Contributed equally
The journey of cancer cells from a primary tumor to distant sites is a multi-step process that involves cellular reprogramming, the breaking or breaching of physical barriers and the preparation of a pre-metastatic niche for colonization. The loss of adhesion between cells, cytoskeletal remodeling, the reduction in size and change in cell shape, the destruction of the extracellular matrix, and the modification of the tumor microenvironment facilitate migration and invasion into surrounding tissues. The promotion of vascular leakiness enables intra- and extravasation, while angiogenesis and immune suppression help metastasizing cells become established in the new site. Tumor-derived exosomes have long been known to harbor microRNAs (miRNAs or miRs) that help prepare secondary sites for metastasis; however, their roles in the early and intermediate steps of the metastatic cascade are only beginning to be characterized. The present review article presents a summary and discussion of the miRNAs that form part of colorectal cancer (CRC)-derived exosomal cargoes and which play distinct roles in epithelial to mesenchymal plasticity and metastatic organotropism. First, an overview of epithelial-to-mesenchymal transition (EMT), metastatic organotropism, as well as exosome biogenesis, cargo sorting and uptake by recipient cells is presented. Lastly, the potential of these exosomal miRNAs as prognostic biomarkers for metastatic CRC, and the blocking of these as a possible therapeutic intervention is discussed.
Colorectal cancer (CRC) remains the third most commonly diagnosed type of cancer globally, only following breast and lung cancer. In addition, it is now the second most common cause of cancer-related mortality following lung cancer (
The journey of metastatic cells from the primary tumor to distant sites of metastases is an arduous one and requires the breaking and breaching of barriers before a new site is colonized. Up until the last decade, a number of the mechanisms that contribute to metastatic dissemination remained obscure. The epithelial-to-mesenchymal (EMT) program is now considered key to understanding invasion and metastasis and explains the physical and ultrastructural changes cells have to undergo to break away from the primary tumor and migrate towards a new metastatic niche. More importantly, it is now recognized that a tumor has to modify its microenvironment for it to thrive and colonize distant sites (
The discovery of exosomes as purveyors of metastatic spread helped explain the incompletely understood concept of metastatic organotropism and the preparation of a pre-metastatic niche (
In the present review, key processes contributing to metastatic spread, including EMT, organotropism and the preparation of the pre-metastatic niche are discussed. Furthermore, a discussion of exosome biogenesis and cargo sorting is included to link the initial steps of the metastatic cascade with those of colonization of distant sites. Lastly, the role of exosomal miRNAs identified from CRC tumor and stromal cells in the metastatic continuum is discussed along with insight on the mechanisms through which they ensure the survival of metastasizing tumors.
EMT is a biological process wherein adherent epithelial cells convert to a migratory mesenchymal phenotype. Epithelial cells are characterized by cell-cell and cell-matrix connections that allow them to function as barriers by forming organized interconnected sheets of cells. These intercellular adhesions prevent movement and establish apical, lateral and basal membrane domains, with cellular components displaying apico-basal polarity. On the other hand, mesenchymal cells lack intercellular junctions and therefore have no clear apical and lateral membranes, no apico-basal polarized distribution of cell components, and are essentially loose motile cells that are capable of invasion (
While EMT is required for key developmental processes, such as embryogenesis and organ formation (type 1 EMT), as well as wound healing and tissue regeneration (type 2 EMT), it is also known to play a role in tumor dissemination and metastasis in epithelium-derived carcinomas (type 3 EMT) (
The term 'transition' in EMT refers to its transient and reversible nature, with the converse process termed mesenchymal-to-epithelial transition (MET). The plasticity of epithelial cells allows them to transition into mesenchymal cells then back to an epithelial phenotype, either fully at either end of the spectrum or only partially, wherein they express both mesenchymal and epithelial characteristics (
Epithelial cells are initially attached to their neighboring cells through cell-cell adhesion complexes mediated by E-cadherin (
The disintegration of cell-cell junctions is also accompanied by the disruption of cell polarity complexes, consequently resulting in epithelial cells losing their apical-basal polarity and acquiring a front-rear polarity (
Cells reorganize their cytoskeletal architecture to enable migration. Peripheral F-actin fibers are replaced by stress fibers, and extracellular matrix (ECM) adhesion molecules such as integrins, paxillin, and focal adhesion kinase localize at the tips (
Once mesenchymal cells reach the metastatic site, they may undergo EMT reversal or MET. Cells revert to an epithelial state, resulting in secondary tumors that resemble the histopathological phenotype of the primary tumor (
EMT is driven by a marked change in transcriptional programming. The modulation of gene expression during EMT involves several signal transduction pathways and transcription factors that reprogram the cell towards a mesenchymal phenotype. The changes in gene expression are responsible for phenotypic manifestations, such as the loss of adhesion and polarity, and an increase in migration and invasiveness.
