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. 2019 Jan 13;234(8):12422–12432. doi: 10.1002/jcp.28080

Tumor‐derived exosomes: Potential biomarkers and therapeutic target in the treatment of colorectal cancer

Sousan Mousavi 1,2,†, Roya Moallem 1, Seyed Mahdi Hassanian 2,†, Mahsa Sadeghzade 2, Ramin Mardani 2, Gordon A Ferns 3, Majid Khazaei 2,4,✉, Amir Avan 2,5,✉
PMCID: PMC13484144  PMID: 30637729

Abstract

Colorectal cancer (CRC) is the third most common cause of cancer‐related death in men and women in many countries. Early detection of CRC helps to prevent the advanced stages of the disease, and may thereby improve the survival of these patients. A noninvasive test with high specificity and sensitivity is required for this. Exosomes are lipid bilayer membrane nanovesicles that are released into most body fluids and especially in the microenvironment of cancer. They carry various proteins, lipids, and nucleic materials such as DNA, RNA, messenger RNA (mRNA), and microRNA (miRNA), and may also alter the function of target cells. In this review, we aimed to describe the biogenesis, composition, function, and the role of tumor‐derived exosomes in cancer progression. Moreover, their applications in tumor diagnosis and treatment are described, with a particular focus on CRC.

Keywords: biomarkers, colorectal cancer, diagnosis, exosomes

The early endosome is formed by endocytosis of phospholipid bilayer of the host cell's membrane. During the transformation of the early to late endosome, intraluminal vesicles are created by inward budding of endosome with the cytoplasm content such as genetic information and proteins. This endosome with multiple intraluminal vesicles is named the multivesicular body (MVB). Afterwards, the MVB fuses with the plasma membrane and releases intraluminal vesicles to the extracellular environment. These released vesicles are called exosomes. Alternatively, the MVB may bind to the lysosome for degradation. The target cell can uptake exosomes in various ways, including fusion with the plasma membrane, endocytosis, and binding to receptors on cell surface. The size of exosomes is 30–100 nm.

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1. INTRODUCTION

Colorectal cancer (CRC) is the third most common cause of cancer mortality in the USA (Siegel, DeSantis, & Jemal, 2014). Numerous risk factors have been linked to the pathogenesis of CRC (smoking, obesity, and red meat consumption; Edwards et al., 2010). It has been estimated that approximately 49,190 Americans will die from CRC in 2017 (Zhang et al., 2017). The liver is the most common organ for metastasis in patients with CRC (Tokarz & Blasiak, 2012; Wang et al., 2015). A UK study has shown that CRC metastasis, which is the main cause of death in patients with CRC, occurs in 24–28% of patients with CRC, and only 6–10% of patients remain at Dukes stage A (invasion into but not through the bowel wall; Hardcastle et al., 1996).The chances of diagnosing CRC in a lifetime is 4.7% in women and 5.0% in men (Siegel et al., 2014; Tokarz & Blasiak, 2012). The reason for the lower rates in women is unknown, but may be associated with exposure to the risk factors and sex hormones (Meissner, Breen, Klabunde, & Vernon, 2006; Murphy et al., 2011). Generally, rectal cancer is often diagnosed at a localized stage, and as a result has a slightly higher survival rate, compared with colon cancer (65.5% vs. 64.2%; Siegel et al., 2014). Screening for precancerous lesions and early‐stage cancer is the best option for preventing CRC and reducing its burden on both patients and society (Hardcastle et al., 1996; Siegel et al., 2014; Zhang et al., 2017). Current screening tests include fecal occult blood testing (FOBT), CT colonography, flexible sigmoidoscopy (FS), and colonoscopy. Zhang et al. in their meta‐analysis found that a disadvantage of these various CRC screening tests is that they diagnose distal rather than proximal colon cancer (Zhang et al., 2017). Moreover, recent studies have indicated that colonoscopy is the most invasive method for CRC screening (Chen, Läcke, Stock, Hoffmeister, & Brenner, 2017; Rank & Shaukat, 2017; Zhang et al., 2017).

