• BMP
• DIPG
• DMG
• H3K27M
• invasion
• pediatric glioma
• quiescence

• Humans
• Child
• Glioma/metabolism
• Histones/metabolism
• Diffuse Intrinsic Pontine Glioma/genetics
• Diffuse Intrinsic Pontine Glioma/metabolism
• Diffuse Intrinsic Pontine Glioma/pathology
• Mutation
• Signal Transduction
• Bone Morphogenetic Proteins/metabolism

• Animals
• Humans
• Fasciola hepatica
• Cholangiocarcinoma/drug therapy
• Dyskinesias
• Bile Duct Neoplasms/drug therapy
• Bile Ducts, Intrahepatic

Docosahexaenoic acid (DHA) is an omega-3 fatty acid abundant in fish oils. It is known to have an inhibitory effect on various diseases such as inflammation, diabetes, and cancer. Epithelial-to-mesenchymal transition (EMT) is a process that epithelial cells gain migratory property to become mesenchymal cells involved in wound healing, organ fibrosis, and cancer progression. Gremlin-1 (GREM1) is a bone morphogenetic protein antagonist known to play a role in EMT. However, the role of GREM1 in the induction of EMT in human breast cancer cells and the effect of DHA on GREM1-induced EMT remain unclear. Establishment of GREM1 knockdown cell lines was performed using lentiviral shRNAs. Expression of EMT markers was determined by qRT-PCR and Western blotting. Effect of GREM1 and/or DHA on cell migration was investigated using wound healing assay. The level of GREM1 expression in human breast cancer tissues was determined by Oncomine database mining. GREM1 induced the expression of genes including N-cadherin, vimentin, and Slug. GREM1 promoted the migration of human breast cancer cells. GREM1 enhanced the expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and the ERK activation was involved in EMT. Interestingly, DHA reduced the expression of GREM1. DHA also inhibited the expression of mesenchymal cell-associated genes and cell migration induced by GREM1. Furthermore, DHA suppressed the expression of p-ERK induced by GREM1. These results indicate that GREM1–ERK axis plays a role in EMT in human breast cancer cells and DHA is a putative compound that can inhibit EMT by inhibiting GREM1 signal transduction.

• Breast cancer
• DHA
• EMT
• GREM1
• extracellular signal-regulated kinases

• biomarker panel
• cholangiocarcinoma
• decision tree algorithm
• diagnosis

• Cholangiocarcinoma (CCA)
• E-cadherin
• bone morphogenetic protein-7 (BMP-7)
• epithelial mesenchymal transition (EMT)
• transforming growth factor-β1 (TGF-β1)

Tubular epithelial cells undergoing epithelial-mesenchymal transition (EMT) is a crucial event in the progression of renal interstitial fibrosis (RIF). Bone morphogenetic protein-7 (BMP-7) has been reported to exhibit anti-fibrotic functions in various renal diseases. However, the function of BMP-7 in regulating EMT and the progression of RIF remains largely unknown. The aim of the present study was to examine the potential effect of BMP-7 on transforming growth factor β1 (TGF-β1)-induced EMT and the underlying mechanisms by which BMP-7 exerted its effects. Human renal proximal tubular epithelial cells (HK-2) were treated with TGF-β1 for various time periods and at various concentrations and lentiviral vectors were used to overexpress BMP-7. Cell Counting Kit-8 and Transwell assays were used to evaluate the viability and migration of HK-2 cells in vitro. EMT was estimated by assessing the changes in cell morphology and the expression of EMT markers. In addition, the activation of the Wnt3/β-catenin and TGF-β1/Smad2/3 signaling pathways were analyzed using western blotting. TGF-β1 induced EMT in a time- and dose-dependent manner in HK-2 cells. Treatment with TGF-β1 induced morphological changes, decreased cell viability and the expression of E-cadherin, increased cell migration and the expression of α-smooth muscle actin, fibroblast-specific protein 1, collagen I and vimentin, and activated the Wnt3/β-catenin and TGF-β1/Smad2/3 signaling pathways in HK-2 cells. However, BMP-7 overexpression notably reversed all these effects. These results suggest that BMP-7 effectively suppresses TGF-β1-induced EMT through the inhibition of the Wnt3/β-catenin and TGF-β1/Smad2/3 signaling pathways, highlighting a potential novel anti-RIF strategy.

