• FSCN1
• MetaLnc9
• Oral submucous fibrosis
• miR-143

• Cancer stem cells
• Cancer therapy
• Immunotherapy
• Tumor heterogeneity
• Tumor microenvironment
• Tumor plasticity

• Humans
• Tumor Microenvironment
• Neoplasms/drug therapy
• Neoplasms/pathology

• DNA repair mechanisms
• cancer stem cell
• chemotherapy resistance
• immunomodulation
• small molecule
• tumor microenvironment

• Humans
• Neoplasm Recurrence, Local
• Drug Delivery Systems
• Combined Modality Therapy

• Cancer-associated fibroblasts
• Lysine demethylase 2A
• Paclitaxel resistance
• Tumor-associated macrophage

• MOST 110-2320-B-214-001 National Science and Technology Council
• ISU-109-02-01A, ISU-110-S-02 I-Shou University
• EDAHT112004 E-DA Healthcare Group

• Borrmann type IV
• Linitis Plastica
• biomarkers
• oncogenes in LP
• surgery
• targeting agents

• Humans
• Linitis Plastica/diagnosis
• Linitis Plastica/genetics
• Linitis Plastica/therapy
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/therapy
• Genomics

• biomarker discovery
• equine
• extracellular vesicle
• immunomodulation
• mesenchymal stem cell
• therapeutic

• R00 CA256353 NCI NIH HHS
• National Cancer Institute

• Breast cancer
• Epithelial–mesenchymal transition
• Metastasis
• MicroRNAs
• Tumor–stromal crosstalk

Corneal fibrosis is a complication of severe corneal injury, one of the major causes of vision loss. The formation of myofibroblasts has emerged as a key stimulative factor of corneal fibrosis. In the current study, we focused on the role of LINC00963 in regulating corneal fibrosis. Transforming growth factor β1 (TGF-β1) was used to induce human corneal stromal cells differentiating into corneal myofibroblasts, and the significant increase of α-smooth muscle actin (α-SMA) was verified by quantitative real-time PCR (qRT-PCR), western blot, and immunofluorescence, respectively. LINC00963 was identified to be one-half decreased compared with nonstimulated human corneal stromal cells, indicating that it might play a role in corneal fibrosis. Interestingly, overexpression of LINC00963 resulted in decreased formation of myofibroblasts indicating that it might exhibit an inhibiting effect. Moreover, bioinformatics tool was applied to predict the downstream target of LINC00963. We investigated that LINC00963 suppressed α-SMA induced by TGF-β1 in corneal fibroblasts, at least in part, by downregulating the expression of miR-143-3p. In addition, either LINC00963 promotion or miR-143-3p inhibition could significantly decrease myofibroblast contractility and collagen I and III secretion, which are the key to contribute to corneal fibrosis. Taken together, our study identified LINC00963 as a promising therapeutic target.

• cornea
• fibrosis
• long noncoding RNAs
• microRNA
• transforming growth factor

• Tumor microenvironment
• drug delivery
• gene therapy
• immunotherapy
• nanoparticles
• proliferation.

Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue disease (CTD), causing death in systemic sclerosis (SSc). The past decade has yielded many scientific insights into microRNA (miRNAs) in PAH and SSc. This growth of knowledge has well-illustrated the complexity of microRNA (miRNA)-based regulation of gene expression in PAH. However, few miRNA-related SSc-PAH were elucidated. This review firstly discusses the role of transforming growth factor-beta (TGF-β) signaling and bone morphogenetic protein receptor type II (BMPR2) in PAH and SSc. Secondly, the miRNAs relating to TGF-β and BMPR2 signaling pathways in PAH and SSc or merely PAH were subsequently summarized. Finally, future studies might develop early diagnostic biomarkers and target-oriented therapeutic strategies for SSc-PAH and PAH treatment.