The use of exosomes as a new noninvasive approach for to disease diagnose have attracted attention (Rashed et al., 2017; Lau et al., 2013; Li et al., 2009; Yu, Cao, Shen, & Feng, 2015). Exosomes are membrane‐derived vesicles of 30–100 nm diameter. They are released with various cell types, either normal or diseased, into extracellular fluids, that include blood, amniotic fluid, urine, breast milk, cerebrospinal fluid (CSF), saliva, lymph, and bile (Rashed et al., 2017; Yu et al., 2015). Over 30 years ago, exosomes were first described as extracellular vesicles, with a presumed function of removing cellular debris (Rashed et al., 2017). In the mid‐1990s, a potential immunological function of exosomes was discovered. Previous studies have established their function in cell–cell communication (by transferring protein and genetic information), immune response, and neuronal activity (Admyre et al., 2007; Gu et al., 2012; Simhadri et al., 2008). They also proposed to play roles in the pathogenesis of atherosclerosis, diabetes, thrombosis, and the development of some diseases such as cancer (Rak & Guha, 2012). Cancer cells secrete significantly more exosomes than normal cells (Rashed et al., 2017; Shao et al., 2016). These tumor‐derived exosomes (TDEs) can increase the transfer of small molecules including growth factors, chemokines, and RNAs (Shao et al., 2016). This might imply that they participate in the progression of cancer (Yu et al., 2015). Exosomes are vesicles with lipid bilayer membrane that enables them to carry and transfer molecules and genetic materials to distant sites. Therefore, they can potentially play a pivotal part in inducing metastasis (Shao et al., 2016).

2. EXOSOMES

Extracellular vesicles can be divided into three categories, depending on their size: Apoptotic bodies (1–5 µm), micro‐vesicles (100–1000 nm), and exosomes (30–100 nm; Rashed et al., 2017; Yu et al., 2015)

2.1. Formation, release, and uptake

Exosomes biogenesis begins with an inward budding of plasma membrane and production of early endosome (Hanson & Cashikar, 2012). During early to late endosome maturation, multivesicular bodies (MVBs) are produced. Later, MVBs can merge with plasma membrane where they will be released into the extracellular space (Boyiadzis & Whiteside, 2017; Escrevente et al., 2011; Théry, Zitvogel, & Amigorena, 2002).

Several proteins participate in the release of exosomes, but secretion mechanisms of these vesicles are different among various cells and they are not completely known. Some studies have suggested pH‐dependent and Ca‐dependent processes are involved in the release mechanisms (Parolini et al., 2009; Savina, Furlán, Vidal, & Colombo, 2003). In some cancer cells, exosome secretion is mediated by the Rab GTPase family of molecules, such as Rab11, Rab27a, and Rab31 which are membrane trafficking proteins (Bobrie, Colombo, Raposo, & Théry, 2011; Ostrowski et al., 2010; Savina, Vidal, & Colombo, 2002). The Rab family, especially Rab35, controls the secretion of exosomes by interacting with TBC1D10A‐c protein which activates GTPase (Hsu et al., 2010). Furthermore, the p53 activation greatly increases exosomes release (Yu, Harris, & Levine, 2006). This tumor suppressor activates pathway‐6 (TSAP6) which enhances the production of exosomes (Amzallag et al., 2004). Lespagnol et al. have also reported that the exosome production was greatly reduced in TSAP6‐null mice (Lespagnol et al., 2008).

Previous studies have shown that the uptake of exosomes could occur through endocytosis mediated by clathrin (Tian et al., 2014), lipid rafts (Svensson et al., 2013), and heparin sulfate proteoglycans (Christianson, Svensson, van Kuppevelt, Li, & Belting, 2013) and also phagocytosis (Feng et al., 2010). Besides endocytosis, exosomes could enter the cells by direct fusion with the plasma membrane (Parolini et al., 2009). Moreover, these extracellular vesicles have adhesion molecules (e.g., phosphatidylserine and lysophosphatidylcholine) on their surface which enables them to bind to cellular receptors (such as TIM4, TIM1, and LFA1) and may enter cells via this route (Pan, Teng, Wu, Adam, & Johnstone, 1985; Figure 1).