• BMPs
• Non-SMAD signaling
• SMAD pathway
• TGFβ
• adult homeostasis
• cancer
• development
• disease
• fibrosis
• signaling

• Animals
• Bone Morphogenetic Proteins/genetics
• Bone Morphogenetic Proteins/physiology
• Disease Progression
• Fibrosis/genetics
• Fibrosis/pathology
• Gene Regulatory Networks/physiology
• Humans
• Neoplasms/genetics
• Neoplasms/pathology
• Organogenesis/genetics
• Signal Transduction/genetics
• Transforming Growth Factor beta/genetics
• Transforming Growth Factor beta/physiology

Cholangiocarcinoma (CCA) is the second most common type of liver cancer, and is highly aggressive with very poor prognosis. CCA is classified into intrahepatic cholangiocarcinoma (iCCA) and extra-hepatic cholangiocarcinoma (eCCA), which is further stratified into perihilar (pCCA) and distal (dCCA). Cancer stem cells (CSCs) are a subpopulation of cancer cells capable of tumor initiation and malignant growth, and are also responsible for chemoresistance. Thus, CSCs play an important role in CCA carcinogenesis. Surface markers such as CD133, CD24, CD44, EpCAM, Sox2, CD49f, and CD117 are important for identifying and isolating CCA CSCs. CSCs are present in the tumor microenvironment (TME), termed ‘CSC niche’, where cellular components and soluble factors interact to promote tumor initiation. Epithelial-to-mesenchymal transition (EMT) is another important mechanism underlying carcinogenesis, involved in the invasiveness, metastasis and chemoresistance of cancer. It has been demonstrated that EMT plays a critical role in generating CSCs. Therapies targeting the surface markers and signaling pathways of CCA CSCs, proteins involved in TME, and immune checkpoint proteins are currently under investigation. Therefore, this review focuses on recent studies on the roles of CSCs in CCA; the possible therapeutic strategies targeting CSCs of CCA are also discussed.

• cancer stem cells
• cholangiocarcinoma
• epithelial-to-mesenchymal transition
• surface markers
• targeted therapy
• tumor microenvironment

• Animals
• Bile Duct Neoplasms/etiology
• Bile Duct Neoplasms/metabolism
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/therapy
• Biomarkers
• Cholangiocarcinoma/etiology
• Cholangiocarcinoma/metabolism
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/therapy
• Combined Modality Therapy
• Disease Management
• Epithelial-Mesenchymal Transition
• Humans
• Immunophenotyping
• Molecular Targeted Therapy
• Neoplastic Stem Cells/metabolism
• Tumor Microenvironment

• TGFβ
• cholangiocarcinoma
• liver cancer
• noncoding RNA
• signaling

• Animals
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Cholangiocarcinoma/genetics
• Cholangiocarcinoma/metabolism
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Signal Transduction/genetics
• Transforming Growth Factor beta/genetics
• Transforming Growth Factor beta/metabolism

• Animals
• Bile Duct Neoplasms/metabolism
• Bile Duct Neoplasms/parasitology
• Bile Duct Neoplasms/pathology
• Bile Ducts/metabolism
• Bile Ducts/parasitology
• Bile Ducts/pathology
• Cell Culture Techniques
• Cells, Cultured
• Cholangiocarcinoma/metabolism
• Cholangiocarcinoma/parasitology
• Cholangiocarcinoma/pathology
• Clonorchiasis/metabolism
• Clonorchiasis/parasitology
• Clonorchis sinensis/pathogenicity
• Coculture Techniques
• Helminth Proteins/metabolism
• Helminth Proteins/toxicity
• Humans
• Male
• Rabbits
• Tumor Cells, Cultured

