• Cancer stem cells
• Cholangiocarcinoma
• Drug targeted therapy
• Metabolic microenvironment
• Metabolic reprogramming

• Humans
• Cholangiocarcinoma/metabolism
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/drug therapy
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Neoplastic Stem Cells/drug effects
• Bile Duct Neoplasms/metabolism
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/drug therapy
• Tumor Microenvironment/drug effects
• Cellular Reprogramming
• Animals
• Autophagy
• Signal Transduction
• Oxidative Phosphorylation
• Metabolic Reprogramming

• Cancer stem cells
• Chemotherapy drugs
• Immunotherapy
• Intrahepatic cholangiocarcinoma
• Prognosis

• amurensin G
• cancer stem cell
• chemoresistance
• cholangiocarcinoma
• gemcitabine

• Humans
• Gemcitabine
• Down-Regulation
• Cholangiocarcinoma/drug therapy
• Bile Duct Neoplasms/drug therapy
• Bile Ducts, Intrahepatic
• Dibenzocycloheptenes
• Resorcinols

• 2022R1A4A1025557 National Research Foundation of Korea

• Cancer stem cells
• Immune evasion
• Targeted therapies
• Tumor microenvironment

• Humans
• Neoplasms/pathology
• Cell Differentiation
• Biomarkers/metabolism
• Neoplastic Stem Cells/metabolism
• Treatment Outcome
• Tumor Microenvironment

• Cancer stem cells
• FZD4/β-catenin
• HLF
• Intrahepatic cholangiocarcinoma
• m6A

• cancer stem cells
• heterogeneity
• liver cancer
• metabolism
• plasticity
• tumor microenvironment

To investigate the clinical value of CD133 and CD44 as putative cancer stem cell markers in distinguishing between basal cell carcinoma (BCC) and trichoblastomas (TB).

Tumor samples from 24 BCC and 23 TB patients were retrospectively retrieved for immunohistochemical staining of CD133 and CD44. The results were interpreted using a semiquantitative scoring system (H score). A receiver operating characteristic (ROC) curve was developed to identify an optimal cutoff value for differentiating between BCC and TB.

Expression of CD133 was significantly higher in BCC patients than in TB patients (median H score: 30 [IQR: 12.5–56.3] vs 0 [IQR: 0–2], P < 0.001). However, there was no significant difference in CD44 expression between the two groups (median H score: 105 [IQR: 63.8–155.0] vs 60 [IQR: 30–120], P = 0.095). The ROC analysis of CD133 immunostaining yielded an area under the curve (AUC) of 0.881 (95% CI: 0.756–1.000) for differentiating between BCC and TB by using a H score of 7 as the cut-off value (98.5% sensitivity and 87.0% specificity). By contrast, immunostaining of CD44 showed a lower diagnostic value, with an AUC of 0.642 (95% CI: 0.476–0.808) at the optimal cut-off value of 85 (62.5% sensitivity and 73.9% specificity). The positive and negative predictive values were 88.5% and 95.2% for CD133 and 71.4% and 65.4% for CD44, respectively. Additionally, CD133 expression was significantly associated with mitotic activity in BCC patients (r = 0.549, P = 0.005).

Our study expanded upon previous studies of CD133 and CD44 expressions in skin tumors, suggesting that CD133, but not CD44, may serve as a novel biomarker for differential diagnosis of BCC, although future studies using a larger number of patients are needed to justify it further.

• breast cancer
• cellular uptake
• curcumin
• cytotoxicity
• hemocompatibility
• quercetin

Cholangiocarcinoma (CCA) is a lethal cancer of bile duct epithelial cells with a high mortality rate and limited therapeutic options. An effective treatment is, therefore, urgently needed to improve treatment outcomes for these patients. To develop a new therapeutic option, we engineered T cells secreting αCD133-αCD3 bispecific T-cell engager and evaluated their antitumor effects against CD133-expressing CCA cells. The cDNA encoding αCD133-αCD3 bispecific T-cell engager (αCD133-αCD3-ENG) was cloned into pCDH lentiviral construct and its expression was tested in Lenti-X 293T cells. T cells from healthy donors were then transduced with engineered lentiviruses to create T cells secreting αCD133-αCD3 engager to evaluate their antitumor activities. The average transduction efficiency into T cells was approximately 60.03±21.65%. In the co-culture system containing T cells secreting αCD133-αCD3 engager (as effector cells) and mWasabi-luciferase-expressing CCA cells (KKU-100 and KKU-213A; as target cells), the effector T cells exhibited significantly higher cytolytic activities against the target CCA cells (49.0±9.76% and 64.10±13.18%, respectively) than those observed against the untransduced T cells (10.97±10.65%; p = 0.0103 and 9.80±11.05%; p = 0.0054) at an effector-to-target ratio of 5:1. In addition, the secreted αCD133-αCD3 engager significantly redirected both transduced T cells and bystander T cells to kill the target CCA cells (up to 73.20±1.68%; p<0.05). Moreover, the transduced and bystander T cells could kill the target CCA spheroids at a rate approximately 5-fold higher than that of the no treatment control condition (p = 0.0011). Our findings demonstrate proof-of-principle that T cells secreting αCD133-αCD3 engager can be an alternative approach to treating CD133-positive CCA, and they pave the way for future in vivo study and clinical trials.