• Pulmonary arterial hypertension
• Systemic sclerosis
• miRNAs

Collagen is a major component in the tumor microenvironment. This study reveals a novel biomarker candidate, type VII collagen (COL7A1), in patients with gastric cancer. To identify genes differentially expressed in gastric cancer tissue, we analyzed cancerous (n = 20) and noncancerous tissues (n = 13) using a DNA microarray. To perform immunohistochemistry and validate the upregulation of COL7A1 expression, we collected 200 more gastric cancer tissues and 100 normal gastric tissues from 200 randomly selected patients who underwent gastrectomy for gastric cancer between January 2010 and December 2013. The correlations between COL7A1 expression and clinicopathological parameters and patients’ overall survival (OS) were analyzed. In the microarray, COL7A1 was upregulated in gastric cancer tissue compared with normal tissue. In the immunohistochemistry study, COL7A1 was more highly expressed in cancer tissue than in normal tissue (p = 0.001). Patients with intracellular COL7A1 expression had significantly poorer five-year OS than those with only extracellular expression (41.5 versus 69.7%, p = 0.001), and the site of expression was an independent prognostic factor of OS (hazard ratio 2.00, 95% CI 1.26–3.16, p = 0.003). Also, we found a significant association between the COL7A1 immunohistochemistry score and distant metastasis (high versus low, odds ratio 4.45, 95% CI 1.40–14.16, p = 0.011). The site and total immunohistochemistry score of COL7A1 expression in gastric cancer showed prognostic significance for OS and distant metastasis, respectively. COL7A1 could be a novel biomarker with diagnostic and therapeutic value.

• biomarker
• distant metastasis
• gastric cancer
• prognosis
• tumor microenvironment
• type VII collagen (COL7A1)

Lung cancer is the leading cause of cancer death among both men and women, partly due to limited therapy responses. New avenues of knowledge are indicating that lung cancer cells do not form a tumor in isolation but rather obtain essential support from their surrounding host tissue rich in altered fibroblasts. Notably, there is growing evidence that tumor progression and even the current limited responses to therapies could be prevented by rescuing the normal behavior of fibroblasts, which are critical housekeepers of normal tissue function. For this purpose, it is key to improve our understanding of the molecular mechanisms driving the pathologic alterations of fibroblasts in cancer. This work provides a comprehensive review of the main molecular mechanisms involved in fibroblast transformation based on epigenetic reprogramming, and summarizes emerging therapeutic approaches to prevent or overcome the pathologic effects of tumor-associated fibroblasts.

Lung cancer is the leading cause of cancer-related death worldwide. The desmoplastic stroma of lung cancer and other solid tumors is rich in tumor-associated fibroblasts (TAFs) exhibiting an activated/myofibroblast-like phenotype. There is growing awareness that TAFs support key steps of tumor progression and are epigenetically reprogrammed compared to healthy fibroblasts. Although the mechanisms underlying such epigenetic reprogramming are incompletely understood, there is increasing evidence that they involve interactions with either cancer cells, pro-fibrotic cytokines such as TGF-β, the stiffening of the surrounding extracellular matrix, smoking cigarette particles and other environmental cues. These aberrant interactions elicit a global DNA hypomethylation and a selective transcriptional repression through hypermethylation of the TGF-β transcription factor SMAD3 in lung TAFs. Likewise, similar DNA methylation changes have been reported in TAFs from other cancer types, as well as histone core modifications and altered microRNA expression. In this review we summarize the evidence of the epigenetic reprogramming of TAFs, how this reprogramming contributes to the acquisition and maintenance of a tumor-promoting phenotype, and how it provides novel venues for therapeutic intervention, with a special focus on lung TAFs.

• TGF-β
• cancer-associated fibroblasts
• desmoplasia
• epigenetics
• lung cancer
• smoking
• tumor stroma

• Gastric cancer (GC)
• adjuvant treatment
• linitis plastica
• risk prediction

• Chemokines
• Cytokines
• Drug targets
• Epithelial-Mesenchymal transition
• Esophageal cancer
• Immune evasion
• Inflammation
• Tumor microenvironment

• Animals
• Chemokines/genetics
• Chemokines/metabolism
• Epithelial-Mesenchymal Transition/genetics
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/pathology
• Humans
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Tumor Microenvironment/genetics

• Sidra Medicine
• Department of Biotechnology , Ministry of Science and Technology
• Medical Research Centre , HMC, Qatar