• Ministry of Education (KR)
• Korea National Institute of Health
• Ministry of Trade, Industry and Energy

• Bile Duct Neoplasms/drug therapy
• Bile Duct Neoplasms/genetics
• Bile Ducts, Intrahepatic/pathology
• Cholangiocarcinoma/drug therapy
• Cholangiocarcinoma/genetics
• Drug Resistance
• Humans
• Molecular Targeted Therapy
• Signal Transduction

• MR/N012615/1 UK Medical Research Council

• Cholangiocarcinoma
• Epithelial-mesenchymal transition
• Lymph node metastasis
• MicroRNA-494
• WDHD1

• Aged
• Animals
• Bile Duct Neoplasms/genetics
• Bile Duct Neoplasms/metabolism
• Bile Duct Neoplasms/pathology
• Cell Line, Tumor
• Cell Proliferation
• Cholangiocarcinoma/genetics
• Cholangiocarcinoma/metabolism
• Cholangiocarcinoma/pathology
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Epithelial-Mesenchymal Transition
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphatic Metastasis/pathology
• Male
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Middle Aged
• Signal Transduction
• Time Factors
• Transfection
• Tumor Burden
• Up-Regulation
• Xenograft Model Antitumor Assays

• zeb2
• bewo
• jeg3
• trophoblast
• epithelial–mesenchymal transition
• invasion

• Blotting, Western
• Cell Differentiation/genetics
• Cell Differentiation/physiology
• Cell Line
• Epidermal Growth Factor/genetics
• Epidermal Growth Factor/metabolism
• Epithelial-Mesenchymal Transition/genetics
• Epithelial-Mesenchymal Transition/physiology
• Humans
• Trophoblasts/cytology
• Trophoblasts/metabolism
• Zinc Finger E-box Binding Homeobox 2/genetics
• Zinc Finger E-box Binding Homeobox 2/metabolism

• R01 CA165077 NCI NIH HHS

Cholangiocarcinoma (CCA) is a relatively rare malignant and lethal tumour derived from bile duct epithelium and the morbidity is now increasing worldwide. This disease is difficult to diagnose at its inchoate stage and has poor prognosis. Therefore, a clear understanding of pathogenesis and major influencing factors is the key to develop effective therapeutic methods for CCA. In previous studies, canonical correlation analysis has demonstrated that tumour microenvironment plays an intricate role in the progression of various types of cancers including CCA. CCA tumour microenvironment is a dynamic environment consisting of authoritative tumour stromal cells and extracellular matrix where tumour stromal cells and cancer cells can thrive. CCA stromal cells include immune and non‐immune cells, such as inflammatory cells, endothelial cells, fibroblasts, and macrophages. Likewise, CCA tumour microenvironment contains abundant proliferative factors and can significantly impact the behaviour of cancer cells. Through abominably intricate interactions with CCA cells, CCA tumour microenvironment plays an important role in promoting tumour proliferation, accelerating neovascularization, facilitating tumour invasion, and preventing tumour cells from organismal immune reactions and apoptosis. This review summarizes the recent research progress regarding the connection between tumour behaviours and tumour stromal cells in CCA, as well as the mechanism underlying the effect of tumour stromal cells on the growth of CCA. A thorough understanding of the relationship between CCA and tumour stromal cells can shed some light on the development of new therapeutic methods for treating CCA.