• cancer
• liver cancer

• Animals
• Bile Duct Neoplasms/genetics
• Bile Duct Neoplasms/pathology
• Body Weight
• Carcinogenesis/genetics
• Carcinogenesis/pathology
• Cell Proliferation
• Cholangiocarcinoma/genetics
• Cholangiocarcinoma/pathology
• Down-Regulation/genetics
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Ki-67 Antigen/metabolism
• Liver/pathology
• Liver Cirrhosis/pathology
• Membrane Proteins/deficiency
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Mice, Inbred C57BL
• Neoplasm Metastasis
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Nerve Tissue Proteins/deficiency
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/metabolism
• Organ Size
• Prognosis
• Protein Domains
• Receptors, Notch/chemistry
• Receptors, Notch/metabolism
• Signal Transduction
• Stem Cells/metabolism
• Transcription Factor HES-1/metabolism
• Mice

• 82072689 National Natural Science Foundation of China (National Science Foundation of China)
• 81872019 National Natural Science Foundation of China (National Science Foundation of China)
• Sichuan Province Science and Technology Planning Project;amp;amp;2018JY0653;amp;amp;
• 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (2020HXFH010)

Biliary tract cancer (BTC) arises from biliary epithelial cells (BECs) and includes intrahepatic cholangiocarcinoma (IHCC), gallbladder cancer (GC), and extrahepatic cholangiocarcinoma (EHCC). Although frequent KRAS mutations and epigenetic changes at the INK4A/ARF locus have been identified, the molecular pathogenesis of BTC is unclear and the development of corresponding anticancer agents remains inadequate. We isolated epithelial cell adhesion molecule (EpCAM)–positive BECs from the mouse intrahepatic bile duct, gallbladder, and extrahepatic bile duct, and established organoids derived from these cells. Introduction of activated KRAS and homozygous deletion of Ink4a/Arf in the cells of each organoid type conferred the ability to form lethal metastatic adenocarcinoma with differentiated components and a pronounced desmoplastic reaction on cell transplantation into syngeneic mice, indicating that the manipulated cells correspond to BTC–initiating cells. The syngeneic mouse models recapitulate the pathological features of human IHCC, GC, and EHCC, and they should therefore prove useful for the investigation of BTC carcinogenesis and the development of new therapeutic strategies. Tumor cells isolated from primary tumors formed organoids in three‐dimensional culture, and serial syngeneic transplantation of these cells revealed that their cancer stem cell properties were supported by organoid culture, but not by adherent culture. Adherent culture thus attenuated tumorigenic activity as well as the expression of both epithelial and stem cell markers, whereas the expression of epithelial‐mesenchymal transition (EMT)–related transcription factor genes and mesenchymal cell markers was induced. Our data show that organoid culture is important for maintenance of epithelial cell characteristics, stemness, and tumorigenic activity of BTC–initiating cells.

• biliary tract cancer
• cancer stem cell
• cholangiocarcinoma
• epithelial-mesenchymal transition
• organoid culture

Biliary tract cancers (BTCs) are aggressive epithelial malignancies that can arise at any point of the biliary tree. Albeit rare, their incidence and mortality rates have been rising steadily over the past 40 years, highlighting the need to improve current diagnostic and therapeutic strategies. BTCs show high inter- and intra-tumour heterogeneity both at the morphological and molecular level. Such complex heterogeneity poses a substantial obstacle to effective interventions. It is widely accepted that the observed heterogeneity may be the result of a complex interplay of different elements, including risk factors, distinct molecular alterations and multiple potential cells of origin. The use of genetic lineage tracing systems in experimental models has identified cholangiocytes, hepatocytes and/or progenitor-like cells as the cells of origin of BTCs. Genomic evidence in support of the distinct cell of origin hypotheses is growing. In this review, we focus on recent advances in the histopathological subtyping of BTCs, discuss current genomic evidence and outline lineage tracing studies that have contributed to the current knowledge surrounding the cell of origin of these tumours.

