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Hepatology (Baltimore, Md.) Apr 2024Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly... (Review)
Review
Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly classified according to their anatomical location and include diverse molecular subclasses harboring inter-tumoral and intratumoral heterogeneity. Besides the tumor cell component, CCA is also characterized by a complex and dynamic tumor microenvironment where tumor cells and stromal cells crosstalk in an intricate network of interactions. Cancer-associated fibroblasts, one of the most abundant cell types in the tumor stroma of CCA, are actively involved in cholangiocarcinogenesis by participating in multiple aspects of the disease including extracellular matrix remodeling, immunomodulation, neo-angiogenesis, and metastasis. Despite their overall tumor-promoting role, recent evidence indicates the presence of transcriptional and functional heterogeneous CAF subtypes with tumor-promoting and tumor-restricting properties. To elucidate the complexity and potentials of cancer-associated fibroblasts as therapeutic targets in CCA, this review will discuss the origin of cancer-associated fibroblasts, their heterogeneity, crosstalk, and role during tumorigenesis, providing an overall picture of the present and future perspectives toward cancer-associated fibroblasts targeting CCA.
Topics: Humans; Cancer-Associated Fibroblasts; Cholangiocarcinoma; Biliary Tract; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Tumor Microenvironment; Contracture; Arachnodactyly
PubMed: 37018128
DOI: 10.1097/HEP.0000000000000206 -
Cell Reports. Medicine Nov 2023Patients with biliary tract cancer (BTC) show different responses to chemotherapy, and there is no effective way to predict chemotherapeutic response. We have generated...
Patients with biliary tract cancer (BTC) show different responses to chemotherapy, and there is no effective way to predict chemotherapeutic response. We have generated 61 BTC patient-derived organoids (PDOs) from 82 tumors (74.4%) that show similar histological and genetic characteristics to the corresponding primary BTC tissues. BTC tumor tissues with enhanced stemness- and proliferation-related gene expression by RNA sequencing can more easily form organoids. As expected, BTC PDOs show different responses to the chemotherapies of gemcitabine, cisplatin, 5-fluoruracil, oxaliplatin, etc. The drug screening results in PDOs are further validated in PDO-based xenografts and confirmed in 92.3% (12/13) of BTC patients with actual clinical response. Moreover, we have identified gene expression signatures of BTC PDOs with different drug responses and established gene expression panels to predict chemotherapy response in BTC patients. In conclusion, BTC PDO is a promising precision medicine tool for anti-cancer therapy in BTC patients.
Topics: Humans; Drug Evaluation, Preclinical; Early Detection of Cancer; Gemcitabine; Biliary Tract Neoplasms; Organoids
PubMed: 37944531
DOI: 10.1016/j.xcrm.2023.101277 -
Clinical Gastroenterology and... Jul 2023Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibroinflammatory damage to the biliary tree, typically in the setting of... (Review)
Review
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibroinflammatory damage to the biliary tree, typically in the setting of inflammatory bowel disease, with an increased risk of liver failure and cholangiocarcinoma. A complex pathophysiology, heterogeneity in clinical features, and the rare nature of the disease have contributed to the lack of effective therapy to date. However, recent innovations in the characterization and prognostication of patients with PSC, in addition to new tools for medical management and emerging pharmacologic agents, give rise to the potential for meaningful progress in the next several years. This review summarizes current concepts in PSC and highlights particular areas in need of further study.