• cholangiocarcinoma
• tumor microenvironment
• tumor stromal cells

• Ex vivo
• Fibrosis
• In vitro
• LY2109761
• TGF-β

• bile duct cancer
• epithelial–mesenchymal transition (emt)
• metastasis
• metalloproteinases (mmps)

• Animals
• Bile Duct Neoplasms/metabolism
• Bile Duct Neoplasms/pathology
• Cell Line, Tumor
• Cholangiocarcinoma/metabolism
• Cholangiocarcinoma/secondary
• Epithelial-Mesenchymal Transition
• Humans
• Lung Neoplasms/metabolism
• Lung Neoplasms/secondary
• Mice
• Mice, Mutant Strains
• Vimentin/antagonists & inhibitors
• Vimentin/metabolism
• Xenograft Model Antitumor Assays

• liver cancer
• metastasis
• epithelial-to-mesenchymal transition (emt)
• tumor reactive stroma
• s100a4

• Animals
• Bile Duct Neoplasms/metabolism
• Bile Duct Neoplasms/pathology
• Cholangiocarcinoma/metabolism
• Cholangiocarcinoma/pathology
• Humans
• Neoplasm Invasiveness
• Signal Transduction
• Tumor Microenvironment

• P30 DK034989 NIDDK NIH HHS
• R01 DK079005 NIDDK NIH HHS
• UL1 TR001863 NCATS NIH HHS

Bone morphogenetic proteins (BMPs) play important roles in embryonic and postnatal development by regulating cell differentiation, proliferation, motility, and survival, thus maintaining homeostasis during organ and tissue development. BMPs can lead to tumorigenesis and regulate cancer progression in different stages. Therefore, we summarized studies on BMP expression, the clinical significance of BMP dysfunction in various cancer types, and the molecular regulation of various BMP-related signaling pathways. We emphasized on the paradoxical effects of BMPs on various aspects of carcinogenesis, including epithelial–mesenchymal transition (EMT), cancer stem cells (CSCs), and angiogenesis. We also reviewed the molecular mechanisms by which BMPs regulate tumor generation and progression as well as potential therapeutic targets against BMPs that might be valuable in preventing tumor growth and invasion.

• BMP signaling pathway
• cancer stem cell
• epithelial–mesenchymal transition
• tumorigenesis

Cardiovascular diseases (CVDs) are a major burden on the healthcare system: indeed, over two million new cases are diagnosed every year worldwide. Unfortunately, important drawbacks for the treatment of these patients derive from our current inability to stop the structural alterations that lead to heart failure, the common endpoint of many CVDs. In this scenario, a better understanding of the role of epigenetics – hereditable changes of chromatin that do not alter the DNA sequence itself – is warranted. To date, hyperacetylation of histones has been reported in hypertension and myocardial infarction, but the use of inhibitors for treating CVDs remains limited. Here, we studied the effect of the histone deacetylase inhibitor Givinostat on a mouse model of acute myocardial infarction. We found that it contributes to decrease endothelial-to-mesenchymal transition and inflammation, reducing cardiac fibrosis and improving heart performance and protecting the blood vessels from apoptosis through the modulatory effect of cardiac fibroblasts on endothelial cells. Therefore, Givinostat may have potential for the treatment of CVDs.

Progranulin (PGRN) is a growth factor normally expressed in rapidly cycling epithelial cells for growth, differentiation, and motility. Several studies have shown the association of PGRN overexpression with the progression of numerous malignancies, including cholangiocarcinoma (CCA). However, the underlying mechanisms on how PGRN modulates CCA cell proliferation and motility is not clear. In this study, we investigated the prognostic significance of PGRN expression in human CCA tissue and the mechanisms of PGRN modulation of CCA cell proliferation and motility. We found that CCA tissues with high PGRN expression were correlated with poor prognosis and likelihood of metastasis. PGRN knockdown KKU-100 and KKU-213 cells demonstrated a reduced rate of proliferation and colony formation and decreased levels of phosphatidyl inositol-3-kinase (PI3K) and phosphorylated Akt (pAkt) proteins. Accumulation of cells at the G1 phase was observed and was accompanied by a reduction of cyclin D1 and CDK4 protein levels. Knockdown cells also induced apoptosis by increasing the Bax-to-Bcl-2 ratio. Increased cell apoptosis was confirmed by annexin V-FITC/PI staining. Moreover, suppression of PGRN reduced CCA cell migration and invasion in vitro. Investigating the biomarkers in epithelial–mesenchymal transition (EMT) revealed a decrease in the expression of vimentin, snail, and metalloproteinase-9. In conclusion, our findings imply that PGRN modulates cell proliferation by dysregulating the G1 phase, inhibiting apoptosis, and that it plays a role in the EMT affecting CCA cell motility, possibly via the PI3K/pAkt pathway.

