Suwen Bai
Zunyun Wang
Minghua Wang
Junai Li
Yuan Wei
Ruihuan Xu
Juan Du- 1Longgang District People´s Hospital of Shenzhen, The Second Affiliated Hospital of The Chinese University of Hong Kong, Shenzhen, China
- 2School of Basic Medical Sciences, Anhui Medical University, Hefei, China
Tumor-derived exosomes (TDEs) are actively produced and released by tumor cells and carry messages from tumor cells to healthy cells or abnormal cells, and they participate in tumor metastasis. In this review, we explore the underlying mechanism of action of TDEs in tumor metastasis. TDEs transport tumor-derived proteins and non-coding RNA to tumor cells and promote migration. Transport to normal cells, such as vascular endothelial cells and immune cells, promotes angiogenesis, inhibits immune cell activation, and improves chances of tumor implantation. Thus, TDEs contribute to tumor metastasis. We summarize the function of TDEs and their components in tumor metastasis and illuminate shortcomings for advancing research on TDEs in tumor metastasis.
Background
Exosomes are extracellular vesicles, approximately 30–150 nm in diameter, that contain functional biomolecules, such as proteins, RNA, DNA, and lipids, and can interact with recipient cells (Balaj et al., 2011; Choi et al., 2013; Peinado et al., 2011; Raposo and Stoorvogel, 2013; Skog et al., 2008; Thakur et al., 2014; Thery et al., 2009; Valadi et al., 2007). Exosomes are present in various body fluids and are regarded as a key component of intercellular communication. Tumor cell-, stromal cell-, or even normal cell–derived exosomes play an important role in tumor progression and can induce angiogenesis and accelerate metastasis (Hood et al., 2011; Luga et al., 2012; Peinado et al., 2012). The components and functions of the exosomes depend on the cell types; some studies have shown many differences in the contents and release rate in different types of cells. But, the complete mechanism and process have not yet been elucidated and need to be further explored. Metastasis is the leading cause of tumor-induced death and is a complex process involving local invasion, survival, and evasion from immunosurveillance, invasion into circulation, and extravasation at secondary organs (Fidler and Kripke, 2015; Wan et al., 2013). Tumor-derived exosomes (TDEs) are a significant component of the tumor microenvironment and are involved in promoting tumor metastasis through several mechanisms, including acquiring primary tumor migration capacity, tumor angiogenesis, escaping immune system organotropic metastasis, forming the pre-metastatic niche, and metastatic tumor growth in the secondary site.
In this review, we summarize the function of exosomes in every aspect of cancer metastasis (Figure 1) to provide a better systematic comprehension of the role of exosomes in tumor metastasis and propose practical implications of early diagnosis, treatment, and prognostic methods for cancer.
FIGURE 1. Function of TDEs in tumor metastasis. TDEs are mainly involved in tumor metastasis through five aspects. Step 1: acquisition of tumor migration ability; Step 2: angiogenesis; Step 3: immunosuppression; Step 4: localization of metastatic sites; and Step 5: enhancement of proliferation ability of tumor cells after migration.
Tumor-Derived Exosomes Enhance the Migration Ability of Tumor Cells
Tumor-Derived Exosomes Promote Epithelial–Mesenchymal Transition to Initiate Metastasis
Epithelial–mesenchymal transition (EMT) frequently initiates the metastatic process (Li et al., 2021). Epithelial tumor cells acquire mesenchymal characteristics under the influence of cancer-associated fibroblasts (CAFs) in the tumor stroma (Diepenbruck and Christofori, 2016). Epithelial markers, including E-cadherin, zona occludens 1 (ZO-1), cytokeratins, desmoplakin, and laminin, are downregulated, and mesenchymal markers, including N-cadherin, β-catenin, and vimentin, are upregulated (Sommers et al., 1994; Li Y. et al., 2019). During EMT, tumor cells lose their apical–basal polarity, basement anchoring, and cell–cell junctions and switch to a low proliferation state with enhanced migratory and invasion capabilities (Basil et al., 2020). Once the tumor cells reach a distant pre-metastatic niche, the reversed process takes place (Maren, 2016). This so-called mesenchymal–epithelial transition (MET) returns tumor cells to a high proliferative state and enables the formation of micrometastases (Bakir et al., 2019). TDEs play an important regulatory role in mediating the EMT and MET transformation (Bigagli et al., 2019). There has been increasing research showing the signaling pathway involved in inducing cancer-related EMT. We propose that the critical components in TDEs can serve to promote EMT.