Several transcription factors that control EMT are dysregulated or aberrantly expressed in CRC. These include SNAI1/SNAI2 (Snail and Slug), ZEB1/ZEB2 (
Multiple signal transduction pathways have been implicated as modulators of the EMT transcriptional program. Transforming growth factor β (TGF-β) is one of the key inducers of EMT in CRC, as well as other types of cancer. Mothers against decapentaplegic homolog (SMAD) family member 4 (SMAD4) is a pro-epithelial factor whose loss leads to heightened EMT through aberrant signal transducer and activator of transcription 3 (STAT3) activation and increased signaling via the TGF-β/bone morphogenetic protein (BMP) pathways (
The Wnt/β-catenin pathway is another crucial driver of EMT in CRC. The canonical Wnt pathway leads to SNAIL upregulation and SLUG stabilization. Consequently, Wnt3a expression is associated with mesenchymal markers in clinical samples, and Wnt inhibition can partially reverse EMT expression. In addition, the non-canonical Wnt pathway has also been implicated in metastatic CRC (
Transcriptional reprogramming during EMT drives the characteristic switch towards mesenchymal marker expression. The common markers of EMT are typically proteins involved in the architecture of cell junctions and the cytoskeleton, controlling cell morphology and interactions with neighboring cells, as well as the extracellular environment, key physical features that are altered in EMT. Thus, the EMT transcriptional program capacitates the cancer cell for metastatic spread by altering the expression of key structural proteins to facilitate pro-metastatic characteristics such as loss of adhesion, cytoskeletal remodeling, migration and invasion.
One hallmark of EMT is the cadherin switch from E-cadherin to N-cadherin. The epithelial marker, E-cadherin, is a cell-surface protein that mediates cell-cell adhesion, and also binds β-catenin at its cytoplasmic domain. The downregulation of E-cadherin results in the loss of adhesion, an important phenotype for cells progressing towards metastasis, and also frees β-catenin for activation of its signaling cascade. On the other hand, N-cadherin, which is upregulated in mesenchymal cells, facilitates dynamic adhesion contacts crucial for migration, and confers an affinity for other N-cadherin-expressing mesenchymal cells. Thus, the E-to-N-cadherin switch results in the loss of adhesion and increased migration (
Claudins and occludins are crucial cell-cell adhesion proteins found in tight junctions, and are subsequently downregulated in EMT to dissolve epithelial apical-basal polarity (
As regards cytoskeletal proteins, EMT is marked by the downregulation of cytokeratin and the upregulation of vimentin, which are both components of intermediate filaments (IFs). The altered composition of IFs facilitates differential trafficking of organelles and proteins, as well as enhanced cellular motility (
Similar to normal stem cells, CSCs also have the capacity for self-renewal and differentiation, and can initiate new tumors, such as in seeding metastatic lesions, or in cancer recurrence following therapy. CSCs are distinguishable by specific expression marker profiles, and can apparently arise from the acquisition of oncogenic alterations in normal stem cells, or from the dedifferentiation of differentiated cancer cells (
EMT has also been implicated in the emergence and maintenance of CSCs. Cancer cells that have undergone EMT often exhibit a CSC phenotype, and conversely, CSCs often express EMT markers, signifying a mesenchymal shift. The close association between EMT and CSCs underscores the important role of both in the overall process of metastatic spread. TGF-β/Smad signaling is a key link, as it modulates both EMT and stemness phenotypes (
A summary of the overall process of EMT in the context of metastasis is illustrated in
Tumors are known to have a predisposition to metastasize to specific organs. This phenomenon, however, remained poorly understood for almost a century. The intrinsic properties of cancer cells, including genes and pathways implicated in the colonization of new metastatic niches, were invoked and constituted the predominant explanation for the phenomenon known as metastatic organotropism (