• EMT
• cholangiocarcinoma
• invasion
• migration
• progranulin
• proliferation

• BMP-7
• TGF-β
• endothelial-to-mesenchymal transition
• liver fibrosis
• vascular disorganization

Cholangiocarcinoma (CCA) and its subtypes (mucin- and mixed-CCA) arise from the neoplastic transformation of cholangiocytes, the epithelial cells lining the biliary tree. CCA has a high mortality rate owing to its aggressiveness, late diagnosis and high resistance to radiotherapy and chemotherapeutics. We have demonstrated that CCA is enriched for cancer stem cells which express epithelial to mesenchymal transition (EMT) traits, with these features being associated with aggressiveness and drug resistance. TGF-β signaling is upregulated in CCA and involved in EMT. We have recently established primary cell cultures from human mucin- and mixed-intrahepatic CCA. In human CCA primary cultures with different levels of EMT trait expression, we evaluated the anticancer effects of: (i) CX-4945, a casein kinase-2 (CK2) inhibitor that blocks TGF-β1-induced EMT; and (ii) LY2157299, a TGF-β receptor I kinase inhibitor. We tested primary cell lines expressing EMT trait markers (vimentin, N-cadherin and nuclear catenin) but negative for epithelial markers, and cell lines expressing epithelial markers (CK19-positive) in association with EMT traits. Cell viability was evaluated by MTS assays, apoptosis by Annexin V FITC and cell migration by wound-healing assay. Results: at a dose of 10 μM, CX4945 significantly decreased cell viability of primary human cell cultures from both mucin and mixed CCA, whereas in CK19-positive cell cultures, the effect of CX4945 on cell viability required higher concentrations (>30μM). At the same concentrations, CX4945 also induced apoptosis (3- fold increase vs controls) which correlated with the expression level of CK2 in the different CCA cell lines (mucin- and mixed-CCA). Indeed, no apoptotic effects were observed in CK19-positive cells expressing lower CK2 levels. The effects of CX4945 on viability and apoptosis were associated with an increased number of γ-H2ax (biomarker for DNA double-strand breaks) foci, suggesting the active role of CK2 as a repair mechanism in CCAs. LY2157299 failed to influence cell proliferation or apoptosis but significantly inhibited cell migration. At a 50 μM concentration, in fact, LY2157299 significantly impaired (at 24, 48 and 120 hrs) the wound-healing of primary cell cultures from both mucin-and mixed-CCA. In conclusion, we demonstrated that CX4945 and LY2157299 exert relevant but distinct anticancer effects against human CCA cells, with CX4945 acting on cell viability and apoptosis, and LY2157299 impairing cell migration. These results suggest that targeting the TGF-β signaling with a combination of CX-4945 and LY2157299 could have potential benefits in the treatment of human CCA.

• Apoptosis
• Cell Line, Tumor
• Cell Movement
• Cell Survival
• Cholangiocarcinoma/metabolism
• Cholangiocarcinoma/pathology
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition
• Humans
• Naphthyridines/chemistry
• Neoplastic Stem Cells/cytology
• Phenazines
• Primary Cell Culture
• Pyrazoles/chemistry
• Quinolines/chemistry
• Signal Transduction
• Transforming Growth Factor beta/metabolism
• Wound Healing