The latest hypothesis is TDEs may be conduits for initiating signals for EMT. For example, TDEs carry EMT derivers, such as transforming growth factor-beta (TGF-β), tumor necrosis factor-alpha (TNF-α), hypoxia-inducible factor 1 alpha (HIF-1α), protein kinase B (AKT), caveolin-1, platelet-derived growth factors (PDGFs), and β-catenin Wnt pathway modulators, that directly enhance the process of EMT (Aga et al., 2014; Kucharzewska et al., 2013; Luga et al., 2012; Ramteke et al., 2015). TDEs transmit non-coding RNA, such as, miR-128-3p, miR-27, LINC00960, linc02470, circ-PVT1, and circ-CPA4, that upregulate EMT (Huang C.-S. et al., 2020; Liu et al., 2019; Wang J. et al., 2018). Therefore, many studies have shown that tumor cells can secrete exosomes into the extracellular space and promote the EMT through their effectors: proteins, miRNAs, circRNAs, and lncRNAs (Figure 2A).
FIGURE 2. TDEs enhance the migration ability of tumor cells by promoting EMT and degrading the ECM. (A): Exosomes carry proteins, miRNA, lncRNA, and circRNA to promote the occurrence and development of EMT. (B): TDEs carry proteins or non-coding RNA to initiate degradation of the ECM.
Tumor-Derived Exosomes Promote Extracellular Matrix Degradation
The extracellular matrix (ECM) is a scaffold for tissues and organs (Eble and Niland, 2019). The ECM is a complex network combined with proteins, proteoglycans, and glycoproteins that can regulate cell growth, survival, motility, and differentiation through specific receptors, such as integrin, syndecan, and discoidin receptors (Leitinger, 2011; Xian et al., 2010). Cancer-associated ECM is not only an integral feature of a tumor but also actively contributes to its histopathology and malignant behavior (Levental et al., 2009; Provenzano et al., 2008). From tumor initiation to metastasis, ECM molecules bind with cell surface receptors and activate intracellular signaling pathways. ECM adhesion–induced signals promote self-sufficient growth through mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) (Pylayeva et al., 2009). Focal adhesion kinase (FAK) signaling inhibits p15 and p21, which are growth suppressors, and p53 to limit the induction of apoptosis (Kim et al., 2008). TGF-β and RhoA/Rac signaling promote EMT induction and enhance promigratory pathways (Leight et al., 2012). The ECM can also enhance angiogenesis and strengthen vascular endothelial growth factor (VEGF) signaling in endothelial cells (Liu and Agarwal, 2010).
TDEs mediate tumor–tumor and tumor–host cell crosstalk (Kalluri, 2016). TDEs interact with and regulate the synthesis of ECM components and are involved in ECM remodeling (Rackov et al., 2018). The proteins on the surface of TDEs promote the activation of membrane-associated proteinases, such as Adamts1, Adamts4, and Adamts5, thus improving proteolytic activity (Ginestra et al., 1997; Lo Cicero et al., 2012). In addition, matrix metalloproteinases (MMPs) derived from TDEs participate in localized degradation and ECM proteolysis during cellular migration and metastasis (Ginestra et al., 1997; Atay et al., 2014). However, besides exosomal surface proteins, non-coding RNA also mediates ECM degradation. For example, breast cancer–derived exosomes carry miR-301 to regulate matrix modulation (Morad et al., 2020). Gastric cancer cell–derived exosomal miR-27a reshapes the ECM at adjacent sites and promotes tumor progression by downregulating CSRP2 expression and upregulating α-SMA expression (Wang et al., 2018). Currently, there are no direct reports on other non-coding RNAs, such as lncRNA and cicrRNA, but TDE-derived lncRNA and circRNA can influence fibroblast, chondrocyte, and epithelial cell function, secreting ECM components into the extracellular space (Tan et al., 2020).
Some data suggested that the ECM is a prerequisite for tumor cell invasion and metastasis (Tan et al., 2020). When the tumor cells metastasize, they detach from the ECM. Furthermore, the exosomes participate in this process (Figure 2B).