As the most important component of the stromal cell population in the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) are crucial players in tumor initiation and progression. The interaction between CAFs and tumor cells, as well as the resulting effect, is much greater than initially expected. Numerous studies have shown that noncoding RNAs (ncRNAs) play an irreplaceable role in this interplay, and related evidence continues to emerge and advance. Under the action of ncRNAs, normal fibroblasts are directly or indirectly activated into CAFs, and their metabolic characteristics are changed; thus, CAFs can more effectively promote tumor progression. Moreover, via ncRNAs, activated CAFs can affect the gene expression and secretory characteristics of cells, alter the TME and enhance malignant biological processes in tumor cells to contribute to tumor promotion. Previously, ncRNA dysregulation was considered the main mechanism by which ncRNAs participate in the crosstalk between CAFs and tumor cells. Recently, however, exosomes containing ncRNAs have been identified as another vital mode of interaction between these two types of cells, with a more direct and clear function. Gaining an in-depth understanding of ncRNAs in CAFs and the complex regulatory network connecting CAFs with tumor cells might help us to establish more effective and safer approaches for cancer therapies targeting ncRNAs and CAFs and offer new hope for cancer patients.

• Cancer
• Cancer-associated fibroblasts
• Cell–cell interaction
• Exosome
• Long noncoding RNA
• MicroRNA
• Noncoding RNA
• Tumor microenvironment

• androgen receptor signaling
• microRNAs
• prostate biology
• prostate cancer

• Borrmann type IV
• Diffuse
• Gastrectomy
• Gastric cancer
• Linitis plastica
• Scirrhous carcinoma
• Signet ring

• Adenocarcinoma/surgery
• Gastrectomy
• Humans
• Linitis Plastica/diagnostic imaging
• Linitis Plastica/pathology
• Linitis Plastica/therapy
• Neoplasm Staging
• Prognosis
• Retrospective Studies
• Stomach Neoplasms/surgery
• Survival Rate

• P30 CA016672 NCI NIH HHS

• Apoptotic bodies
• Cancer cell interactions
• Cancer models
• Cancer therapy
• Cell-free DNA
• Circulating tumor cells
• Exosome
• Extracellular matrix
• Horizontal transfer
• Stroma cell
• Tumor microenvironment

• Animals
• Carcinogenesis/metabolism
• Cell Communication
• Extracellular Matrix/metabolism
• Humans
• Neoplasms/metabolism
• Stromal Cells/cytology
• Stromal Cells/metabolism
• Tumor Microenvironment

The establishment and spreading of cancer involve the acquirement of many biological functions including resistance to apoptosis, enhanced proliferation and the ability to invade the surrounding tissue, extravasate from the primary site, survive in circulating blood, and finally extravasate and colonize distant organs giving origin to metastatic lesions, the major cause of cancer deaths. Dramatic changes in the expression of protein coding genes due to altered transcription factors activity or to epigenetic modifications orchestrate these events, intertwining with a microRNA regulatory network that is often disrupted in cancer cells. microRNAs-143 and -145 represent puzzling players of this game, with apparently contradictory functions. They were at first classified as tumor suppressive due to their frequently reduced levels in tumors, correlating with cell survival, proliferation, and migration. More recently, pro-oncogenic roles of these microRNAs have been described, challenging their simplistic definition as merely tumor-suppressive. Here we review their known activities in tumors, whether oncogenic or onco-suppressive, and highlight how their expression and functions are strongly dependent on their complex regulation downstream and upstream of cytokines and growth factors, on the cell type of expression and on the specific tumor stage.

• EMT
• miRNA-143
• miRNA-145
• oncogenes
• oncosuppressors
• tumorigenesis

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, including tumor microenvironment. Cancer cells cooperate with stromal cells and elements of the extracellular matrix (ECM) to establish a comfortable niche to grow, to evade the immune system, and to expand. Within the tumor microenvironment, cells release ECmiRNAs and other factors in order to influence and hijack the physiological processes of surrounding cells, fostering tumor progression. Here, we discuss the role of miRNAs in the pathogenesis of multicomplex diseases, such as Alzheimer’s disease, obesity, and cancer, focusing on the contribution of both intracellular miRNAs, and of released ECmiRNAs in the establishment and development of cancer niche. We also review growing evidence suggesting the use of miRNAs as novel targets or potential tools for therapeutic applications.