• FIRB

Zinc finger and BTB domain containing 7A (ZBTB7A) is aberrantly expressed in breast cancer, but the involvement of ZBTB7A in breast cancer remains controversial. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine which promotes breast cancer metastasis. ZBTB7A and TGF-β are important factors in tumor development. However, the association between ZBTB7A and TGF-β in breast cancer remains unknown. The results of the present study revealed that TGF-β1 induced the expression of ZBTB7A via the phosphoinositide 3-kinase-protein kinase B signaling pathway in human breast cancer cells, and ZBTB7A inhibited the expression of TGF-β1 through indirectly suppressing the promoter activity of TGF-β1. Furthermore, no significant correlation between the expression of ZBTB7A and TGF-β1 were identified in breast cancer tissues using tissue microarray assay and human cancer genomics analysis. These results have identified a negative feedback loop between ZBTB7A and TGF-β signaling, suggesting ZBTB7A as a potential modulator of breast cancer metastasis. Thus, the results of the present study suggested that ZBTB7A is a potential prognostic biomarker for breast cancer.

• breast cancer
• metastasis
• negative feedback
• transforming growth factor-β1
• zinc finger and BTB domain containing 7A

• Chemoresistance
• Cholangiocarcinoma
• Epithelial-mesenchymal transition
• Invasiveness
• Tumor microenvironment

Bone morphogenetic protein-7 (BMP-7) inhibited the pathogenesis of renal injury in response to a variety of stimuli. However, little is known about the molecular regulation and mechanism of endogenous BMP-7 and its renoprotective functions. This study examined the regulation of BMP-7 and its role in the fibronectin secretion and apoptosis of NRK-52E cells resulting from transforming growth factor-β1 (TGF-β1) in vitro. Results showed that TGF-β1 promoted factor-associated suicide (FAS), FAS ligand (FASL), fibronectin (FN), and miRNA-21 expression, while it downregulated phospho-Smad1 (pSmad1), pSmad5, and pSmad8 expressions in NRK-52E cells. In contrast, BMP-7 alleviated TGF-β1-induced cell apoptosis, inhibited TGF-β1-induced higher expression of miRNA-21 and FN, and enhanced TGF-β1-attenuated phosphorylation of Smad1, Smad5, and Smad8. Furthermore, a chemical inhibitor of miRNA-21 also negatively affected TGF-β1-induced apoptosis and FN secretion. On the other hand, overexpression of miRNA-21 counteracted the inhibitory effect of BMP-7 on TGF-β1-induced FN secretion and apoptosis. However, BMP-7 showed no effects on TGF-β1-induced FN secretion and apoptosis following knockdown of miRNA-21. Taken together, these findings demonstrated that BMP-7 might inhibit TGF-β1-induced FN secretion and apoptosis by the suppression of miRNA-21 in NRK-52E cells.

• Breast
• epithelial to mesenchymal transition
• genomics, transcription factor
• non-small-cell lung cancer

• EMT
• microenvironment
• prostate cancer
• stroma

• P01 CA098912 NCI NIH HHS
• R01 CA108646 NCI NIH HHS
• T32 DK007770 NIDDK NIH HHS

AIM: To investigate the effect of small interfering RNA (siRNA) mediated bone morphogenetic protein 7 (BMP7) knockdown on the proliferation and migration of human hepatoma HepG2 cells.

METHODS: Three pairs of siRNAs targeting BMP7 were transiently transfected into HepG2 cells using TransLipid HL Transfection Reagent. HepG2 cells were divided into five groups including a normal control group, a negative-siRNA group and three transfected groups (transfected with BMP7-siRNA-1, BMP7-siRNA-2, and BMP7-siRNA-3, respectively). The expression of BMP7 mRNA and protein was measured by reverse transcript-polymerase chain reaction (RT-PCR) and Western blot, respectively, and the optimal siRNA sequence for BMP7 silencing was selected. The proliferation and migration of HepG2 cells after transfection were assessed by MTT assay and transwell migration assay, respectively. The expression of apoptosis-related proteins (Bax, Bcl-2, and Caspase3) in each group was determined by Western blot, and the cell cycle was analyzed by flow cytometry.