Tumor-Derived Exosomes Promote Angiogenesis Directly or Indirectly
Regardless of tumor size, metastasis may occur; however, in most cases, metastasis is associated with large primary neoplasms (Fidler and Kripke, 2015). If a tumor mass exceeds 1 mm in diameter, angiogenesis is bound to occur (Folkman, 1971; Nagy and Dvorak, 2012). Therefore, exploring tumor angiogenesis is an important way to understand tumor metastasis.
Tumor-Derived Exosomes Promote Angiogenesis by Activating Macrophages
Cancer-derived exosomes stimulate macrophage infiltration and polarization for establishing a pre-metastatic niche. For example, exosomes derived from CT-26, a colon cancer cell, can provoke macrophages to secrete significantly high levels of monocyte chemoattractant protein-1 (MCP-1) and TNF, thus promoting the growth and migration of colorectal cancer cells. Lung cancer cell–derived exosomes containing miRNA-103 upregulate angiogenic VEGF-A and angiopoietin-1 expression from M2 macrophages (Hsu et al., 2018; Wu et al., 2019). Therefore, TDEs can motivate the angiogenic property of macrophages such as secretion of VEGF (Wu et al., 2019). It can induce angiogenesis by tumor cells. In addition, other immune cells also contribute to tumor angiogenesis, such as neutrophils, myeloid precursor cells (MPCs), and dendritic cells (DCs) (Albini et al., 2018). But, there are no reports about TDE-educated neutrophils, MPCs, or DCs to promote angiogenesis in metastasis.
Tumor-Derived Exosomes Carry Non-coding RNA and Proteins to Promote Angiogenesis Directly
TDEs carry non-coding RNAs, including microRNA, lncRNA, and circRNA, that play an indispensable role in angiogenesis. TDEs carry miR-25-3p that regulates VEGFR2, ZO-1, occludin, and claudin5 expression in ECs by targeting KLF2 and KLF4 and eventually promotes vascular permeability and angiogenesis (Felcht et al., 2012; Wu et al., 2019). TDEs deliver miR-130a to vascular cells to promote angiogenesis by targeting c-MYB (Yang et al., 2018). Exosomal miR-155-5p can induce angiogenesis through the SOCS1/JAK2/STAT3 signaling pathway (Zhou X. et al., 2018). Exosomal miR-135b promotes angiogenesis by inhibiting FOXO1 expression. Exosomal miR-23a induces angiogenesis by targeting TSGA10, prolyl hydroxylase, tight junction protein ZO-1, and SIRT1 (Sruthi et al., 2018; Bai et al., 2019). Exosomal miR-1229 promotes angiogenesis by targeting HIPK2. Exosomal miR-21 promotes angiogenesis by targeting STAT3 (Liu and Cao et al., 2016). In addition, lncRNA containing lncCCAT2, lncMALAT1, lncRNA-p21, and lncPOU3F3 or circRNA, such as TDE-derived circRNA-100338, also promote angiogenesis (Castellano et al., 2020; Huang X.-Y. et al., 2020; Lang, Hu, & Chen et al., 2017; Lang, Hu, &; Zhang Z. et al., 2017; Qiu J.-J. et al., 2018). LncRNA and circRNA are often used as “sponges” to regulate miRNA expression in cells. Moreover, TDEs carry a variety of angiogenic proteins, such as VEGF, IGFBP3, MMP2, ICAM-1, and IL-8, thus enhancing angiogenesis through in vitro and in vivo ligand/receptor signaling (Ludwig and Whiteside, 2018). Therefore, a combination of multiple non-coding RNAs and exosomal proteins promotes tumor angiogenesis.
The importance of angiogenesis in tumor metastasis cannot be understated, TDEs can carry proteins and non-coding RNAs that directly promote angiogenesis or they can mediate angiogenesis indirectly by “educating” macrophages to release proangiogenic factors (Figure 3).
FIGURE 3. Exosomes directly or indirectly promote angiogenesis. TDEs promote macrophages to release TNF and VEGF to promote angiogenesis factors by carrying miRNAs or proteins. In addition, TDEs carry proteins, miRNAs, lncRNA, or circRNA to promote angiogenesis directly by targeting endothelial cells.
