New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma is an aggressive malignancy and is one of the most devastating cancers of the gastrointestinal tract. The molecular mechanisms contributing to the pathogenesis of these cancers are not well understood. The recognition and distinction of these cancers from other tumors such as perihilar or extrahepatic distal cholangiocarcinoma and hepatocellular carcinoma are important in defining the pathogenesis. New insights into molecular mechanisms contributing to disease pathogenesis are emerging from recent epidemiological, genome-wide profiling and laboratory based studies. These have contributed to an improved understanding of risk factors, genetic mutations and pathophysiological mechanisms that are associated with these tumors. The contribution of well-established risk factors such as biliary tract inflammation and key signaling pathways involved in intrahepatic cholangiocarcinoma are being further defined. These new insights have several important implications for both molecular diagnosis and therapy of these cancers.     

Molecular pathogenesis of intrahepatic cholangiocarcinoma

Cholangiocarcinoma (CCA) is an orphan cancer of the hepatobiliary tract, the incidence of which has increased in the past decade. The molecular pathogenesis of this treatment‐refractory disease is poorly understood. Desmoplasia is a key causal feature of CCA; however, a majority of tumors develop with no apparent etiological background. The impact of the stromal compartment on tumor progression as well as resistance to therapy is in vogue, and the epithelial‐stromal crosstalk may present a target for novel treatment strategies. As such, the complexity of tumor cellularity and the molecular mechanisms underlying the diversity of growth patterns of this malignancy remain a clinical concern. It is crucial to advance our present understanding of the molecular pathogenesis of CCA to improve current clinical strategies and patient outcome. This will facilitate the delineation of patient subsets and individualization for precision therapies. Many questions persevere as to the evolutionary process and cellular origin of the initial transforming event, the context of intratumoral plasticity and the causal driver action. Next‐generation sequencing has begun to underline the persistent alterations, which may be the trigger of acquired drug resistance, and the cause of metastasis and disease recurrence. A complex issue that remains is to account for the heterogeneous pool of “backseat” aberrations, which in chromosomal proximity to the causative variant are likely to influence, for example, drug response. This review explores the recent advances in defining the molecular pathways implicated in the development of this devastating disease and, which present putative clinical strategies.     

The molecular pathogenesis of hepatocellular carcinoma

SUMMARY. Some of the multiple factors involved in the molecular pathogenesis of hepatocellular carcinoma have been elucidated in recent years but no clear picture of how and in what sequence these factors interact at the molecular level has emerged yet. Transformation of hepatocytes to the malignant phenotype may occur irrespective of the aetiological agent through a pathway of chronic liver injury, regeneration and cirrhosis. The activation of cellular oncogenes, the inactivation of tumour suppressor genes and overexpression of certain growth factors contribute to the development of HCC. There is increasing evidence that the hepatitis B virus may play a direct role in the molecular pathogenesis of HCC. Aflatoxins have been shown to induce specific mutations of the p53 tumour suppressor gene thus providing a clue to how an environmental factor may contribute to tumour development at the molecular level.     

The molecular pathogenesis of hereditary hemochromatosis

Hereditary hemochromatosis is a genetic disorder of iron overload. Over the past 15 years, significant advances have been made in understanding the molecular pathogenesis of this disorder. First, genetic studies linked this disorder to mutations in several genes, including HFE, transferrin receptor 2 ( TFR2), hepcidin ( HAMP), ferroportin ( SLC40A1), and hemojuvelin ( HFE2). Recent progress has generated significant insight into the function of these molecules in systemic iron homeostasis, and has revealed that despite the genetic and phenotypic diversity of hereditary hemochromatosis, there are common pathogenic mechanisms underlying this disease. The common downstream mechanism of iron overload in hereditary hemochromatosis is abnormal regulation of the hepcidin-ferroportin axis, leading to a failure to prevent excess iron from entering the circulation. Recent data are starting to unravel the molecular mechanisms by which iron regulates hepcidin production, and has demonstrated a key role for the bone morphogenetic protein-hemojuvelin-SMAD signaling pathway in this process. Future studies will be needed to more fully understand the molecular mechanisms of iron sensing and the roles of HFE and TFR2 in this process. Here, the authors review the current state of knowledge on the molecular pathogenesis of hereditary hemochromatosis.     

Experimental models to unravel the molecular pathogenesis,cell of origin and stem cell properties of cholangiocarcinoma

Human cholangiocarcinoma (CCA) is an aggressive tumour entity arising from the biliary tree, whose molecular pathogenesis remains largely undeciphered. Over the last decade, the advent of high‐throughput and cell‐based techniques has significantly increased our knowledge on the molecular mechanisms underlying this disease while, at the same time, unravelling CCA complexity. In particular, it becomes clear that CCA displays pronounced inter‐ and intratumoural heterogeneity, which is presumably the consequence of the interplay between distinct tissues and cells of origin, the underlying diseases, and the associated molecular alterations. To better characterize these events and to design novel and more effective therapeutic strategies, a number of CCA experimental and preclinical models have been developed and are currently generated. This review summarizes the current knowledge and understanding of these models, critically underlining their translational usefulness and limitations. Furthermore, this review aims to provide a comprehensive overview on cells of origin, cancers stem cells and their dynamic interplay within CCA tissue.     