• cancer therapy
• cell–cell communication
• extracellular miRNA
• microRNA
• tumor microenvironment

• Cell Communication/genetics
• Clinical Trials as Topic
• Exosomes/genetics
• Humans
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Multifactorial Inheritance/genetics
• Tumor Microenvironment/genetics

• TAK1
• autoimmune hepatitis
• gene therapy
• liver fibrosis
• miR-143

• Animals
• Hepatitis, Autoimmune/complications
• Hepatitis, Autoimmune/pathology
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Inflammation/etiology
• Inflammation/metabolism
• Inflammation/pathology
• Inflammation/prevention & control
• Liver Cirrhosis/etiology
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Liver Cirrhosis/prevention & control
• MAP Kinase Kinase Kinases/genetics
• MAP Kinase Kinase Kinases/metabolism
• Male
• Mice
• MicroRNAs/administration & dosage
• MicroRNAs/genetics

• National Natural Science Foundation of China

• Cardiac fibrosis
• MAPK pathway
• MiR-143-3p
• SPRY3

Cancer-associated fibroblasts (CAFs), one of the principal constituents of the tumor microenvironment, have a pivotal role in tumor progression. Dysregulation of microRNAs (miRNAs) in CAFs contributes to the tumor-promoting ability of CAFs. However, the mechanism underlying the involvement of miRNAs in CAFs of gastric cancer (GC) is not fully understood. This study aimed to explore the effects of miRNA-214 in CAFs on GC migration and invasion.

The primary CAFs and corresponding normal fibroblasts (NFs) were isolated. Cell counting kit-8, EdU cell proliferation staining and Transwell assays were used to determine the role of miRNA-214 in GC progression. Real-time polymerase chain reaction, Western blot analysis, and dual-luciferase reporter assay were performed to verify the target genes of miRNA-214. Immunofluorescence and Western blot analysis were applied to detect the expression of epithelial–mesenchymal transition (EMT) markers. Immunohistochemistry and in situ hybridization were implemented to analyze the fibroblast growth factor 9 (FGF9) and miRNA-214 expression in human GC tissues, respectively. Finally, to assess its prognostic relevance, Kaplan–Meier survival analysis was conducted.

MiRNA-214 was significantly downregulated in CAFs of GC compared with NFs. The upregulation of miRNA-214 in CAFs inhibited GC cell migration and invasion in vitro but failed to affect proliferation. Moreover, GC cells cultured with conditioned medium from CAFs transfected with miR-214 mimic showed increased expression of E-cadherin and decreased expression of Vimentin, N-cadherin and Snail, indicating the suppression of EMT of GC cells. Furthermore, FGF9 was proved to be a direct target gene of miR-214. The expression of FGF9 was higher in CAFs than that in tumor cells not only in primary tumor but also in lymph node metastatic sites (30.0% vs 11.9%, P < 0.01 and 32.1% vs 12.3%, P < 0.01, respectively). Abnormal expression of FGF9 in CAFs of lymph node metastatic sites was significantly associated with poor prognosis in patients with GC (P < 0.05).

This study showed that miR-214 inhibited the tumor-promoting effect of CAFs on GC through targeting FGF9 in CAFs and regulating the EMT process in GC cells, suggesting miRNA-214/FGF9 in CAFs as a potential target for therapeutic approaches in GC.

The online version of this article (10.1186/s13046-018-0995-9) contains supplementary material, which is available to authorized users.

• Cancer-associated fibroblasts
• Epithelial–mesenchymal transition
• FGF9
• Gastric cancer
• microRNA-214

MicroRNAs (miRNAs) are small non-coding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs). They are ~22 nucleotides long and control both physiological and pathological processes. Altered expression of miRNAs is often associated with human diseases. Thus, miRNAs have become important therapeutic targets, and some clinical trials investigating the effect of miRNA-based therapeutics in different types of diseases have already been conducted. The tumor microenvironment (TME) comprises cells such as infiltrated immune cells, cancer-associated endothelial cells (CAEs) and cancer-associated fibroblasts (CAFs), and all the components participate in the complicated crosstalk with tumor cells to affect tumor progression. Altered miRNAs expression in both these stromal and tumor cells could drive tumorigenesis. Thus, in this review, we discuss how aberrantly expressed miRNAs influence tumor progression; summarize the crosstalk between infiltrated immune cells, CAEs, CAFs, and tumor cells through miRNAs, and clarify the important roles of miRNAs in the tumor microenvironment, which may facilitate the clinical application of miRNA-based therapies.

