therapeutic drugs, exosomes can likewise deliver several tumor antigens, nanobodies, apoptotic-containing proteins, proteasomes, deficient or mutant anti-apoptosis proteins, tumor and tissue-specific peptides, transferrins, and lactoferrins within tumor cells for targeting remedy (Aspe et al., 2014; Cho et al., 2005; Hall et al., 2016; Hung & Leonard, 2015; Kooijmans et al., 2016; Lai et al., 2012; Malhotra et al., 2016).

(5) Also, exosomes based cell-free vaccines could indicate an alternating to dendritic cells (DCs) treatment for inhibiting tumor development through the function of exosomes in the immune system. So researchers detected that the nanovesicles originated from peptide-pulsed DCs, can present antigens to T cells to affect their immune response. These DC-originated exosomes include MHC-peptide complexes and co-stimulatory molecules on their membrane, that permit them to continue antigen presentation and increase immunization in mice comparing with antigen-presenting DCs (Luketic et al., 2007).

(6) Moreover, miRNAs are widely detected in exosomes derived cancer cells or isolated from bodily fluids that contribute to exosome-mediated cell–cell communication, and induce anti-cancer traits. For instance EGFR-specific binding peptide GE11 can lead let-7a-containing exosomes to EGFR-positive cancer cells, that considerably suppressed EGFR-positive human breast tumor cell development in a heterograft mouse model (Ohno et al., 2013; Yu et al., 2015).

Functions and Remedial Roles of Exosomes in different kinds of Human Cancers

The tumor exosomes originated from the ascites of a very aggressive murine T-cell lymphoma (EVs A) can effect on dendritic cells activity, thus disturbing the immune system to distinguish and destroy cancer cells. Also, the expression of marker-proteins including ALIX, TSG-101, CD63, CD81, and CD9 has detected in EVs A. This research illustrated that EVs A triggered both humoral and cellular immune reactions. Altogether, the outcomes indicated that the endosome-originated EVs secreted via an advanced-stage T-cell lymphoma, stimulated a special immune reaction (Menay et al., 2017). Besides, exosomes released through chronic myelogenous leukemia (CML) cells remedied with Curcumin, which originated from the plant Curcuma longa, has the anticancer effects, include a wide quantity of miR-21 that is transported into the endothelial cells in a biologically active form. The treatment of HUVECs with CML Curcu-exosomes diminished RhoB expression and conversely modified endothelial cells motility. The research illustrated that the addition of CML control exosomes to HUVECs induced promotion of IL8 and VCAM1 levels, but Curcu-exosomes returned this efficacy, therefore, diminished their angiogenic properties. Overall, this research showed that besides Curcumin reduces the exosome’s capability to enhance the angiogenic phenotype and to modify the endothelial barrier organization (Taverna et al., 2016). As exosomes emerge as a novel manner of intercellular communication, the cargo includes through exosome is formed via somatic evolution. Regarding evaluating the effect of exosomes originated from several melanoma-related cell lines on primary CD8+ T cells act, exosomes from each of the cell lines were different. The B16F0 exosomes dose-associated inhibited T-cell proliferation. Notwithstanding, Cloudman S91 exosomes enhanced T-cell proliferation and Melan-A exosomes load an insufficient impact on primary CD8+ T cells. Importantly, B16F0 exosomes suppressed T-cell proliferation through high-expressed of PTPN11 to tumor permeating lymphocytes would escape the extracellular control of the immune checkpoints (Wu et al., 2015). Regarding increasing evidence, extracellular vesicles (EVs) are inherently trigger intercellular relation through shuttling molecular information between cells. Therefore, the autologous cancer-cell originated EVs can be utilized as helpful carries of Paclitaxel to the prostate cancer cells, bringing the drug into the cells via an endocytic process and released into the cell cytosol leading to cell death. Most considerably, the EV-mediated delivery promoted the cytotoxic efficacy of the drug. This research suggested that the autologous EVs may be helpful for impressive transporting of chemotherapeutic agents to prostate cancer cells (Saari et al., 2015). It is noteworthy that the effective role of exosomes in relevance among cancer cells and surrounding stroma indicated that the TrkB expression in exosomes is necessitated including aggressiveness phenotype. In this report, the YKL-40 silencing contributes for reducing of TrkB, sortilin and P75^NTR expression, related to a low aggressive phenotype. The release of TrkB in exosomes from normal glioma cells was able to relieve both migration and activation of YKL-40-inactivated cells. Furthermore, TrkB-containing exosomes may be remarked as a considerable biomarker for glioblastoma diagnosis (Pinet et al., 2016). Also, MVs originated from HLSC (MV-HLSC) can suppress the growth of hepatoma tumors through shuttling genetic information that mediates with deregulated survival and proliferation of these cells. The antitumor effect of MV-HLSC was relevant to the decreased internalization, due to the lack of CD29 on MV-fibroblast or a decreased expression of antitumor miRNAs including miR-24, miR-31, miR-122, miR-125b, miR-223, and miR-451. Consequently, the promoted internalization was not relevant to an increased biological activity when MV-fibroblast expressing CD-29 were utilized. Hence, the various composition of miRNA content between MV-HLSC and MV-fibroblast was the remarkable reason for the various biological actions. Therefore, the transferring of these miRNAs through MVs originated from stem cells may suppress tumor growth development and stimulate apoptosis (Fonsato et al., 2012). Another research illustrated that exosomes originated from curcumin-pretreated H1299 cells were utilized to remedy BEAS-2B cells, which triggered proliferation, colony organization, and migration of BEAS-2B cells. Curcumin is a new drug lung cancer remedy. Although, the procedure associated with the antitumor effect of curcumin is related to the promoted expression of TCF-21, triggered through a low expression of DNMT1. Therefore, mechanism of curcumin is remarkable in cancer remedy, and creates the pivotal biomarkers for developing cancer diagnostic and remedial procedures (Wu et al., 2016). The new research suggested that PSC (Pancreatic Stellate Cells) originated exosomes can trigger and elevate the proliferation and migration of PANC-1 and SUIT-2. The exosomes differentially varied expression of a plethora of genes controlling multiple cellular procedures containing cell cycle, cellular assembly and organization, DNA replication, recombinant and repair, cell death and survival, cellular development, and growth in the recipient cancer cells. Also, three chemokines, CCL20, CXCL1, and CXCL2 were detected high expressed in exosome-treated cancer cells. Besides, GPC1 (glypican-1), a glycoprotein discovered in PSC exosomes, as a pivotal biomarker to distinguish PDAC (Pancreatic Ductal Adenocarcinoma), and as a tumor promoter shuttled among cells through exosomes (Ali et al., 2015; Charrier et al., 2014; Farrow et al., 2003). The exosome/staphylococcal enterotoxin B is a considerable sample for apopto-immunotherapy. The contribution of Exo and its lipid rafts in this structure assigns the feasibility of binding to pancreatic cancer cells. SEB and the characterized lipid rafts trigger the apoptotic signal both through extrinsic and mitochondria-dependent pathways. Also, the presence of tumor antigens associated with superantigen causing promotion of specific antitumor immune response (Mahmoodzadeh et al., 2014). Even more recent research detected that gastric cancer cells may release exosomes for transferring apoptotic signals without direct cell–cell contact to anti-cancer T cells. The Cbl-b and Cbl-c of ubiquitin ligases might have a considerable role in exosome-induced apoptosis of Jurkat T cells through enhancing PI3K proteasome degradation, that can cause inactivation of PI3K/Akt signaling, therefore led to activation of caspase 3, 8, and 9. Thus, relation among exosomes and immune response is presumably to assign considerable point of view through the process of tumor immune inhibition (Qu et al., 2009). Recently study illustrated that miR-375 promoted the growth inhibitory effect, Cell progression and dissemination of colon cancer through the Bcl-2 pathway. Therefore the miR-375 down-regulated in metastatic CRC, and it has important role for Bcl-2 blocking, with the significant minimally invasive prognostic biomarker for CRC through suppression of malignant proliferation and dissemination (Zaharie et al., 2015). Further, research reported that a HIV-Nef SMR-originated peptide suppressed the progress of human breast tumor cells through arresting cancer cell cycle and including blockade of exosome secretion. The SMR peptide inhibited the cancer cell cycle through G2/M phase boundary. While the SMR peptide and chemotherapeutic drugs were compound to remedy cancer cells, PEG-SMRwt-Clu synergically enhanced the anti-proliferative efficacies of drugs, considerably promoted the tumor cell growth suppression efficacy of drugs and inhibited exosomes secretion in breast cancer cell lines MCF-7 and MDA-MB-231 cells. Therefore the considerable usage of PEG-SMRwt-Clu peptide is pivotal process for the prevention and therapy of human breast tumor cells (Huang et al., 2017).