• ARID1A, AT-rich interactive domain-containing protein 1A
• BAP1, BRCA1-associated protein 1
• BRAF, v-Raf murine sarcoma viral oncogene homolog B
• BTC, biliary tract cancer
• Biliary tract cancers
• CCA, cholangiocarcinoma
• CDKN2A/B, cyclin-dependent kinase inhibitor 2A/B
• CK, cytokeratin
• CLC, cholangiolocarcinoma
• Cell of origin
• Cholangiocarcinoma
• CoH, Canal of Hering
• DCR, disease control rate
• ER, estrogen receptor
• ERBB2/3, Erb-B2 Receptor Tyrosine Kinase 2/3
• FGFR, fibroblast growth factor receptor
• FGFR2, Fibroblast Growth Factor Receptor 2
• GBC, gallbladder cancer
• GEMM, genetically engineered mouse models
• Genomics
• HCC, hepatocellular carcinoma
• HPCs, hepatic progenitor cells
• IDH, isocitrate dehydrogenase
• KRAS, Kirsten Rat Sarcoma Viral Oncogene Homolog
• Lineage tracing
• MET, Hepatocyte Growth Factor Receptor
• MST1, Macrophage Stimulating 1
• NA, not applicable
• NAFLD, non-alcoholic fatty liver disease
• NASH, non-alcoholic steatohepatitis
• NGS, next-generation sequencing
• NR, not reported
• NTRK, Neurotrophic Receptor Tyrosine Kinase 1
• ORR, objective response rate
• OS, overall survival
• PBG, peribiliary gland
• PFS, progression- free survival
• PIK3CA, Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha
• PLC, primary liver cancer
• PRKACA/B, Protein Kinase CAMP-Activated Catalytic Subunit Alpha/Beta
• PROM1, Prominin 1
• PSC, primary sclerosing cholangitis
• Personalized therapy
• RNF43, Ring Finger Protein 43
• SMAD4, SMAD Family Member 4
• TBG, thyroid binding globulin
• TP53, Tumor Protein P53
• WHO, World Health Organization
• dCCA, distal cholangiocarcinoma
• eCCA, extrahepatic cholangiocarcinoma
• iCCA, intrahepatic cholangiocarcinoma
• mo, months
• pCCA, perihilar cholangiocarcinoma

• EZH2
• biliary tract cancer
• cholangiocarcinoma
• gallbladder cancer
• lncRNA
• long-noncoding RNA

• alkaline extracellular microenvironment
• cancer-favoring vaccinia virus (CVV)
• cholangiocarcinoma (CCA)

• NRF-2016R1D1A1B03935221 National Research Foundation of Korea
• NRF-2017R1C1B5015034 National Research Foundation of Korea
• NRF-2018R1D1A1B07050358 National Research Foundation of Korea

• Cancer stem cells
• Cholangiocarcinoma
• Cyclopamine
• Epithelial to mesenchymal transition
• Hypoxia
• Sonic Hedgehog pathway

• cancer-associated fibroblasts (CAFs)
• cholangiocarcinoma (CCA)
• cholangiocytes
• epithelial to mesenchymal transition (EMT)
• hepatocytes
• mitogen-activated protein kinases (MAPK)

• Bile Duct Neoplasms/diagnosis
• Bile Duct Neoplasms/metabolism
• Biomarkers, Tumor/metabolism
• Cholangiocarcinoma/diagnosis
• Cholangiocarcinoma/metabolism
• Early Detection of Cancer
• Gene Expression Regulation, Neoplastic
• Humans
• MAP Kinase Signaling System
• Mitogen-Activated Protein Kinases/metabolism
• Phosphorylation

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

• cholangiocellular cancer
• delta hepatitis
• hypercalcemia
• malignancie
• paraneoplastic