Tumor-Derived Exosomes can Protect Tumor Cells During Metastasis
Tumor cells shed from primary or secondary tumors are called circulating tumor cells (CTCs) (Paoletti and Hayes, 2016). CTCs invade the bloodstream and attach to the endothelium in the target organ. They then invade the surrounding parenchyma to form new tumors (Garcia et al., 2018). Blood is an unfavorable environment for CTCs, and they struggle with circulating immune cells (Agarwal et al., 2018). TDEs help CTCs metastasize smoothly by inhibiting immune cell activity and conferring a protective layer on them, thus maintaining cellular integrity (Figure 4).
FIGURE 4. Role of TDEs in protecting CTCs. TDEs from CTCs and activated platelets suppress NK cell, T cell, and B cell function. In addition, activated platelets can form thrombi that adhere to the surface to protect CTCs.
Tumor-Derived Exosomes can Suppress Immune Cells to Protect CTCs
The immune system inhibits the progression of cancer cells. Many immune cells are found circulating in human blood, including T lymphocytes, natural killer (NK) cells, and B lymphocytes (de la Cruz-Merino et al., 2008; Grivennikov et al., 2010; McCarthy, 2001). These immune cells play crucial roles in immune surveillance, immunosuppression, and killing effects and mainly act on CTCs (Deepak and Acharya, 2010; Pahl and Cerwenka, 2017; Wernersson and Pejler, 2014; Ye et al., 2017). Immune cells can recognize and attack CTCs under normal circumstances; therefore, immunosuppression is necessary for the metastasis of CTCs (Guo et al., 2019). Many researchers have found that TDEs can suppress immune cells. Exosomes carry bioactive molecules that can impair immune cell function (Becker et al., 2016; Kalluri, 2016; Robbins and Morelli, 2014). Programmed cell death receptor ligand 1 (PD-L1) can bind to programmed cell death protein 1 (PD-1) to inactivate T cells through its extracellular domain (L. Chen and Han, 2015; Chen et al., 2015; Garcia-Diaz et al., 2019). TDEs carry PD-L1 on their surface and suppress CD8+ T cell function in metastatic melanoma (Chen et al., 2018). In addition to PD-1, TDEs can also carry others to inhibit T cell function, and prolyl hydroxylase can inhibit CD4+ and CD8+ T cell functions by oxygen sensing (Clever et al., 2016). TDEs block T cell activation and enhance T cell apoptosis (Czernek and Dutchler, 2017; Ludwig et al., 2017). TDEs can also cause NK cell dysfunction. NK cells do not express PD-1; however, TDEs interfere with the TGFβ/TGFβRI/II pathway and other common molecular pathways, such as the adenosine pathway, eventually driving NK cell responses (Hong et al., 2017). In addition, TDEs can inhibit NK cell cytotoxicity by suppressing STAT5 activation (Zhang et al., 2007). B cells play a critical role in immunoglobulin, antigen, and proinflammatory cytokine secretion (Mauri and Bosma, 2012). TDE HMGB1 regulates the proliferation of T cell Ig and mucin domain-1+ (TIM-1+) B cells and fosters cancer cell immune evasion (Ye et al., 2018). We can design therapeutic modalities to enhance immune cell surveillance and killing of these tumors by understanding these signaling pathways.
CTCs Activate Platelets Directly or by Releasing Exosomes
Platelets play major roles in hemostasis and coagulation and regulate the efficiency of canceration, tumor angiogenesis, tumor metastasis, and chemotherapy (Sharma et al., 2014). Platelets and cancer cells interact, thus affecting tumor growth and metastasis (Sharma P. et al., 2018). During blood circulation, other nontumor help is essential, for example, platelets can protect CTCs from blood flow shear forces by providing a protective layer. CTCs release soluble mediators, such as adenosine diphosphate (ADP), thromboxane (TX) A2, or high-mobility group box 1 (HMGB1), that can ligate toll-like receptor 4 (TLR4) to instigate localized platelet activation and form thrombus encasing tumor cells, thus protecting them from cytolysis by NK cells (Aitokallio-Tallberg et al., 1985; Nieswandt et al., 1999; Yu et al., 2014; Zucchella et al., 1989).