RESULTS: BMP7-siRNA-3 group demonstrated the lowest level of BMP7 expression among the five groups (P < 0.01). Cell growth was significantly slower in the BMP7-siRNA-3 group than in the control groups 48 h and 72 h after cells were transfected (P < 0.01). The numbers of cell passing the membrane were significantly lower in the BMP7-siRNA-3 group than in the control groups 24 h after cells were transfected (P < 0.01). The expression of Bax and Caspase3 (P < 0.01) was significantly increased after BMP7 silencing, and there was no statistically significant difference in the Bcl-2 expression. Flow cytometery showed that cells were significantly blocked in G₂ phase 48 h after cells were transfected with BMP7-siRNA-3 (P < 0.01).

CONCLUSION: SiRNA mediated BMP7 knockdown can inhibit HepG2 cell proliferation and migration, promote apoptosis and block cells in G₂ phase.

• Small interfering RNA
• Bone morphogenetic protein 7
• Liver cancer
• Proliferation and migration

In addition to its well-established role in embryo development, epithelial-to-mesenchymal transition (EMT) has been proposed as a general mechanism favoring tumor metastatization in several epithelial malignancies. Herein, we review the topic of EMT in cholangiocarcinoma (CCA), a primary liver cancer arising from the epithelial cells lining the bile ducts (cholangiocytes) and characterized by an abundant stromal reaction. CCA carries a dismal prognosis, owing to a pronounced invasiveness and scarce therapeutic opportunities. In CCA, several reports indicate that cancer cells acquire a number of EMT biomarkers and functions. These phenotypic changes are likely induced by both autocrine and paracrine signals released in the tumor microenvironment (cytokines, growth factors, morphogens) and intracellular stimuli (microRNAs, oncogenes, tumor suppressor genes) variably associated with specific disease mechanisms, including chronic inflammation and hypoxia. Nevertheless, evidence supporting a complete EMT of neoplastic cholangiocytes into stromal cells is lacking, and the gain of EMT-like changes by CCA cells rather reflects a shift towards an enhanced pro-invasive phenotype, likely induced by the tumor stroma. This concept may help to identify new biomarkers of early metastatic behavior along with potential therapeutic targets.

• cancer-associated fibroblast
• cholangiocarcinoma
• cholangiocyte
• epithelial-to-mesenchymal transition
• invasiveness
• metastatization
• tumor reactive stroma

• R01 DK079005 NIDDK NIH HHS

Transforming growth factor (TGF-β)/TGF-β receptor signal is known to promote cell migration. Up-regulation of TGF-β in serum/peritoneal fluid and increased levels of pluripotent transcription factor OCT4 in endometriotic tissues are frequently observed in patients with endometriosis. However, the mechanisms underlying how TGF-β/TGF-β receptor and OCT4 affect endometriotic cell migration still remain largely unknown. Therefore, endometriotic tissue with high cell migratory capacity were collected from patients with adenomyotic myometrium (n = 23) and chocolate cyst (n = 24); and endometrial tissue with low cell migratory capacity in normal endometrium or hyperplastic endometrium (n = 8) were collected as the controls. We found the mRNA levels of TGF-β receptor I (TGF-β RI) and OCT4 were significantly higher in the high-migratory ectopic endometriotic tissues than those of the low-migratory normal or hyperplastic endometrium. Positive correlations between TGF-β RI and OCT4, and either TGF-β RI or OCT4 with migration-related genes (SNAIL, SLUG and TWIST) regarding the mRNA levels were observed in human endometriotic tissues. TGF-βI dose-dependently increased the gene and protein levels of OCT4, SNAIL and N-Cadherin (N-CAD) and silencing of endogenous OCT4 significantly suppressed the TGF-βI-induced expressions of N-CAD and SNAIL in primary human endometriotic stromal cells and human endometrial carcinoma cell lines RL95-2 and HEC1A. Furthermore, TGF-βI significantly increased the migration ability of endometriotic cells and silencing of OCT4 dramatically suppressed the TGF-βI-induced cell migration activity evidenced by wound-closure assay, transwell assay, and confocal image of F-actin cellular distribution. In conclusion, the present findings demonstrate that the niche TGF-β plays a critical role in initiating expressions of pluripotent transcription factor OCT4 which may contribute to the ectopic endometrial growth by stimulating endometrial cell migration. These findings would be useful for developing therapeutic strategies targeting TGF-β-OCT4 signaling to prevent endometriosis in the future.