Figure 1.

Figure 1

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The early endosome is formed by endocytosis of phospholipid bilayer of the host cell's membrane. During the transformation of the early to late endosome, intraluminal vesicles are created by inward budding of endosome with the cytoplasm content such as genetic information and proteins. This endosome with multiple intraluminal vesicles is named the multivesicular body (MVB). Afterwards, the MVB fuses with the plasma membrane and releases intraluminal vesicles to the extracellular environment. These released vesicles are called exosomes. Alternatively, the MVB may bind to the lysosome for degradation. The target cell can uptake exosomes in various ways, including fusion with the plasma membrane, endocytosis, and binding to receptors on cell surface. The size of exosomes is 30–100 nm

2.2. Components

Whilst some component of the exosomes are dependent on their cellular origin, all of these extracellular vesicles contain particular proteins as their markers, such as CD9, CD63, and Rab GTPase family (Mathivanan, Fahner, Reid, & Simpson, 2011; Mincheva‐Nilsson & Baranov, 2010; Théry, Ostrowski, & Segura, 2009; Vlassov, Magdaleno, Setterquist, & Conrad, 2012). Lipids are the major constituent of exosomes. They carry cholesterol, phospholipids, and bioactive lipids including prostaglandins (PGs), leukotrienes to alter the function of target cells. For instance, exosomes with a high level of PGE2 may play a role in tumor growth (Record, Carayon, Poirot, & Silvente‐Poirot, 2014; Xiang et al., 2009). In addition to lipids and proteins, exosomes also contain genetic material that can be transferred to recipient cells after their fusion of exosomes with these cells. Hence, they can participate in signaling pathways and protein expression. For example, they can inhibit the function of tumor suppressors or stop tumor invasion (Ohshima et al., 2010; Ostenfeld et al., 2014; Valadi et al., 2007). Moreover, exosomes could carry the genetic material of prions or viruses, such as Epstein‐Barr virus (EBV) and hepatitis C virus (HCV). These exosomes might play an important role in the transmission of infection (Ahmed, Philip, Tariq, & Khan, 2014; Ramakrishnaiah et al., 2013; Vazirabadi, Geiger, Coffin, & Martin, 2003).

2.3. Isolation

Whereas body fluids of a patient with malignancy contain TDEs, non‐TDEs are also present. To further investigate TDE, they are first isolated from plasma and then separated from other exosomes (Taylor & Shah, 2015). Ultracentrifugation (UC) is the most common method to separate exosomes, but this procedure is difficult and time consuming (Caradec et al., 2014; Théry, Amigorena, Raposo, & Clayton, 2006). The use of specific antibodies can be used to capture exosomes based on their specific markers (Logozzi et al., 2009).

2.4. Functions

Exosomes were initially known as “cellular garbage removers,” disposing of undesirable product and harmful molecules such as drugs (Johnstone, 1992; Morelli et al., 2004; Pan et al., 1985). Other physiological and pathological roles of exosomes have now been discovered (Admyre et al., 2007). Since exosomes are derived from the cell membrane, they probably have multiple receptors and adhesion molecules which enables them to transfer information, allowing intercellular communication (King, Michael, & Gleadle, 2012).

2.4.1. Physiological roles of exosomes

Exosomes play a part in the preservation of physiological conditions (Lai, Chen, & Lim, 2011). They are released by donor cells to the extracellular space and facilitate the communication between cells (Cadigan, 2002; Lakkaraju & Rodriguez‐Boulan, 2008). Stem cells release exosomes that may participate in tissue regeneration and cell phenotype modulation. For instance, hepatic stem cells could raise hepatocyte regeneration by producing and releasing particular exosomes (Camussi et al., 2011; Herrera et al., 2010; Ratajczak et al., 2012). Recent studies show that exosomes play a pivotal role in wound healing. Injured epithelial cells boost the generation and release of TGFβ1 containing exosomes which provoke the fibroblast differentiation to establish tissue regeneration and consequently fibrosis (Borges et al., 2012).