While events that render the pre-metastatic niche favorable for dissemination and the growth of tumor cells upon arrival were being characterized, among these being angiogenesis and immunosuppression (
Exosomes are spherical membrane-enclosed nanovesicles secreted by all types of living cells into the extracellular milieu, notably in abundance by tumor cells. They have been detected in a range of biological fluids, including blood, urine, saliva, breast milk and pleural effusions (
Exosomes can be differentiated from other extracellular vesicles based on their mode of biogenesis: microvesicles (100 to 1,000 nm) originate from the cell surface and are formed through the direct outward budding of the plasma membrane (
The formation of intraluminal vesicles occurs via multiple mechanisms. The most well-described pathway is dependent on the endosomal sorting complex required for transport (ESCRT) budding machinery, where ESCRT-0 recognizes and forms domains of ubiquitylated proteins, which are later confined when the endosomal membrane is deformed by the ESCRT-I and ESCRT-II complexes. ESCRT-III then cleaves the bud neck to form intraluminal vesicles (
The major cargo residing within exosomes are proteins, lipids, RNA and a minimal amount of DNA. The contents of exosomes are highly heterogeneous, depending on the tissue, cell type and physiological or pathological context. Notably, exosome profiles do not fully reflect that of parent cells, signifying a selective mechanism for sorting cellular genetic material into exosomes (
Deep sequencing has revealed a variety of exosomal RNA cargo, including mRNAs, miRNAs, long non-coding RNAs (lncRNAs), ribosomal RNAs, transfer RNAs, piwi-interacting RNAs, small nuclear RNAs, small nucleolar RNAs and even circular RNAs, each present at varying levels of abundance (
Apart from cell state, exosome secretion is influenced by several factors, such as cellular stress, heat, ischemia, pH, the loss of cellular attachment and the accumulation of intracellular calcium (
Exosome internalization by recipient cells highlights the critical role of exosomes in cell-to-cell crosstalk, with the unique advantage of targeting specific locations compared to cytokines and hormones in the systemic circulation. Exosomes can transfer genetic information to neighboring or distant cells through three principal mechanisms: i) Direct fusion of the exosomal lipid membrane with the cellular membrane of recipient cells, releasing the exosome cargo into the cytosol (
Exosomes were once considered to serve only as a means of cellular waste disposal when they were first described for removal of plasma membrane proteins during reticulocyte maturation (
In the context of cancer, cumulative evidence suggests that exosomes can promote tumorigenesis through the horizontal transfer of oncogenic material to recipient cells. Likewise, cancer cells can utilize exosomes to discard tumor-suppressive genetic material not beneficial for tumor growth so as to increase their own oncogenicity (
Exosomes can also promote tumor resistance by encapsulating drugs and their metabolites into exosomes for export, as a drug efflux mechanism (
Various miRNAs can inhibit EMT progression by directly targeting components of the EMT regulatory pathways. CRC exosomes may be enriched with oncogenic miRNAs that downregulate EMT inhibitors. Alternatively, tumor suppressive miRNAs that downregulate inducers of EMT may themselves be downregulated or disposed of in CRC exosomes. Exosomal cargo can both originate from and be delivered to either tumor cells or cells in the tumor microenvironment, enhancing the capacity for metastasis by both driving EMT in tumor cells and influencing the properties of the microenvironment. Moreover, miRNAs carried by serum exosomes can be delivered to sites distant from the originating tumor, further extending metastatic potential. The promotion of EMT by altered regulation of exosomal miRNAs results in expression of characteristic mesenchymal markers and enhanced phenotypic features of pro-metastatic cells.