• cancer-associated endothelial cells
• cancer-associated fibroblasts
• crosstalk
• immune cells
• microRNAs
• tumor cells
• tumor microenvironment

Bladder cancer is a very common malignancy. Although new treatment strategies have been developed, the identification of new therapeutic targets and reliable diagnostic/prognostic biomarkers for bladder cancer remains a priority. Generally, they are found among differentially expressed genes between patients and healthy subjects or among patients with different tumor stages. However, the classical approach includes processing these data taking into consideration only the expression of each single gene regardless of the expression of other genes. These complex gene interaction networks can be revealed by a recently developed systems biology approach called Weighted Gene Co-expression Network Analysis (WGCNA). It takes into account the expression of all genes assessed in an experiment in order to reveal the clusters of co-expressed genes (modules) that, very probably, are also co-regulated. If some genes are co-expressed in controls but not in pathological samples, it can be hypothesized that a regulatory mechanism was altered and that it could be the cause or the effect of the disease. Therefore, genes within these modules could play a role in cancer and thus be considered as potential therapeutic targets or diagnostic/prognostic biomarkers. Here, we have reviewed all the studies where WGCNA has been applied to gene expression data from bladder cancer patients. We have shown the importance of this new approach in identifying candidate biomarkers and therapeutic targets. They include both genes and miRNAs and some of them have already been identified in the literature to have a role in bladder cancer initiation, progression, metastasis, and patient survival.

• WGCNA
• bladder cancer
• gene expression
• heterogeneity
• tumor biomarkers

• DNA methylation
• chromatin remodeling
• epigenetics
• histone modifications
• non-coding RNAs
• ovarian cancer
• tumor microenvironment

• 458788 (K.P.N.) Ovarian Cancer Research Fund Alliance
• (K.P.N.) Leo and Anne Albert Charitable Trust
• (Y.K.) Indiana Clinical and Translational Sciences Institute Grant Award

Hepatitis B virus (HBV) infection is a leading cause of persistent liver diseases, cirrhosis and hepatocellular carcinoma (HCC) worldwide. Since deregulation of microRNA (miRNA) expression by HBV infection contributes to enhanced viral replication and pathogenesis, modulation of miRNA activity can be a novel therapeutic approach towards HBV eradication. As the effects of the vast majority of miRNAs on HBV replication have not been empirically investigated, here, we aim to identify novel therapeutic targets that have a strong antiviral effect on HBV.

HepG2-hNTCP-C4 cells were infected with HBV, and then were individually transfected with the library mimics of 2048 miRNAs. To assess the amount of intracellular and extracellular DNA and HBsAg, qPCR and ELISA were performed respectively.

From miRNA library screening, we identified 39 miRNAs as candidate repressors of HBV replication. Among them, 9 miRNAs, including miR-204, strongly decreased both HBV DNA and HBsAg in culture supernatant of HepG2-hNTCP-C4 cells. Furthermore, we also showed that inhibition of Rab22a, one of the targets of miR-204, also suppressed intracellular and extracellular HBV DNA expression in HepG2.2.15.7 cells.

Our findings contribute to the understanding of the roles of miRNAs underlying HBV replication and show the possibility of developing a novel strategy for miRNA-mediated HBV treatment.

• Rab22a
• hepatitis B virus
• miR-204
• microRNA

• Biomarkers
• Hepatitis B
• Hepatitis B virus
• Liver fibrosis
• MicroRNAs
• chronic

• Cell line
• Characterization
• Establishment
• Mouse models
• Scirrhous gastric cancer

• microrna-3129
• gastric cancer
• prb
• proliferation
• cell cycle

• Adult
• Cell Line, Tumor
• Cell Proliferation/genetics
• Cell Survival
• Down-Regulation
• Female
• Flow Cytometry
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Male
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Middle Aged
• Neoplasm Staging
• Real-Time Polymerase Chain Reaction
• Retinoblastoma Protein/genetics
• Retinoblastoma Protein/metabolism
• Signal Transduction
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Transfection
• Up-Regulation