• cancer stem cells
• chelators
• ferroptosis
• iron
• liver cancer

• carcinogenesis
• cholangiocarcinoma
• hepatocellular carcinoma
• liver

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the 2 most common primary malignant liver tumors, with hepatocellular and bile ductular differentiation, respectively. This article reviews the key histopathological findings of these 2 primary liver cancers and includes a review of the role of ancillary testing for differential diagnosis, risk stratification according to the American Joint Committee on Cancer (AJCC) staging recommendation, and a review of precancerous lesions. A literature review was conducted to identify articles with information relevant to precancerous precursors, current histopathological classification, ancillary testing, and risk stratification of primary malignant liver tumors. The histomorphology of normal liver, preinvasive precursors, primary malignancies, and morphological variants, and the utilization of ancillary tests for the pathological diagnosis are described. Dysplastic nodules are the preinvasive precursors of HCC, and intraductal papillary neoplasms of bile ducts and biliary intraepithelial neoplasia are the preinvasive precursors of CC. Benign liver nodules including focal nodular hyperplasia and adenomas are included in this review, since some forms of adenomas progress to HCC and often they have to be differentiated from well-differentiated HCC. A number of morphological variants of HCC have been described in the literature, and it is necessary to be aware of them in order to render the correct diagnosis. Risk stratification is still dependent on the AJCC staging system. The diagnosis of primary liver carcinomas is usually straightforward. Application of the appropriate ancillary studies aids in the differential diagnosis of difficult cases. The understanding of the carcinogenesis of these malignancies has improved with the standardization of the pathological classification of preinvasive precursors and studies of the molecular pathogenesis. Risk stratification still depends on pathological staging.

• biliary intraepithelial neoplasia
• cholangiocarcinoma
• dysplastic nodule
• focal nodular hyperplasia
• hepatic adenoma
• hepatocellular carcinoma
• intraductal papillary neoplasm

Hepatocellular-cholangiocarcinoma (H-ChC) is a rare subtype of liver cancer with clinicopathological features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). To date, molecular mechanisms underlying the co-existence of HCC and iCCA components in a single tumor remain elusive. Here, we show that H-ChC samples contain substantial private mutations from WES analyses, ranging from 33.1 to 86.4%, indicative of substantive intratumor heterogeneity (ITH). However, on the other hand, numerous ubiquitous mutations shared by HCC and iCCA suggest the monoclonal origin of H-ChC. Mutated genes identified herein, e.g., VCAN, ACVR2A, and FCGBP, are speculated to contribute to distinct differentiation of HCC and iCCA within H-ChC. Moreover, immunohistochemistry demonstrates that EpCAM is highly expressed in 80% of H-ChC, implying the stemness of such liver cancer. In summary, our data highlight the monoclonal origin and stemness of H-ChC, as well as substantial intratumoral heterogeneity.

Hepatocellular-cholangiocarcinoma (H-ChC) is a rare subtype of liver cancer with features of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Here, the authors utilize whole exome sequencing to highlight the monoclonal origin and stemness of H-ChC, as well as substantial intratumoral heterogeneity.

Poor prognosis and high recurrence remain leading causes of primary liver cancerassociated mortality. The spread of circulating tumor cells (CTCs) in the blood plays a major role in the initiation of metastasis and tumor recurrence after surgery. Nevertheless, only a subset of CTCs can survive, migrate to distant sites and establish secondary tumors. Consistent with cancer stem cell (CSC) hypothesis, stem-like CTCs might represent a potential source for cancer relapse and distant metastasis. Thus, identification of stem-like metastasis-initiating CTC-subset may provide useful clinically prognostic information. This review will emphasize the most relevant findings of CTCs in the context of stem-like biology associated to liver carcinogenesis. In this view, the emerging field of stem-like CTCs may deliver substantial contribution in liver cancer field in order to move to personalized approaches for diagnosis, prognosis and therapy.

• cancer stem cells
• circulating tumor cells
• primary liver cancer

Quercetin, nature’s most common flavonoid, possesses anticarcinogenic properties against various forms of cancer. The aim of this study was to investigate the effect of quercetin on breast cancer stem cells in the MDA-MB-231 cell line, and to elucidate the possible mechanisms for those effects.

We evaluated breast cancer stem cell proliferation, clone generation, and mammosphere formation to determine the effect of quercetin treatment on breast cancer stem cells.

In our study, quercetin suppressed breast cancer stem cell proliferation, self-renewal, and invasiveness. It also lowered the expression levels of proteins related to tumorigenesis and cancer progression, such as aldehyde dehydrogenase 1A1, C-X-C chemokine receptor type 4, mucin 1, and epithelial cell adhesion molecules.

These results indicate that quercetin targets and destroys breast cancer stem cells, making it a potential novel drug in the fight against cancer.