CAFs are essential components of the TME, with roles in matrix deposition and remodeling (
The exosomal cargo of CAFs in CRC may also include the lncRNA H19. H19 can attenuate the inhibitory effects of miR-141 and can then activate the Wnt/β-catenin pathway to promote stemness (
In patients with metastatic CRC, serum exosomal miR-106b-3p has been found to be upregulated and correlated with metastatic progression (
Exosomal miR-106b-3p from highly metastatic CRC cells also has profound effects on cell adhesion. They are released to less metastatic CRC cells and are then able to upregulate N-cadherin and downregulate E-cadherin protein expression. This is also achieved via the downregulation of DLC-1, effectively promoting metastasis
Exosomal miR-1246 in CRC, on the other hand, has been linked to the degradation of the ECM. Gain-of-function mutations in the p53 gene found in CRC cells have been shown to increase miR-1246 levels in exosomes, which are in turn able to reprogram macrophages into TAMs, the major component of tumor-infiltrating immune cells (
Tumor-derived exosomal miRNAs may promote EMT reversal or MET by suppressing effectors, inducers, transcription factors, and other players involved in EMT. An increased expression of miR-200c and miR-141 in exosomes is indicative of MET in CRC cells. In a previous study, upon treatment with the drug decitabine, SW480 (primary CRC) cells did not exhibit any significant differences, while the metastatic cell lines SW620 (derived from lymph node metastasis) and SW620/OxR (derived from lymph node metastasis with acquired resistance to oxaliplatin) exhibited decreased migration and invasion properties. This was accompanied by the upregulation of E-cadherin and exosomal miR-200c and miR-141, which together suggest the acquisition of epithelial characteristics through the reversal of EMT (
CRC-derived exosomal miR-200c, miR-141 and miR-429 can also inhibit EMT by directly targeting the ZEB family in endothelial cells. In a previous study, in 3D spheroid models, co-culture with naïve CRC cells did not demonstrate disruption of lymphatic (exomiR-200c) (
Another tumor suppressor exosomal miRNA is miR-1255b-5p, which has been found to be an EMT inhibitory miRNA downregulated in serum exosomes of CRC patients (
CSC and EMT plasticity can also be modulated by miRNA action, involving the deregulation of key tumor suppressor miRNAs, such as miR-200c, miR-203 and miR-183 repressed by TGF-β/Zeb1 (
As exosomes are considered to play a role in CSC homeostasis (
The downregulation of tumor suppressive exosomal miRNAs, as well as disposal via cargo sorting are also resorted to by CRC cells to promote invasion and metastasis. The tumor suppressive miR-149 and miR-96-5p are both downregulated in exosomes of CRC cells, while expression levels of glypican-1 (GPC1), its direct
The tumor suppressive miR-486-5p is downregulated in CRC tissues, in part because of promoter hypermethylation. miR-486-5p is a negative regulator of pleiomorphic adenoma gene-like 2 (PLAGL2), a transcription factor for β-catenin and insulin-like growth factor 2 (IGF2) with roles in promoting proliferation, cell survival and metastasis, as well as decreasing E-cadherin and increasing N-cadherin expression. Interestingly, miR-486-5p was found to be particularly enriched in plasma exosomes (
Similar observations have been reported for the tumor suppressive miR-8073 and miR-193a. While miR-8073 has invariant expression intracellularly and in exosomes of normal colorectal cells, it is preferentially sorted into exosomes at up to 60 times the concentration found inside CRC cells. Thus, its oncogenic mRNA targets are effectively de-repressed. These include, among others, FOXM1, which is involved in cancer growth and metastasis, as well as Methyl-CpG-binding domain protein 3 (MBD3) which is known to induce pluripotent stem cells (
The journey of metastatic cells continues way after they have detached from the primary tumor, remodeled their cytoskeletal architecture, and breached tissue boundaries. The remaining steps of the metastatic cascade are fraught with further hurdles that include intravasation into the circulation, extravasation into the secondary site, and preparation of the pre-metastatic niche prior to colonization. The latter entails forming new blood vessels as well as immune-proofing of the new microenvironment.