The roles of non-coding RNAs in controlling clinical and biological heterogeneity in bladder cancer remain unclear. We used TCGA's published dataset (n = 405 tumors) as a discovery cohort and created a new validation cohort to define the miRNA expression patterns in the basal and luminal molecular subtypes of muscle-invasive bladder cancer (MIBC). We identified 63 miRNAs by PAM, which optimally identified basal and luminal tumors. The targets of the top luminal miRNAs were activators of EMT (ZEB1, ZEB2) and basal subtype transcription (IL-6, EGFR, STAT3), whereas the targets of the top basal miRNAs were involved in adipogenesis pathways and luminal breast cancer (ERBB2, ERBB3). We also identified a 15-miRNA signature that identified stromally infiltrated basal and luminal MIBCs corresponding to the “cluster IV/immune undifferentiated/claudin-low” and “cluster II/luminal immune” subtypes identified previously, which likely contain samples with higher infiltration rates. Using the 63-miRNA signature, we accurately assigned MIBCs to the basal and luminal subtypes and confirmed that patients with basal tumors had shorter overall survival. The results strongly suggest that miRNAs contribute to the control of the gene expression patterns observed in basal and luminal MIBCs and that they can be used as biomarkers and candidate therapeutic targets.

• EMT
• PPARG
• TCGA
• consensus clustering
• urothelial cancer

• TGFBR2
• cell proliferation
• gastric cancer
• miR-17-5p
• migration

MicroRNAs regulate multiple aspects of the host response to viral infection. This study verified that the expression of cfa-miR-143 was upregulated in vivo and in vitro by canine influenza virus (CIV) H3N2 infection. To understand the role of cfa-miR-143 in CIV-infected cells, the target gene of cfa-miR-143 was identified and assessed for correlations with proteins involved in the apoptosis pathway. A dual luciferase reporter assay showed that cfa-miR-143 targets insulin-like growth factor binding protein 5 (Igfbp5). Furthermore, a miRNA agomir and antagomir of cfa-miR-143 caused the downregulation and upregulation of Igfbp5, respectively, in CIV-infected madin-darby canine kidney (MDCK) cells. This study demonstrated that cfa-miR-143 stimulated p53 and caspase3 activation and induced apoptosis via the p53 pathway in CIV H3N2-infected cells. In conclusion, CIV H3N2 induced the upregulation of cfa-miR-143, which contributes to apoptosis via indirectly activating the p53-caspase3 pathway.

• apoptosis
• canine influenza virus
• caspase
• cfa-miR-143
• p53

• Animals
• Apoptosis
• Caspase 3/genetics
• Caspase 3/metabolism
• Cell Count
• Dog Diseases/virology
• Dogs
• Down-Regulation
• Genes, Reporter
• HEK293 Cells
• Humans
• Influenza A Virus, H3N2 Subtype/genetics
• Influenza A Virus, H3N2 Subtype/pathogenicity
• Influenza, Human/virology
• Lung/virology
• Madin Darby Canine Kidney Cells
• MicroRNAs/genetics
• Orthomyxoviridae Infections/veterinary
• Orthomyxoviridae Infections/virology
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Up-Regulation

• K-Ras
• MiR-143
• apoptosis
• pituitary tumor

The present review aimed to assess the role of exosomal miRNAs in cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancer cells. The roles of exosomal miRNAs and miRNA dysregulation in CAF formation and activation were summarized.

All relevant publications were retrieved from the PubMed database, with key words such as CAFs, CAF, stromal fibroblasts, cancer-associated fibroblasts, miRNA, exosomal, exosome, and similar terms.

Recent studies have revealed that CAFs, NFs, and cancer cells can secrete exosomal miRNAs to affect each other. Dysregulation of miRNAs and exosomal miRNAs influence the formation and activation of CAFs. Furthermore, miRNA dysregulation in CAFs is considered to be associated with a secretory phenotype change, tumor invasion, tumor migration and metastasis, drug resistance, and poor prognosis.

Finding of exosomal miRNA secretion provides novel insights into communication among CAFs, NFs, and cancer cells. MicroRNA dysregulation is also involved in the whole processes of CAF formation and function. Dysregulation of miRNAs in CAFs can affect the secretory phenotype of the latter cells.

• Cancer
• Cancer-associated fibroblasts
• Exosome
• Mechanism
• MiRNA

• gastric cancer
• meta-analysis
• microRNA
• prognosis

• DNMT3A
• Gastric cancer
• cell invasion
• cell proliferation
• miR-143

Linitis plastica due to gastric adenocarcinoma is a condition with a long history, but still lacks a standardized definition and is commonly confused with Borrmann type IV, Lauren diffuse, and signet-cell type gastric cancer. The absence of a clear definition is a problem when investigating its biological characteristics and role as a possible independent factor for prognosis. Nevertheless, the biological behavior for linitis plastica, which is unique, may be valuable in risk stratification and have implications for treatment. A definition of linitis plastica based on molecular or genomic criteria could represent a useful starting point for investigating new targeted therapies.