The interaction between platelets and CTCs can lead to platelet activation, and platelets release cytokines conducive to the survival and proliferation of tumor cells. When platelets combine with circulating tumor cells, platelet-derived soluble factors (TGF β and PDGF) mediate and prevent NK cells from detecting and dissolving tumor cells (Lambert et al., 2017; Lee J.-K. et al., 2013).
Finally, platelets prevent tumor cells from being eliminated by the immune system. Platelet-derived TGF-β can downregulate NKG2D expression and inactivate NK cells (Y. Chen et al., 2015; Kopp et al., 2009). The platelet expression profile in tumor and nontumor patients varies substantially (Santarpia et al., 2018). The interaction between CTCs and platelets can protect CTCs from immune surveillance during circulation and help tumor cells adhere to the endothelial cells at the metastasis site (Santarpia et al., 2018). Kuznetsov et al. showed that luminal breast cancer cells carried platelets that loaded factors with the effect of pro-inflammatory and pro-angiogenic activities and confirmed that these factors were released at distant tumors sites (Kuznetsov et al., 2012). Platelets are essential for releasing proangiogenic cytokines and recruiting angiogenic vascular endothelial growth factor receptor 2+ (VEGFR2+) cells that promote malignant progression (Schlesinger, 2018). Moreover, studies have shown that platelets may not just have a secondary role but may also drive malignant progression (or metastasis) (Kuo et al., 2011).
In human blood, platelets are considered to be the major contributors of exosomes (Caby et al., 2005). Goetzl et al. showed that endothelial cells absorb platelet-derived exosomes and enhance their adhesion by increasing endothelial cell adhesion protein expression and anti-adhesion factor production, thereby promoting CTC adhesion in vascular endothelial cells (Goetzl et al., 2016). Platelet-derived exosomes also increase platelet adhesion to monocytes and consequently monocyte activation, thus promoting the formation of inflammatory phenotypes (Goetzl et al., 2016).
Therefore, many researchers believe that blood platelets may be a potential source of biomarkers to aid cancer diagnosis. Nonetheless, the mechanism using which CTC-educated platelets mediate CTCs to avoid damage in the circulatory system still needs further research. We firmly believe that these CTC-educated platelet-derived exosomes play an important role in preventing damage to CTCs.
Integrins of Tumor-Derived Exosomes Determine Organotropic Metastasis
That different types of cancer cells preferentially colonize and metastasize to different organs is the salient feature of metastasis (Nguyen et al., 2009). Current research shows that tumors mainly metastasize to lung, brain, lymph node, bone, and liver tissues. We have summarized organotropic metastasis with respect to cancer types (Table 1). Many studies focus on tumor cell adhesion function, and extracellular matrix molecules, such as integrins, have been determined to be related to the choice of organotropic metastasis (Valastyan and Weinberg, 2011).
TABLE 1. Chart for organotropic metastasis with respect to cancer types.
Integrins, a large family of adhesion molecules, can mediate cell–cell and cell–extracellular matrix interactions (Desgrosellier and Cheresh, 2010). Many integrins are associated with tumor angiogenesis, such as αvβ3, αvβ5, and α5β1 (Cascone et al., 2005; Lee et al., 2013a; Huang and Rofstad, 2018). β1 integrins bind to vascular cell adhesion molecule 1 (VCAM-1) on ECs and play an important role in trans-endothelial migration (Klemke et al., 2007). Integrins participate in tumor angiogenesis by interacting with the VEGF–VEGFR and ANG–TIE pathways (Klemke et al., 2007). αvβ3 integrin binds to the adhesion molecule L1 on ECs driving trans-endothelial migration (Voura et al., 2001). αvβ3 integrin is the most abundant and influential receptor among integrins on ECs and can regulate angiogenesis (De et al., 2005; Mahabeleshwar et al., 2008; Shattil and Ginsberg, 1997). It can be activated and colocalized with VEGFR-2 on ECs of proliferating blood vessels (Mahabeleshwar et al., 2008). VEGF-stimulated c-Src can be the phosphorylate β3 subunit on ECs, promoting VEGFR-2 phosphorylation and activation (De et al., 2005; Mahabeleshwar et al., 2008; Mahabeleshwar et al., 2007). In addition, αvβ3 is necessary for the survival and maturation of new blood vessels, and proliferative angiogenic EC apoptosis occurs after treatment with αvβ3 antagonists (Brooks et al., 1994). Briefly, integrin subunits α1, α2, α3, α4, α5, α6, α9, αv, β1, β3, and β5 are involved in physiological or pathological angiogenesis. Exosomes affect several steps of angiogenesis including motility, cytokine production, cell adhesion, and cell signaling (Taverna et al., 2012). These can improve the tumor survival environment before metastasis.