Tumor growth and metastasis depend on blood vessels for the supply of oxygen and nutrients, for the removal of waste products, and as routes for cancer cells to be able to migrate to a different site (
Among the pro-angiogenic exosomal miRNAs in CRC are miR-25-3p, miR-92a, miR-1229, miR-183-5p and miR-1246. CRC cells are able to transfer the metastasis-promoting miR-25-3p to endothelial cells via exosome transfer. By targeting Kruppel-like factor (KLF)2, vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) expression is upregulated, promoting angiogenesis (
Exosomal miR-92a-3p facilitates tumor angiogenesis by inducing partial EMT in endothelial cells (
CRC-derived exosomal miR-1229 promotes tube formation in HUVECs through the inhibition of homeodomain-interacting protein kinase 2 (HIPK2) and the subsequent activation of the VEGF pathway. In patients with CRC, serum exosomes harbor increased levels of miR-1229 which correlate with tumor size, lymphatic metastasis, 'tumor, nodes, metastases' (TNM) stage and poor survival (
Anti-angiogenic exosomal miRNAs in CRC include miR-126, miR-125a-3p and miR-125a-5p. miR-126 has been reported to target VEGF, an activator of angiogenesis (
miR-125a-3p targets fucosyltransferase (FUT)5 and FUT6, which regulate the PI3K/Akt signaling pathway. The overexpression of miR-125a-3p has been shown to result in the downregulation of FUT5 and FUT6, subsequently inhibiting the proliferation, migration, invasion and angiogenesis of CRC cells (
miR-125a-5p is a known tumor suppressor in CRC, since it directly targets: i) VEGFA, resulting in reduced tube formation in HUVECs and a suppressed cell proliferation, migration and invasion in CRC (
Tumor-derived exosomes act as intercellular messengers between cancer cells and immune cells to either activate or inhibit immune response and/or escape recognition by the immune system. In tumors, an immunosuppressive microenvironment is mainly induced by inflammation (
CRC cell-derived exosomal miR-934 has been found to induce M2 polarization in macrophages, enabling the induced TAMs to promote liver metastasis via secretion of the chemokine C-X-C motif chemokine ligand 13 (CXCL13) to remodel the premetastatic niche (
Much has been achieved in terms of identifying the morphological and structural changes that accompany EMT, the signaling pathways involved, and the transcriptional reprogramming that has to take place to bring about these changes. Investigations into the contributions of the tumor microenvironment to cancer progression has provided further insight on the mechanisms through which tumor cells can modify stromal cells, and vice versa, to break free from the primary site
Exosomes are an ideal source of disease biomarkers since they contain genetic material representative of the parental tumor (
Given their role in disease pathogenesis, exosomes can serve as therapeutic targets, either by inhibiting exosome formation, release, and uptake or by targeting bioactive cargo that can contribute to tumor metastasis. Exosomes can also serve as therapeutic agents, as unlike common drug delivery vehicles, such as liposomes and polymer nanoparticles, exosomes have minimal immunogenicity and toxicity and can be modified with synthetic peptides to carry small molecule drugs for targeting specific cells and tissues. Furthermore, unlike monoclonal antibodies (mAbs), which are used as targeted drug delivery vehicles, smaller iterations of therapeutic mAbs, such as fragment antibodies, domain antibodies and nanobodies can themselves be part of the exosomal cargo that can be internalized by recipient cells. Lastly, the exomiRs implicated in metastasis can themselves be potential targets for antagomiRs loaded onto exosomes.
Not applicable.
All three authors (JMCD, AGGU and RLG) contributed equally in organizing and writing the present review article. JMCD, AGGU and RLG confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing interests.
The figures presented herein were created with BioRender. com on a student plan premium license.
An overview of EMT and the metastatic process. Transcriptional reprogramming during EMT, a core component of the metastatic cascade, is driven by pro-EMT signaling pathways, such as TGF-β and Wnt/β-catenin, and EMT transcription factors of the SNAIL, ZEB, and TWIST families, among others. The resulting physical changes help cells assume a motile phenotype. This shift is accompanied by the downregulation of epithelial markers and the upregulation of mesenchymal markers, as well as an enhanced capability for degradation of the extracellular matrix. The primed metastatic cell intravasates and travels through the circulation to the distant metastatic site, where it extravasates and undergoes EMT reversal, or MET. Angiogenic induction is crucial for establishing metastasis. Stromal cells in the TME, such as TAMs and CAFs, modulate EMT and help sculpt the metastatic niche. EMT, epithelial-mesenchymal transition; TGF-β, transforming growth factor β; ZEB, Zinc finger E-box-binding homeobox; MET, mesenchymal-epithelial transition; TAMs, tumor-associated macrophages; CAFs, cancer-associated fibroblasts.
Tumor-and stroma-derived exosomes as major drivers of EMT and pre-metastatic niche formation. Exosomes are formed via the endocytic pathway. In the primary tumor site, both cancer cells and stromal cells in the tumor microenvironment release exosomal miRNA to promote cancer metastasis. Tumor-derived exosomes can reprogram fibroblasts, macrophages, mesenchymal stem cells, and endothelial cells, as well as induce epithelial to mesenchymal transition to enable cell migration and invasion. At the metastatic site, the exosomes participate in pre-metastatic niche formation through immune modulation and angiogenesis, and induce EMT reversal or mesenchymal to epithelial transition to facilitate colonization of the foreign environment. EMT, epithelial-mesenchymal transition; miRNA, microRNA.