Topics: Humans; Cholangitis, Sclerosing; Cholangiocarcinoma; Cholestasis; Bile Ducts, Intrahepatic; Bile Duct Neoplasms
PubMed: 37084929
DOI: 10.1016/j.cgh.2023.04.004 -
Hepatology (Baltimore, Md.) Nov 2023Cancer cells often encounter hypoxic and hypo-nutrient conditions, which force them to make adaptive changes to meet their high demands for energy and various... (Review)
Review
Cancer cells often encounter hypoxic and hypo-nutrient conditions, which force them to make adaptive changes to meet their high demands for energy and various biomaterials for biomass synthesis. As a result, enhanced catabolism (breakdown of macromolecules for energy production) and anabolism (macromolecule synthesis from bio-precursors) are induced in cancer. This phenomenon is called "metabolic reprogramming," a cancer hallmark contributing to cancer development, metastasis, and drug resistance. HCC and cholangiocarcinoma (CCA) are 2 different liver cancers with high intertumoral heterogeneity in terms of etiologies, mutational landscapes, transcriptomes, and histological representations. In agreement, metabolism in HCC or CCA is remarkably heterogeneous, although changes in the glycolytic pathways and an increase in the generation of lactate (the Warburg effect) have been frequently detected in those tumors. For example, HCC tumors with activated β-catenin are addicted to fatty acid catabolism, whereas HCC tumors derived from fatty liver avoid using fatty acids. In this review, we describe common metabolic alterations in HCC and CCA as well as metabolic features unique for their subsets. We discuss metabolism of NAFLD as well, because NAFLD will likely become a leading etiology of liver cancer in the coming years due to the obesity epidemic in the Western world. Furthermore, we outline the clinical implication of liver cancer metabolism and highlight the computation and systems biology approaches, such as genome-wide metabolic models, as a valuable tool allowing us to identify therapeutic targets and develop personalized treatments for liver cancer patients.
Topics: Humans; Liver Neoplasms; Carcinoma, Hepatocellular; Non-alcoholic Fatty Liver Disease; Bile Duct Neoplasms; Bile Ducts, Intrahepatic
PubMed: 36626639
DOI: 10.1097/HEP.0000000000000005 -
Nature Communications Jul 2023Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars...
Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars reticulata (SNr) contribute to the motor deficit of HE. The present study aims to investigate the effects of oxidative stress on HE in male mice. The results validate the existence of oxidative stress in both liver and SNr across two murine models of HE induced by thioacetamide (TAA) and bile duct ligation (BDL). Systemic mitochondria-targeted antioxidative drug mitoquinone (Mito-Q) rescues mitochondrial dysfunction and oxidative injury in SNr, so as to restore the locomotor impairment in TAA and BDL mice. Furthermore, the GAD2-expressing SNr population (SNr) is activated by HE. Both overexpression of mitochondrial uncoupling protein 2 (UCP2) targeted to SNr and SNr-targeted chemogenetic inhibition targeted to SNr rescue mitochondrial dysfunction in TAA-induced HE. These results define the key role of oxidative stress in the pathogenesis of HE.
Topics: Male; Animals; Mice; Hepatic Encephalopathy; Oxidative Stress; Antioxidants; Bile Ducts; Thioacetamide
PubMed: 37488119
DOI: 10.1038/s41467-023-40081-8 -
Clinica Chimica Acta; International... Nov 2023Biliary tract cancers are heterogeneous in etiology, morphology and molecular characteristics thus impacting disease management. Diagnosis is complex and prognosis poor.... (Review)
Review
Biliary tract cancers are heterogeneous in etiology, morphology and molecular characteristics thus impacting disease management. Diagnosis is complex and prognosis poor. The advent of liquid biopsy has provided a unique approach to more thoroughly understand tumor biology in general and biliary tract cancers specifically. Due to their minimally invasive nature, liquid biopsy can be used to serially monitor disease progression and allow real-time monitoring of tumor genetic profiles as well as therapeutic response. Due to the unique anatomic location of biliary tract cancer, bile provides a promising biologic fluid for this purpose. This review focuses on the composition of bile and the use of these various components, ie, cells, extracellular vesicles, nucleic acids, proteins and metabolites as potential biomarkers. Based on the disease characteristics and research status of biliary tract cancer, considerable effort should be made to increase understanding of this disease, promote research and development into early diagnosis, develop efficient diagnostic, therapeutic and prognostic markers.
Topics: Humans; Bile; Biomarkers, Tumor; Biliary Tract Neoplasms; Prognosis; Liquid Biopsy
PubMed: 37839517
DOI: 10.1016/j.cca.2023.117593 -
Annals of Medicine Dec 2023Currently, there are still no definitive consensus in the treatment of intrahepatic cholangiocarcinoma (iCCA). This study aimed to build a clinical decision support tool...
BACKGROUND AND AIMS
Currently, there are still no definitive consensus in the treatment of intrahepatic cholangiocarcinoma (iCCA). This study aimed to build a clinical decision support tool based on machine learning using the Surveillance, Epidemiology, and End Results (SEER) database and the data from the Fifth Medical Center of the PLA General Hospital in China.