2.4.2. Pathologic roles of exosomes

Tumor cells exchange information with other cells by secreting chemokines, growth factors, and other small mediators such as TDEs, which have been playing a notable role in tumor biology (Majka, 2001; Ponsaerts & Berneman, 2006). Some studies have shown that TDEs play an important role in the progression and spread of cancer cells by modifying the function of stromal cells and suppressing antitumor immune cells (Corrado et al., 2014; McCready, Sims, Chan, & Jay, 2010; Valadi et al., 2007; Whiteside, 2016). In addition, they may be transferred to specific distant areas to establish suitable microenvironments and premetastatic niches (Hood, San, & Wickline, 2011; Jung et al., 2009). Several studies have shown that cells of some specific cancers, such as melanoma release exosomes that are capable of promoting angiogenesis and vessel density. Therefore, cancer cells can adapt to a hypoxic environment (Hegmans et al., 2004; Hood et al., 2011; Park et al., 2010).

2.5. Exosomes and CRC diagnosis

Cancer cells secrete specific molecules that participate in tumor progression and metastasis by using a large number of autocrine, paracrine, and endocrine mechanisms (Scheel et al., 2011). Accumulation of these molecules leads to leakage into the circulation in breast and several other cancers (Goel, Tovar‐Camargo, & Toden, 2016; Mar‐Aguilar, Rodríguez‐Padilla, & Reséndez‐Pérez, 2014). Thus, detecting such molecules in blood samples is a feasible method for cancer diagnosis (Goel et al., 2016). For instance, carcinoembryonic antigen (CEA) is a protein‐based marker for CRC diagnosis, but unfortunately, it is not detectable in the early stages of CRC (Gold & Freedman, 1965; 1965; Moertel et al., 1993). Epithelial cell adhesion molecule (EpCAM) is another CRC marker. It is a glycosyl‐phosphatidylinositol (GPI) on the epithelial cell surface to mediate epithelium‐specific intercellular adhesion. EpCAM is elevated in patients with colon cancer, but this can be due to a higher level in other epithelial cancers. Therefore, it has low specificity for CRC diagnosis (Patriarca, Macchi, Marschner, & Mellstedt, 2012).

DNA and RNA‐based markers are other options. Although fecal‐based microRNA (miRNA) tests are cost‐effective and simple methods for CRC diagnosis, miRNAs are not resistant to RNase digestion. On the other hand, exosomal miRNAs are covered with exosome membranes and they are not exposed to RNase (Koga et al., 2011). Furthermore, they are easily detected and secreted at higher levels by tumor cells compared with normal cells (Goel et al., 2016). Besides, they are stable at room temperature for several weeks (Ge et al., 2014). Furthermore, cancer organ or cellular origin can be identified by detecting antigens that are presented on TDEs’ surface membrane (Mathivanan et al., 2010). Interestingly, protein markers of these exosomes can be used to anticipate future organ metastasis (Tominaga et al., 2015). New studies of TDEs have indicated that CEA and EpCAM, are both are highly expressed on the surface of CRC‐derived exosomes (Dai et al., 2005; Tauro et al., 2013). Previous investigations have reported some protein markers of CRC‐derived exosomes such as vaccinia virus (VACV) antigen A33, CEA, epidermal growth factor receptor (EGFR), mitogen‐activated protein kinase 4 (MAPK4), EpCAM, proliferating cell nuclear antigen (PCNA), and keratin 18 (Mathivanan et al., 2010). Furthermore, there are two types of exosomes which carry CD26, CD63, and major histocompatibility complex class molecule II (MHC II). They interact with dendritic cells, and this results in an increased immune surveillance at the mucosal surface (Heath et al., 1997; Mallegol et al., 2007).