Summary of exosomal miRNAs and their affected metastatic processes in CRC.
Exosomal miRNA (target, if identified) | Process affected | Author, year of publication | (Refs.) |
---|---|---|---|
Reciprocal transfer between CRC cells and CAFs
| |||
miR-10b (PIK3CA) | CAF activation via inhibition of PI3K | Dai |
( |
miR-92a (FBXW7, MOAP1) | Wnt/β-catenin activation | Hu |
( |
miR-21 | Enhanced liver metastasis | Bhome |
( |
| |||
Cytoskeletal remodeling, loss of adhesion and ECM degradation
| |||
miR-106b-3p (DLC-1) | Cytoskeletal rearrangement, adhesion through DLC-1 RhoGAP; cadherin switch | Liu |
( |
miR-210 | Induced EMT and anoikis resistance | Bigagli |
( |
miR-1246 | Macrophage reprogramming into TAM | Cooks |
( |
| |||
EMT reversal (MET) or EMT inhibition
| |||
miR-200c, miR-141 | Upregulated in decitabine-treated CRC cells, resulting in pro-epithelial phenotype in metastatic CRC cells | Tanaka |
( |
miR-200c, miR-141, miR-429 | Downregulated in exosomes from 5FU-resistant | Holzner |
( |
(ZEB transcription factors) | CRC cells, resulting in enhanced endothelial disruption | Senfter |
( |
miR-1255b-5p (hTERT) | Downregulated in hypoxia; inhibits Wnt signaling | Zhang |
( |
| |||
Maintenance of CSCs
| |||
miR-142-3p (Numb) | Relieves inhibition of Notch signaling, enlarging the CSC population | Li and Li, 2018 | ( |
miR-92a-3p (FBXW7, MOAP1) | Promotes stemness and EMT in CRC cells | Hu |
( |
miR-128-3p (Bmi1) (MRP5) | Upregulation of E-cadherin, EMT inhibition Sensitization to oxaliplatin | Liu |
( |
| |||
Downregulation or disposal of tumor suppressor exomiRs
| |||
miR-149, miR-96-5p (GPC1) | Downregulated in CRC exosomes, increasing pro-EMT GPC-1 expression | Li |
( |
miR-486-5p (PLAGL2) | Disposed in CRC exosomes, promoting β-catenin and IGF2 pathways | Liu |
( |
miR-8073 (FOXM1, MBD3, CCND1, KLK10, CASP2) | Disposed in exosomes, derepressing pro-oncogenic target genes | Mizoguchi |
( |
miR-193a (Caprin1) | Disposed in exosomes, promoting cell cycle progression and proliferation | Teng |
( |
| |||
Vascular leakiness and angiogenesis
| |||
miR-25-3p (KLF2, KLF4) | Promotes vascular permeability and angiogenesis in endothelial cells | Zeng |
( |
miR-92a-3p (Dkk-3) | Wnt/β-catenin activation | Yamada |
( |
(claudin-11) | Tight junction disruption | Yamada |
( |
miR-1229 (HIPK2) | VEGF pathway activation | Hu |
( |
miR-183-5p (FOXO1) | Enhances angiogenesis | Shang |
( |
miR-1246 (PML) | Activation of Smad1/5/8 signaling | Yamada |
( |
miR-126 | Anti-angiogenic (VEGF inhibition) | Ebrahimi |
( |
Pro-angiogenic signaling | Hansen |
( | |
miR-125a-3p (FUT5, FUT6) | Upregulated in plasma exosomes; PI3K/Akt regulation; tumor suppressive miRNA | Wang |
( |
Liang |
( | ||
miR-125a-5p (VEGFA) | Downregulated in plasma exosomes; anti-angiogenic and tumor suppressive | Wang |
( |
Yang |
( | ||
| |||
Modulation or suppression of the immune system
| |||
miR-203 (SOCS3) | Pro-M2/TAM monocyte differentiation | Takano |
( |
miR-934 (PTEN) | Pro-M2/TAM polarization, CXCL13 secretion directing liver metastasis | Zhao |
( |
miR-25, miR-130b, miR-425 (PTEN) | Pro-M2/TAM polarization in CXCL12/CXCR4-dependent liver metastasis | Wang |
( |
let-7d (CCL7) | Inhibition of monocyte migration (immune evasion by interfering with chemotaxis) | Noh |
( |