• Adult
• Cadherins/genetics
• Cadherins/metabolism
• Cell Line, Tumor
• Cell Movement
• Endometriosis/metabolism
• Female
• Humans
• Middle Aged
• Nuclear Proteins/genetics
• Nuclear Proteins/metabolism
• Octamer Transcription Factor-3/genetics
• Octamer Transcription Factor-3/metabolism
• Protein Serine-Threonine Kinases/genetics
• Protein Serine-Threonine Kinases/metabolism
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta/genetics
• Receptors, Transforming Growth Factor beta/metabolism
• Snail Family Transcription Factors
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Transforming Growth Factor beta1/genetics
• Transforming Growth Factor beta1/metabolism
• Twist-Related Protein 1/genetics
• Twist-Related Protein 1/metabolism

Tumor metastasis is a major cause of death in patients with solid tumors. Epithelial mesenchymal transition (EMT) is a process in which the epithelial cells are transformed into the stroma cells. This process is accompanied by changes in gene expression and cell phenotype, which are often activated during tumor invasion and metastasis. Cholangiocarcinoma is a kind of malignancy originating from the bile duct epithelium, and its main biological characteristics are early invasion, metastasis and recurrence. The research of cholangiocarcinoma metastasis could provide a theoretical basis for the development of new treatment strategies to manage this malignancy. This paper reviews the roles of EMT related molecular markers metastasis in the invasion and metastasis of cholangiocarcinoma.

• Epithelial mesenchymal transition
• Tumor metastasis
• Cholangiocarcinoma
• Molecular markers

• adenocarcinoma
• bone morphogenetic protein
• non-small-cell lung cancer
• prognostic biomarker
• squamous cell carcinoma

• Adenocarcinoma/metabolism
• Biomarkers, Tumor/metabolism
• Bone Morphogenetic Protein 5/metabolism
• Carcinoma, Squamous Cell/metabolism
• Humans
• Lung Neoplasms/metabolism

Epithelial-to-mesenchymal transition (EMT) represents conversion of an epithelial cell in an elongated cell with mesenchymal phenotype, which can occur in physiologic and pathologic processes such as embryogenesis (type 1 EMT), wound healing and/or fibrosis (type 2 EMT) and malignant tumors (type 3 EMT). The proliferation rate, metastasizing and recurrence capacity, as also the individualized response at chemotherapics, in both epithelial and mesenchymal malignant tumors is known to be influenced by reversible switch between EMT and mesenchymal-to-epithelial transition (MET). Although much research work has already been done in these fields, the specific molecular pathways of EMT, relating to the tumor type and tumor localization, are yet to be elucidated. In this paper, based on the literature and personal experience of the authors, an update in the field of EMT vs MET in epithelial and mesenchymal tumors is presented. The authors tried to present the latest data about the particularities of these processes, and also of the so-called endothelial-to-mesenchymal transition, based on tumor location. The EMT-angiogenesis link is discussed as a possible valuable parameter for clinical follow-up and targeted therapeutic oncologic management. The paper begins with presentation of the basic aspects of EMT, its classification and assessment possibilities, and concludes with prognostic and therapeutic perspectives. The particularities of EMT and MET in gastric and colorectal carcinomas, pancreatic cancer, hepatocellular and cholangiocarcinomas, and lung, breast and prostate cancers, respectively in sarcomas and gastrointestinal stromal tumors are presented in detail.

• Gastrointestinal stromal tumor
• Carcinoma
• Gastrointestinal cancer
• Hepatic cancer
• Sarcoma