Although integrins are secreted by tumor cells, it is transported by exosomes to a distant organ (Peinado et al., 2017). Lyden et al. showed that tumor exosome integrins can determine organotropic metastasis. They suggested that tumor exosome integrins can fuse with organ-specific resident cells and activate Src phosphorylation and proinflammatory S100 expression to establish a pre-metastatic niche (Hoshino et al., 2015). In addition, more bodies of evidence identified that different integrins on the surface of exosomes play varied roles in metastasis to specific organs (Alderton, 2015; Hoshino et al., 2015; Paolillo and Schinelli, 2017). For instance, exosomal integrins α6β4 and α6β1 preferentially direct tumor cells to the lungs, and αvβ5 induces liver metastasis (Hoshino et al., 2015). Tumor exosomes can prepare pre-metastatic niches to facilitate organ-specific metastasis, even for cancer cells equipped to metastasize (Figure 5).
FIGURE 5. Choice of metastatic organs. The integrin on the surface of the exosome determines where the tumor metastasizes.
Tumor Cell Growth at the Metastasis Site
Once tumor cells migrate to tissues and organs, TDEs provide them with a good growth environment and the ability to promote their growth.
Tumor-Derived Exosomes Promote Pre-metastatic Niche Formation
A pre-metastasis niche is a primary tumor in secondary organs and tissues that creates a favorable microenvironment for subsequent metastasis. Tumor-derived molecules secreted by primary tumors play a key role in preparing distant sites for the formation of new pre-metastasis niches, promoting metastasis and even determining the orientation of metastatic organs. These major tumor-derived molecules are usually tumor-derived secretory factors, extracellular vesicles (EVs), and other molecular components (Minciacchi et al., 2015). Exosomes containing protein, mRNA, or DNA fragments promote the pre-metastasis niche formation by mediating the communication between tumor cells and surrounding components or transferring their contents to recipient cells (Chin and Wang, 2016; Zhou et al., 2014).
Tumor cells are “seeds”. With tumor-secreting factors, tumor cell–secreting vesicles, and exosomes acting as catalysts, tumor cells can promote the formation of the “soil” (host microenvironment) in a distant metastasis site and promote the growth of cancer cells. Cancer metastasis is preceded by the interaction between the seed and soil (Y. Chen et al., 2015; Lambert et al., 2017; Liu and Cao, 2016; Minciacchi et al., 2015). Primary tumor cells influence and change the microenvironment at secondary organs by promoting pre-metastasis niche factor before tumor cells arrive (Chin and Wang, 2016; He et al., 2017).
The characteristics of a pre-metastasis niche include the following six aspects. First, pre-metastasis niche formation is accompanied by the recruitment of bone marrow–derived cells (BMDC) (Y. Chen et al., 2015; Minciacchi et al., 2015). Literature suggests that extracellular matrix metalloproteinase inducer (EMMPRIN) in cancer cells can induce the secretion and expression of many factors, such as SDF and VEGF, which mediate the recruitment of BMDC to the liver and lungs (Y. Chen et al., 2015; Minciacchi et al., 2015). Second, the immune cells involved in the pre-transfer niche formation are heterogenous. Pre-metastasis niche formation involves not only the recruitment of foreign cells but also the reprogramming of resident stromal cells, promoting metastasis. Pre-metastasis niche formation also involves the change of the ECM. Niche formation before transfer is accompanied by a change in the vascular system. Metastatic breast cancer cells reduce tight junctions between endothelial cells by secreting exosomes containing mir-105, thus inducing systemic vascular leakage and promoting metastasis (Kong et al., 2019). Breast cancer cells secrete exosomes containing miR-122, which are absorbed by niche cells, and reduce glucose consumption by targeting pyruvate kinase, thus increasing the proliferation rate and survival rate of cancer cells and promoting metastasis (Fong et al., 2015). Pancreatic cancer–derived exosomes, rich in macrophage migration inhibitory factors, recruit macrophages and induce pre-metastasis niche formation in the liver (Costa-Silva et al., 2015). Modulation of the pre-metastatic niche formation by controlling TDEs is a new area for future chemotherapy research.