miRNAs play important parts in physiological processes but they are dysregulated in tumors. Therefore, detecting exosomes containing such miRNAs may be alternate way for cancer diagnosis (Hansen, Carlsen, Heegaard, Sørensen, & Jakobsen, 2015). One of these miRNAs for CRC detection is serum‐miR‐21. It is highly expressed in CRC‐derived exosomes and it can be a possible marker for early‐stage diagnosis (Tanaka et al., 2013; Toiyama et al., 2013). Although the miR‐21 expression is elevated in patients with CRC in a stage‐dependent way, it is not specific for this cancer, since its level is raised in other cancers such as hepatocellular (Meng et al., 2007), esophageal (Hu et al., 2011), ovarian (Iorio et al., 2007), cervical (Lui, Pourmand, Patterson, & Fire, 2007), and breast cancer (Iorio et al., 2005). In 2014, Ogata‐Kawata et al. identified 16 miRNAs of CRC‐derived exosomes that can be used as biomarkers, which are as follows: miR‐1915, miR‐1308, miR‐1290, miR‐1268, miR‐1246, miR‐1229, miR‐1224, miR‐638, miR‐483‐5p, miR‐223, miR‐181d, miR‐181b, miR‐150, miR‐23a, miR‐21, and let‐7a (Ogata‐Kawata et al., 2014). Among these circulating miRNA‐based markers, miR‐1246 and miR‐23a had the greatest sensitivities (95% and 92%, respectively), and this suggests that they may be used as possible markers for CRC diagnosis. Another study has shown that miR‐17–92, a miRNA in CRC‐derived exosomes, can be used as a biomarker for the recurrence of CRC (Matsumura et al., 2015). Furthermore, an association between CRC metastasis and miR‐21, miR‐221, and miR‐192 has been reported. These miRNAs have been isolated from three types of CRC cells (HCT‐15, WiDr, and SW480) which use CD81 as a marker of their exosomes (Chiba, Kimura, & Asari, 2012). Plasma miR‐221 concentrations have been found to correlate with p53 expression is a biomarker for patients with CRC with poor outcome (Pu et al., 2010). Besides these miRNAs, miR141, and miR‐29a are other valuable prognostic factors. Plasma miR‐141 has a positive association with Stage IV CRC (Cheng et al., 2011). Another study showed that the level of miR‐29a was higher in patients with CRC with liver metastasis than other CRC patients (Wang & Gu, 2012). Moreover, the level of miR‐143 is downregulated in patients with CRC, though it is increased in CRC KRAS‐wild‐type patients. Thus, this miRNA could be a useful biomarker to detect these specific patients with CRC (Pichler et al., 2012). Senfter et al. studied drug‐resistant cells in vitro and recognized these cells release less tumor‐suppressive miR‐200 than the same normal cells and it has been revealed that cells which secrete exosomes with low expression of miR‐200 family members invade the lymphatic and blood system more than other cancer cells (Senfter et al., 2015; Figure 2). Another study investigated the level of circulating mRNA126 in patients with metastatic CRC, who were treated with first‐line chemotherapy plus bevacizumab. The results showed that there was a relationship between the changes of circulating mRNA126 level during treatment and response to chemotherapy + bevacizumab. Actually, an increase in the level of circulating mRNA126 was found to be associated with a lack of treatment benefit, whereas the reduction in the level of circulating mRNA126 correlated with response to treatment. Therefore, circulating mRNA126 is a possible biomarker to predict response to this treatment (Hansen et al., 2015).

Figure 2.

Figure 2

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CRC‐derived exosome composition. Exosomes comprise lipid bilayer membrane nanovesicles (30–100 nm) that contain different molecules, including lipids (such as cholesterol), proteins (e.g., signaling proteins and enzymes), and nucleic acids (such as miRNA, mRNA, and DNA). CRC‐derived exosomes contain different miRNAs in which their elevated level can be a possible marker for diagnosis, e.g., miR‐21 for early stage of CRC, miR‐17–92 for CRC recurrence, miR‐21, miR‐221, and miR192 for CRC metastasis and poor prognosis, miR‐141 for Stage IV CRC, miR‐29a for CRC metastasis to liver, and miR‐143 for CRC KRAS‐wild‐type. Besides these markers, low level of miR‐200 can imply more invasion to lymphatic and blood system. CRC‐derived exosomes have various molecules on their surface, including epithelial cell adhesion molecule (EpCAM), carcinoembryonic antigen (CEA), transmembrane proteins, Tetraspanins, membrane trafficking proteins, and also tissue‐specific proteins like major histocompatibility complex (MHC) that are on some types of CRC‐derived exosomes. CRC, colorectal cancer; miRNA, microRNA; mRNA, messenger RNA