Conclusions

Prosperity in remedy against intricate cancers relies on our full comprehension of the complications among various components within tumors. The above studies supported the viewpoint that exosomes can play a pivotal role in the growth, and promotion of cancer cells via regulation of intercellular communication into the tumor microenvironment through the release of several biological molecules ranging from virions of mRNA, miRNA, protein, lipid, and DNA cargos. An overview of the roles of exosomes in different types of cancer and the molecular mechanisms that have been used to evaluate the effect of EV in cancer progression and metastasis were presented in Table 1. The exploration of exosomes derived cancer cells contents may permit the progression of new diagnostic and remedial procedures, with minimally invasive approaches. Exosomes derived cancer cells also can cause cancer cell development and metastasis through suppressing the immune response and via enhancing chemoresistance by elimination of chemotherapeutic anti-cancer drugs. So they might be significant targets for remedial interventions through their alternation or elimination. The field of nanotechnology has widely benefitted exosome research to load nanovesicles with tiny molecules or drugs for cancer treatment because of their small size, lack of toxicity and target specificity toward prosperous immunotherapy in clinical trials. Besides exosomes can be considerable biomarkers for diagnosis of cancer and targeted remedy due to their nearly display the situation of their parental cells that are relatively constant in the blood circulation and could be feasibility obtained from body fluids. Most significantly the role of miRNA in the context of exosomes for targeting inactivation of cancer-causing miRNAs would probably provide a novel strategy for most cancers. It is expected that further research on these microvesicles will not only determine great potential and hopeful effect on their functions in the pathogenesis of cancer but also will open the new strategies for cancer diagnosis and remedies.