• cholangiocarcinoma
• cytokeratin
• hepatocellular carcinoma
• sal-like protein 4

• Liver
• MRI
• hepatocellular carcinoma
• liver cirrhosis
• mass-forming intrahepatic cholangiocellular carcinoma

• Adult
• Aged
• Aged, 80 and over
• Bile Duct Neoplasms/diagnostic imaging
• Bile Ducts, Intrahepatic/diagnostic imaging
• Carcinoma, Hepatocellular/diagnostic imaging
• Case-Control Studies
• Cholangiocarcinoma/diagnostic imaging
• Contrast Media/administration & dosage
• Humans
• Liver Cirrhosis/diagnostic imaging
• Liver Neoplasms/diagnostic imaging
• Magnetic Resonance Imaging
• Middle Aged
• Retrospective Studies
• Sensitivity and Specificity

Cholangiocarcinoma is a malignant neoplasm originating from biliary epithelial cells. The incidence and mortality of this cancer are rising in the world. Currently, cholangiocarcinoma is accepted as a stem cell disease with many risk factors. Diagnosis is relatively simple but therapy is extremely difficult. Surgery is the mainstay of treatment for early stage patients. Endobiliary approaches, chemotherapy and radiotherapy are other therapeutic approaches.

• Cholangiocarcinoma
• stem cell disease
• pathogenesis

• Biliary tract cancer
• Cancer stem cell markers
• Micro-RNAs
• Tumor microenvironment
• cancer stem cells

• Animals
• Antineoplastic Agents/therapeutic use
• Biliary Tract Neoplasms/drug therapy
• Biliary Tract Neoplasms/metabolism
• Biliary Tract Neoplasms/pathology
• Biomarkers, Tumor/metabolism
• Cell Lineage
• Cell Movement
• Cell Proliferation
• Humans
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/pathology
• Phenotype
• Signal Transduction
• Tumor Microenvironment

• Biliary tract cancer
• MEK
• PI3K
• STAT3
• cholangiocarcinoma
• targeted therapy

• CART cocktail immunotherapy
• CD133
• Cholangiocarcinoma
• EGFR

• EpCAM
• apoptosis
• cancer stem cells
• chemotherapy
• mucin1

• biomarkers
• clinic-pathological
• early diagnosis
• hepatocellular carcinoma
• prognosis

The BRCA/Fanconi anemia (FA) pathway plays a key role in the repair of DNA double strand breaks. We focused on this pathway to clarify chemoresistance mechanisms in biliary tract cancer (BTC). We also investigated changes in the CD24⁺/44⁺ population that may be involved in chemoresistance, as this population likely includes cancer stem cells. We used three BTC cell lines to establish gemcitabine (GEM)-resistant (GR) cells and evaluated the expression of BRCA/FA pathway components, chemoresistance, and the effect of BRCA/FA pathway inhibition on the CD24⁺/44⁺ population. FANCD2 and CD24 expression were evaluated in 108 resected BTC specimens. GR cells highly expressed the BRCA/FA components. The BRCA/FA pathway was upregulated by GEM and cisplatin (CDDP) exposure. Inhibition using siRNA and RAD51 inhibitor sensitized GR cells to GEM or CDDP. The CD24⁺/44⁺ population was increased in GR and parent BTC cells treated with GEM or CDDP and highly expressed BRCA/FA genes. FANCD2 was related to CD24 expression in resected BTC specimens. Inhibition of the BRCA/FA pathway under GEM reduced the CD24⁺/44⁺ population in MzChA1-GR cells. Thus, high expression of the BRCA/FA pathway is one mechanism of chemoresistance against GEM and/or CDDP and is related to the CD24⁺/44⁺ population in BTC.

• BRCA2
• CD24
• FANCD2
• Fanconi anemia
• RAD51c

• Cancer stem cells
• Cholangiocarcinoma
• Tumour associated macrophages
• Tumour microenvironment

• Biomarkers
• Intrahepatic cholangiocarcinoma
• Prognosis

• AC133 Antigen
• Aged
• Antigens, CD/genetics
• Antigens, CD/metabolism
• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/metabolism
• Bile Duct Neoplasms/genetics
• Bile Duct Neoplasms/mortality
• Bile Duct Neoplasms/surgery
• Bile Ducts, Intrahepatic/surgery
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Cell Adhesion/physiology
• Cell Adhesion Molecules/genetics
• Cell Adhesion Molecules/metabolism
• Cholangiocarcinoma/genetics
• Cholangiocarcinoma/mortality
• Cholangiocarcinoma/surgery
• Epithelial Cell Adhesion Molecule
• Epithelial Cells/cytology
• Female
• Follow-Up Studies
• Glycoproteins/genetics
• Glycoproteins/metabolism
• Humans
• Hyaluronan Receptors/genetics
• Hyaluronan Receptors/metabolism
• Male
• Middle Aged
• Neoplasm Recurrence, Local/mortality
• Peptides/genetics
• Peptides/metabolism
• Predictive Value of Tests
• Prognosis
• Proportional Hazards Models
• Risk Factors
• Transcriptome