METHODS
4,398 eligible patients from the SEER database and 504 eligible patients from the hospital data, who presented with histologically proven iCCA, were enrolled for modeling by cross-validation based on machine learning. All the models were trained using the open-source Python library scikit-survival version 0.16.0. Shapley additive explanations method was used to help clinicians better understand the obtained results. Permutation importance was calculated using library ELI5.
RESULTS
All involved treatment modalities could contribute to a better prognosis. Three models were derived and tested using different data sources, with concordance indices of 0.67, 0.69, and 0.73, respectively. The prediction results were consistent with those under actual situations involving randomly selected patients. Model 2, trained using the hospital data, was selected to develop an online tool, due to its advantage in predicting short-term prognosis.
CONCLUSION
The prediction model and tool established in this study can be applied to predict the prognosis of iCCA after treatment by inputting the patient's clinical parameters or TNM stages and treatment options, thus contributing to optimal clinical decisions.KEY MESSAGESA prognostic model related to disease staging and treatment mode was conducted using the method of machine learning, based on the big data of multi centers.The online calculator can predict the short-term survival prognosis of intrahepatic cholangiocarcinoma, thus, help to make the best clinical decision.The online calculator built to calculate the mortality risk and overall survival can be easily obtained and applied.
Topics: Humans; Feasibility Studies; Cholangiocarcinoma; Prognosis; Machine Learning; Bile Ducts, Intrahepatic; Bile Duct Neoplasms
PubMed: 36576390
DOI: 10.1080/07853890.2022.2160008 -
Cell Proliferation Dec 2023Having been reported to be a crucial prognostic factor in solid tumours, the role of high endothelial venule (HEV) in intrahepatic cholangiocarcinoma (ICC) remains...
Having been reported to be a crucial prognostic factor in solid tumours, the role of high endothelial venule (HEV) in intrahepatic cholangiocarcinoma (ICC) remains unclear, however. The data of ICC and healthy individuals were downloaded from the Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) databases. Meanwhile, a cutting-edge ICC high-resolution spatial transcriptome was also acquired before these data were comprehensively analysed using bioinformatics approaches. Moreover, 95 individuals with ICC who had undergone resection surgery were enrolled in this study to investigate the relationship between HEV and tumour microenvironment (TME) applying immunohistochemistry and multiple immunofluorescence techniques. The high-HEV subtype contains rich immune infiltrates including tertiary lymphoid structure (TLS), CD8+ T cells, and CD20+ B cells. Furthermore, HEV and TLS exhibited a strong relationship of spatial colocalization. Correlated with improved prognostic outcomes in ICC, the high-HEV subtype could be an independent prognostic indicator for individuals with ICC. This study revealed the association of HEV with immune function and observed a strong spatial colocalization correlation between HEV and TLS. Moreover, correlated with immunotherapeutic response, HEV could improve prognostic outcomes, which may be a potential indicator of immunotherapy pathology in ICC.
Topics: Humans; Prognosis; Venules; Cholangiocarcinoma; Biomarkers; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Tumor Microenvironment
PubMed: 37401015
DOI: 10.1111/cpr.13513 -
Rhode Island Medical Journal (2013) May 2024Cholangiocarcinoma (CCA) is a rare cancer of the bile duct epithelium, and in the last few decades its incidence rate has been increasing. It is associated with a high... (Review)
Review
Cholangiocarcinoma (CCA) is a rare cancer of the bile duct epithelium, and in the last few decades its incidence rate has been increasing. It is associated with a high mortality rate due to late diagnosis and its aggressive nature. Many risk factors have been identified; some are more common in certain regions than others. CCA can be classified according to its anatomical location or macroscopic growth pattern, the latter being most helpful for imaging interpretation. Clinical features can vary from obstructive-like symptoms to nonspecific symptoms, such as weight loss and malaise. Imaging, specifically MRI/MRCP, is crucial in diagnosing CCA, staging, and treatment planning. Surgery with chemotherapy is the mainstay treatment option, and other palliative treatment options exist for those who have unresectable disease.
Topics: Humans; Cholangiocarcinoma; Bile Duct Neoplasms; Risk Factors; Magnetic Resonance Imaging; Bile Ducts, Intrahepatic
PubMed: 38687269
DOI: No ID Found