Tumor-Derived Exosomes Promote the Growth of Metastasis Tumor
The growth of metastatic tumors requires suitable “soil”. MET returns the cancer cells to a highly proliferative state but with the loss of their migration characteristics, enabling tumor growth at the metastasis site (Li K. et al., 2019). The characteristics of MET are increased expression of mesenchymal markers, such as vimentin, and decreased expression of epithelial markers, such as E-cadherin, compared with that of EMT (Wells et al., 2008). MET supports the reacquisition of epithelial features to promote metastasis (Brabletz et al., 2001). Several signaling pathways are involved in regulating MET, including transforming growth factor (TGF), fibroblast growth factors (FGFs), bone morphogenic protein (BMP), epidermal growth factor receptor (EGFR), hepatocyte growth factor (HGF), Wnt/β-catenin, and Notch pathways (Said and Williams, 2011). TDEs can support tumor progression and remodel surrounding parenchymal tissues at the metastatic site (Greening et al., 2015). TDEs play an important regulatory role mediating EMT and transforming MET (Bigagli et al., 2019). Gastric cancer cell–derived exosomes can mediate the stimulation of proinflammatory cytokine IL-1β secretion and activate the Akt and MAPK pathways to promote tumor growth at the metastatic site (Che et al., 2018; Wang et al., 2019e). In addition, TDEs can transform stromal cells into tumor-associated stromal cells (TASCs) that can secrete many pro-tumorigenic factors, including IL-6 and IL-8. These factors can enhance the proliferation ability of tumor cells (Bussard et al., 2016). Hence, TDEs can enable tumor cells to acquire proliferation capacity directly through the MET process or promote tumor proliferation by inducing TASC formation and releasing related factors (Figure 6). Nevertheless, there is still a dearth of research on exosomes and their contribution to MET.
FIGURE 6. TDEs promote tumor growth at the metastasis site. MET and TASCs promote tumor growth at metastatic sites, and TDEs can derive MET and TASC formation.
Conclusion
Exosomes play an important role in every step leading to tumor metastasis. Although there are many reports on the role of exosomes in metastasis, much is left to be explored of the potential mechanisms underlying metastasis. Although a few studies still have unclear results, we have summarized the published literature on the substances that exosomes carry, their main functions in different tumors, the target cells affected, and steps involved in metastasis. (Table 2). Exploring these underlying mechanisms will enlighten us about cancer biology and contribute to the prevention of and therapeutic strategies for malignancies. We can manipulate TDEs to impede not just metastasis formation but even established metastases.
TABLE 2. Role and target of the components of TDEs in tumor metastasis.
Author Contributions
SB and ZW developed the first draft of the manuscript. All authors contributed to the planning, organization, data collection, and writing of the manuscript. JD completed all figures and provided critical edits. The final version of the manuscript was approved by all authors.
Funding
The study was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81972539 and U1732157).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
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Keywords: tumor-derived exosomes, metastasis, pre-metastatic niche, angiogenesis, immunosuppression
Citation: Bai S, Wang Z, Wang M, Li J, Wei Y, Xu R and Du J (2022) Tumor-Derived Exosomes Modulate Primary Site Tumor Metastasis. Front. Cell Dev. Biol. 10:752818. doi: 10.3389/fcell.2022.752818
Received: 03 August 2021; Accepted: 10 February 2022;
Published: 02 March 2022.
Edited by:
Peti Thuwajit, Mahidol University, ThailandReviewed by:
Nabanita Chatterjee, The Ohio State University, United StatesPaola Massimi, International Centre for Genetic Engineering and Biotechnology, Italy
Copyright © 2022 Bai, Wang, Wang, Li, Wei, Xu and Du. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Juan Du, ZHVqdWFuQGN1aGsuZWR1LmNu
†These authors have contributed equally to this work and share first authorship