Single nucleotide polymorphisms (SNPs) are other molecular biomarkers which are associated with miRNAs. SNPs in primary miRNAs (pri‐miRNA) and precursor miRNAs (pre‐miRNA) can alter the processing and maturation of miRNA and consequently change the level of miRNAs expression. Xing et al. demonstrated that SNPs in pre‐miR‐608 (rs4919510) and pre‐miR‐423 (rs6505162) lead to pre‐miRNAs polymorphisms and these variant genotypes are notably associated with CRC prognosis, especially in patients who are receiving chemotherapy (Xing et al., 2011). Besides these SNPs, the presence of this molecule in a lethal‐7 miRNA complementary site (LCS6) in KRAS 3′‐untranslated region (3′‐UTR) is prognostic in patients with early‐stage CRC. Moreover, there are better outcomes for KRAS‐mutated patients with CRC who have the KRAS‐LCS6 variant (Smits et al., 2011).

2.6. Exosomes as a potential therapeutic option

Besides exosomes diagnostic purposes, they also have properties that make them a potential option for new therapeutic approaches for the treatment of cancer. According to previous studies, tumor cells secrete exosomes more than normal cells (Goel et al., 2016). Thus, modifying the high level of circulating exosomes to normal level could be a feasible therapeutic method. Based on this view, several investigations have been planned to regulate TDEs release by targeting their formation, secretion, or interaction with recipient cells (Raposo & Stoorvogel, 2013).

Tetraspanins are transmembrane proteins with four domains which participate in many physiological processes of cells (Charrin, Jouannet, Boucheix, & Rubinstein, 2014). A recent study showed that tetraspanin 8 (TSPAN8) expression in pancreatic adenocarcinoma cells of rats might regulate the protein composition and mRNA content of the exosomes derived from these tumor cells (Nazarenko et al., 2010). Apart from this, Ras homolog family member A or ADP‐ribosylation factor 6 may control exosomes formation by provoking some particular signaling pathways (Li, Antonyak, Zhang, & Cerione, 2012; Muralidharan‐Chari et al., 2009). Targeting these pathways leads to inhibition of TDEs formation.

Rab27a, Rab27b, and several their effector proteins such as small GTPases play important roles in exosomes secretion (Hendrix & De Wever, 2013; Ostrowski et al., 2010). Bobrie et al. observed that suppressing Rab27a caused prevention of TDEs‐dependent/independent mechanisms which alter tumor microenvironment and probably reduce cancer development and its metastasis (Bobrie et al., 2012). Other proteins of the Rab family, including Rab35 and Rab11, prevent the fusion of TDEs to the plasma membrane and consequently decrease exosomes secretion (Del Conde, Shrimpton, Thiagarajan, & López, 2005; Savina, Fader, Damiani, & Colombo, 2005). In addition, Alonso et al. demonstrated that downregulation of diacylglycerol kinase alpha (DGKA) might lead to a reduced release of exosomes which contain Fas‐ligand (Alonso et al., 2011). Further research showed the increase of dimethyl amiloride (a voltage‐gated calcium channel inhibitor) leads to a reduction in exosomes release (Chalmin et al., 2010; Savina et al., 2003). Microenvironmental pH can also participate in the release of exosomes. Hence, modifying proton pump inhibitors is another possible choice (Federici et al., 2014). Normal cells release exosomes to affect many physiological processes, inhibition of exosomes secretion might result in complications and toxicity. Therefore, using this method clinically as a tumor therapeutic strategy is a possibility, but requires further study (Rashed et al., 2017).