This literature review of linitis plastica will focus on the current classifications for gastric cancer, illustrating how the concept of linitis plastica relates to them in most cases and identifying a clear and reproducible definition. Moreover, the review will highlight the diagnostic challenges associated with linitis plastica, its prognostic implications, and the therapeutic options available. Future perspectives for its management are also addressed.

Linitis plastica is a carcinoma with a scirrhous stroma, involving the submucosal and muscular layers of the stomach even in the absence of mucosal alteration. In most cases, the primary cancer cells are signet-ring cells or scattered cells in the context of a poorly differentiated carcinoma. Diagnosis is challenging. Staging should be thorough, including diagnostic laparoscopy in all cases due to the high incidence of peritoneal involvement. The prognostic significance of linitis plastica is still controversial. Curative-intent surgery, when feasible, should be performed, with a multimodality treatment approach. Cancer-stroma interactions are important features of this disease, and represent attaining potential target for future therapies. Future pathologic assessments of gastric cancer should report the stromal reaction in order to allow better characterization of the tumor.

• Borrmann type IV
• Diffuse
• Gastric cancer
• Linitis plastica
• Scirrhous carcinoma
• Signet ring

The tumor microenvironment, including cancer-associated fibroblasts (CAF), has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer. Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations. This review summarizes the current understanding on miR involvement in cancer cell—tumor environment/stroma communication, transformation of NFs into CAFs, their involved targets and signaling pathways in these interactions; and clinical relevance of CAF-related miR expression profiles. There is evidence that miRs have very similar roles in activating hepatic (HSC) and pancreatic stellate cells (PSC) as part of precancerous fibrotic diseases. In summary, deregulated miRs affect various intracellular functional complexes, such as transcriptional factors, extracellular matrix, cytoskeleton, EMT/MET regulation, soluble factors, tyrosine kinase and G-protein signaling, apoptosis and cell cycle & differentiation, but also formation and composition of the extracellular microenvironment. These processes result in the clinical appearance of desmoplasia involving CAFs and fibrosis characterized by deregulated stellate cells. In addition, modulated release of soluble factors can act as (auto)activating feedback loop for transition of NFs into their pathological counterparts. Furthermore, epigenetic communication between CAFs and cancer cells may confer to cancer specific functional readouts and transition of NF. MiR related epigenetic regulation with many similarities should be considered as key factor in development of cancer and fibrosis specific environment.

• cancer associated fibroblasts
• cell-cell communication
• epigenetic
• microRNA
• transformation

• DNA methylation
• epigenetic modulation
• gastric cancer
• histone modulation
• non-coding RNA

Cancer microenvironment is composed of numerous components that can support cancer cell proliferation, promote cancer progression and contribute to cancer treatment resistance. The major components of caner microenvironment are fibroblasts, endothelial cells, immune cells as well as cytokines, chemokines, and extracellular matrix (ECM) all of which surround tumor cells as the core and cross talk with each other. Among them, cancer-associated fibroblasts (CAFs) play an important role in promoting cancer progression by secreting various pro-inflammatory factors. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate protein expression both in cancer cell and normal stromal cells. Changes of miRNAs expression in cancer-associated fibroblasts can be induced both by cancer cells and other stromal cells. This change can arise through direct interaction or by secreted paracrine factors or even by secreted miRNAs. The desregulated miRNAs in cancer-associated fibroblasts then enhance the CAFs phenotype and assist their cancer promotion ability. Explore the regulatory function of miRNAs in the complex communication between cancer cells and cancer microenvironment is important to understand the process of tumor progression and may help to develop new therapeutic strategies. This review provides an updated content of latest research advances about the relevance of miRNAs in the interaction between cancer cells and the CAFs. We will describe miRNAs which are differential expressed by NFs and CAFs, their function in regulating fibroblasts activation as well as miRNAs expressed in CAFs as prognostic factors in cancer stroma in recent studies. We will also discuss miRNA as an important player in CAFs mediated regulation of cancer progression and metastasis, cancer metabolism, cancer stem cell property and chemoresistance.

• Cancer Microenvironment
• Cancer associated fibroblasts
• MiRNAs