• Cancer stem cell
• Chemoresistance
• Hematologic disease
• Leukemia
• Marker
• Oncology
• Relapse

With recent advances in cancer stem cell analysis, it has been postulated that the transformation of hepatic stem and progenitor cells underlies the development of certain liver cancers. Human C-KIT is a transmembrane type III receptor protein with intrinsic tyrosine kinase activity that has been proposed as a marker for human embryonic stem cells. In addition, human C-KIT functions in maintaining the undifferentiated state of stem cells, and has been identified as a marker for human hematopoietic and hepatic stem/progenitor cells. The present study identified an unusual case of a C-KIT-positive hepatic tumor with an undifferentiated stem cell phenotype distinct from existing descriptions of liver tumors. A 69-year-old male with Ampulla of Vater (AoV) cancer was admitted to the hospital for the treatment of a hepatic mass that was incidentally detected during evaluation of AoV cancer. Microscopically, the hepatic tumor was composed of solidly packed small, round and uniform undifferentiated cells, which resembled that of a small-blue-round-cell tumor. The immunophenotype of neoplastic cells (C-KIT⁺/EpCAM⁺/E-cadherin⁺/keratin 7⁻/keratin 19⁻/α-fetoprotein⁻/albumin⁻) supported primitive stem cell features with no hepatic or biliary phenotypes. Polymerase chain reaction and direct DNA sequencing revealed no C-KIT mutations. It is suggested that this tumor may have originated from transformed C-KIT⁺/EpCAM⁺/E-cadherin⁺ cells, which are more primitive and undifferentiated than bipotential hepatic progenitor cells.

• C-KIT
• liver
• stem cell

AIM: To investigate the roles of peribiliary glands around the bile ducts in the pathophysiology of the biliary tract.

METHODS: The expression of fetal pancreatic markers, pancreatic duodenal homeobox factor 1 (PDX1) and hairy and enhancer of split 1 (HES1) and endodermal stem/progenitor (S/P) cell markers [CD44s, chemokine receptor type 4 (CXCR4), SOX9 and epithelial cell adhesion molecule (EpCAM)] were examined immunohistochemically in 32 normal adult livers (autopsy livers) and 22 hepatolithiatic livers (surgically resected livers). The latter was characterized by the proliferation of the peribiliary glands. Immunohistochemistry was performed using formalin-fixed, paraffin-embedded tissue sections after deparaffinization. Although PDX1 and HES1 were expressed in both the nucleus and cytoplasm of epithelial cells, only nuclear staining was evaluated. SOX9 was expressed in the nucleus, while CD44s, CXCR4 and EpCAM were expressed in the cell membranes. The frequency and extent of the expression of these molecules in the lining epithelia and peribiliary glands were evaluated semi-quantitatively based on the percentage of positive cells: 0, 1+ (focal), 2+ (moderate) and 3+ (extensive).

RESULTS: In normal livers, PDX1 was infrequently expressed in the lining epithelia, but was frequently expressed in the peribiliary glands. In contrast, HES1 was frequently expressed in the lining epithelia, but its expression in the peribiliary glands was focal, suggesting that the peribiliary glands retain the potential of differentiation toward the pancreas and the lining epithelia exhibit properties to inhibit such differentiation. This unique combination was also seen in hepatolithiatic livers. The expression of endodermal S/P cell markers varied in the peribiliary glands in normal livers: SOX9 and EpCAM were frequently expressed, CD44s infrequently, and CXCR4 almost not at all. The expression of these markers, particularly CD44s and CXCR4, increased in the peribiliary glands and lining epithelia in hepatolithiatic livers. This increased expression of endodermal S/P cell markers may be related to the increased production of intestinal and gastric mucin and also to the biliary neoplasia associated with the gastric and intestinal phenotypes reported in hepatolithiasis.

CONCLUSION: The unique expression pattern of PDX1 and HES1 and increased expression of endodermal S/P cell markers in the peribiliary glands may be involved in biliary pathophysiologies.

• Biliary tree
• Peribiliary glands
• Pancreatic duodenal homeobox factor 1
• Stem cells
• Differentiation
• Pancreas