A further possibility for cancer treatment is inhibition of exosomes uptake. Cells use various endocytic pathways, including clathrin‐dependent or independent endocytosis to take up exosomes (Feng et al., 2010; Fitzner et al., 2011; Tian et al., 2014). There is evidence that proteins on the surface of exosomes might play pivotal roles in exosomes uptake (Escrevente et al., 2011). Phosphatidylserine on the surface of TDEs is one of these molecules to mediate uptake of exosomes. Diannexin, an annexin A5 homodimer, can bind to this mediator with high affinity and reduce uptake (Lima, Chammas, Monteiro, Moreira, & Barcinski, 2009; Rand et al., 2012). An important uptake pathway is heparan sulfate proteoglycan receptors. Blocking them by heparin notably decreased TDEs‐mediated stimulation of tumor cell migration (Christianson et al., 2013). Plus, heparin interferes in the fusion of exosomes with recipient cells and consequently prevents transferring of oncogenic EGFRvIII mRNA (Atai et al., 2013). Another possible choice is deactivating Dynamin2 that is an essential protein for caveolin‐ and clathrin‐dependent endocytosis (Feng et al., 2010).

2.6.1. Exosomes removal

Taking out TDEs from circulation has been suggested as a tumor therapeutic adjuvant. The biotechnology company Aethlon Medical Inc. (San Diego, CA) has developed a plasmapheresis platform with an affinity for specific exosomes to reduce circulatory HER2‐containing exosomes. This strategy prevented the progression of HER2‐positive breast cancer (Marleau, Chen, Joyce, & Tullis, 2012).

2.6.2. Exosome as cancer immunotherapy

Exosomes that are derived from antigen‐presenting cells (APCs) carry tumor antigen complexes that loaded major histocompatibility complex (MHC) molecules. These exosomes present MHCs to dendritic cells that mediate T‐cell activation and T‐cell dependent immune responses against cancer cells. Accordingly, these exosomes are a possible option for cancer therapy as cell‐free anticancer vaccines (Zitvogel et al., 1998). Since APC‐derived exosomes are dependent to MHC, they have to match with MHC haplotype. Therefore, these exosomes need to be tailored for each patient (Cho, Lee, Kim, Ko, & Kim, 2009). On the other hand, TDEs do not require MHC haplotypes matching. Thus, it is possible to create effective cell‐free antitumor vaccines that are not essential to be fabricated for each person individually. Moreover, these exosomes carry tumor antigens which are not specific to one cancer, hence these shared antigens might lead to cross protection against various tumors (Wolfers et al., 2001). Human mucin I (hMUCI), a large glycoprotein, is a tumor antigen that is associated with rapid cancer progression and poor prognosis. Exosomes can be loaded by this molecule and act as antitumor vaccines for cancers which express hMUCI (Cho et al., 2005). Cell hyperthermia result in an increased production of Hsp70 in cells and their concentration in exosomes. This protein provokes dendritic cells and monocytes and also increases TDEs‐stimulated immune response (Cho et al., 2009). Furthermore, Hsp70 can activate natural killer cells (NKCs) to release Granzyme B which leads to NKC‐mediated apoptosis of cancer cells (Kahlert & Kalluri, 2013). Apart from TDEs, in several investigations, ascites‐derived exosomes appeared as a beneficial strategy for cancer therapy (Andre et al., 2002). When CRC cells metastasize to the peritoneal cavity, they might cause malignant ascites. This kind of CRC patients always has a poor prognosis (Ayantunde & Parsons, 2007). Dai et al. showed that ascites‐derived exosomes from CRC patients in combination with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) were more beneficial than ascites‐derived exosomes alone to induce CEA‐specific anticancer immunity in these patients and consequently improve the clinical outcomes. Furthermore, they revealed that ascites‐derived exosome was a safe, tolerable, and feasible approach for CRC therapy (Dai et al., 2008).

2.6.3. Exosome as drug delivery vehicle

Exosomes have some properties, such as several adhesion molecules on their surface‐that enable them to be promising drug delivery vectors (Vickers & Remaley, 2012). These small lipid‐soluble vectors with their flexibility can easily cross biological barriers, including blood–brain barrier (Alvarez‐Erviti et al., 2011). In recent years, nanotechnique drug delivery system such as liposomes have been established, but unfortunately, all of them have toxic properties, and therefore the immune system immediately clears the drugs (Peng et al., 2013). On the other hand, exosomes are secreted membrane vesicles with homing capacity that makes them be potent drug delivery nanovehicles with minimized toxicity (Lai, Yeo, Tan, & Lim, 2013). In our bodies naturally, exosomes are used to carry and deliver proteins and genetic information such as mRNAs, noncoding RNAs, miRNAs, and mitochondrial DNAs (Kahlert et al., 2014; Thakur et al., 2014). Thus, they can be encapsulated by therapeutic particles, including interfering RNAs like miRNAs (Munoz et al., 2013; Ohno et al., 2013), small interfering RNA (siRNAs; Andaloussi, Lakhal, Mäger, & Wood, 2013; Wahlgren et al., 2012), and short hairpin RNA (shRNAs; Pan et al., 2012), anti‐inflammatory agents such as curcumin (Sun et al., 2010; Zhuang et al., 2011), and antitumor agents like doxorubicin (Tian et al., 2014) and paclitaxel (Yang et al., 2015). Importantly, using exosomes to deliver doxorubicin may enhance its efficacy compared with other delivery systems and also caused lower toxicity (Tian et al., 2014).

ADAM‐17 is a peptidase protein that belongs to a disintegrin and metalloprotease (ADAM) family. This transmembrane enzyme manages the ligand shedding of epidermal growth factor receptor (EGFR) and therefore regulates its activity (Blanchot‐Jossic et al., 2005). ADAM‐17 overexpression boosts the EGFR activation, that probably plays an important role in the development and dissemination of tumor. Multidrug‐resistant (MDR) CRC cells raise the activity of ADAM‐17. In these patients, miRNA‐222, which targets ADAM‐17 and reduces its activity, is downregulated. Thus, transfection of miRNA‐222 elevates its level and subsequently modulates ADAM‐17 expression (Xu et al., 2012).

2.6.4. M‐trap

In 2015, de la Fuente et al. suggested a new interesting exosome‐based therapeutic strategy for cancers. They fabricated a capture device called M‐trap (metastatic trap) by embedding exosomes in a 3D scaffold. Afterwards, these M‐traps are implanted into the peritoneum of ovarian cancer mice. Actually, M‐trap is a preferential spot for metastatic cells that competes with the intact peritoneum and totally remodels the peritoneal metastatic pattern. They also demonstrated that M‐traps significantly increase survival in a murine model (de la Fuente et al., 2015).

3. CONCLUSION

Taken together the information gathered from several studies suggested that TDEs play important roles in cancer progression. These exosomes contain parental cancer cells composition including DNAs, mRNAs, miRNAs, and proteins. Detecting these molecules will be a blood‐based noninvasive approach for cancer diagnosis (Hoshino et al., 2015). Tumor cells produce more exosomes than normal cells, which have high stability in blood. In previous years, miRNAs have been known as potential biomarkers but it measuring their levels had been difficult. Quantifying exosomal miRNAs can make this a promising noninvasive approach. Apart from diagnostic purposes, exosomes may be used in cancer treatment. They play pivotal roles in tumor development, therefore reducing exosomes is a possible way to treat cancer. They can also be encapsulated by therapeutic particles. In conclusion, this would be a fruitful area for further work. So far, we might have just seen the tip of the iceberg, that most of it is under water and unknown. Thus, much more studies should be investigated to reveal the unknown information about the application of exosomes in cancer diagnosis and treatment.

FUNDING

This study was supported by a grant awarded to Dr Amir Avan by National Institute for Medical Research Development, NIMAD, grant no. NIMAD 962782

CONFLICTS OF INTEREST

The authors have no conflicts of interest to disclose.

Contributor Information

Majid Khazaei, Email: khazaeim@mums.ac.ir.

Amir Avan, Email: avana@mums.ac.ir.

References

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