The molecular pathogenesis of ACTH insensitivity syndromes

ACTH insensitivity results from a group of rare autosomal recessive genetic defects. Familial glucocorticoid deficiency is one of these syndromes in which about half of all cases have inactivating mutations of the ACTH receptor. The remaining patients with this syndrome have defects in one or more other as yet unidentified genes that are unlinked to the ACTH receptor. The triple A syndrome is a distinct clinical syndrome which includes alacrima (absence of tears), achalasia and various neurological defects in addition to ACTH insensitivity. In all cases the defect lies in a gene located on chromosome 12.     

Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma

Cholangiocarcinoma (CCA) is a fatal cancer of the biliary epithelium, arising either within the liver (intrahepatic, ICC) or in the extrahepatic bile ducts (extrahepatic ECC). Globally, CCA is the second most common primary hepatic malignancy. Several recent epidemiological studies have shown that the incidence and mortality rates of ICC are increasing. This review of the literature on the international epidemiological rates of CCA, both intra- and extrahepatic, explores possible explanations for the trends found. The possible role of epidemiological artifact in the findings is discussed and the known risk factors for CCA are summarized. These include primary sclerosing cholangitis, liver fluke infestation, congenital fibropolycystic liver, bile duct adenomas, and biliary papillomatosis, hepatolithiasis, chemical carcinogens such as nitrosamines, Thorotrast, chronic viral hepatitis, cirrhosis, chronic non-alcoholic liver disease and obesity. Potential pathways involved in the molecular pathogenesis of CCA are also summarized.     

Anatomic and molecular pathology of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignant tumor of the liver, and ICC is reportedly increasing recently. ICC is usually adenocarcinoma with variable desmoplastic reaction, although there are several special or unusual histological features. ICC may arise at the large intrahepatic bile duct near the hepatic hilus and also from the bile ductules at the border of the hepatic parenchyma. On the anatomical level, the pathology of ICC differs depending on the region from which the ICC arises. At the large intrahepatic bile duct, ICC presents papillary growth and periductal infiltration. Some cases show extensive papillary growth and intraluminal spread with marked gastroenteric metaplasia. Mucus core protein 1 is expressed in aggressive ICC. ICC arising from ductules shares phenotypes of hepatocellular carcinoma. ICC in chronic biliary diseases, particularly arising in hepatolithiasis, presents precancerous lesions that include biliary epithelial dysplasia, as well as in-situ carcinoma. Chronic advanced hepatitis C is one of the background diseases of ICC. Chronic inflammation, with the upregulation of cyclooxygenase-2 and growth factors, and the formation of reactive oxygen species are one of the causative factors in the DNA damage of biliary epithelial cells. K-ras mutation and aberrant expression of p53 are found in one-third of ICCs. The latter may be due to mdm-2 upregulation. Hepatocyte growth factor/met and interleukin 6 (IL6)/IL6 receptor are involved in cell proliferation/mitoinhibition and apoptosis in ICC. Fibrous stroma formation and invasion involve the proliferation of Α-smooth muscle antigen-positive stromal cells, and cell-to-cell and cell-to-matrix interactions involving E-cadherin/catenin and CD44 and matrix proteinases may be involved in the invasion of ICC. Evasion of immune surveillance involving the Fas/FasL system is important in the malignant progression of ICC. Further molecular and genetic studies are mandatory to evaluate the pathogenesis and progression of ICC.     

华支睾吸虫致胆管癌发生发展的研究进展

华支睾吸虫是一种食源性寄生虫,其感染可导致宿主肝胆管病变,甚至诱发胆管癌。本文结合近年来的相关研究,从虫体的毒性作用、宿主的异常免疫反应以及其他病原体共感染等方面对华支睾吸虫导致胆管癌发生发展的致病机制进行阐述。     

The pathogenesis of slow virus infections: molecular analyses

Slow infections raise some novel issues in understanding the pathogenesis of viral diseases that have been increasingly addressed at the molecular level with in situ hybridization. These developments are reviewed as the framework for discussion of the realized and potential impact of these investigations for major neurological afflictions of humans and for AIDS.     

Anatomical,histomorphological and molecular classification of cholangiocarcinoma

Cholangiocarcinoma constitutes a heterogeneous group of malignancies that can emerge at any point of the biliary tree. Cholangiocarcinoma is classified into intrahepatic, perihilar and distal based on its anatomical location. Histologically, conventional perihilar/distal cholangiocarcinomas are mucin‐producing adenocarcinomas or papillary tumours; intrahepatic cholangiocarcinomas are more heterogeneous and can be sub‐classified according to the level or size of the displayed bile duct. Cholangiocarcinoma develops through multistep carcinogenesis and is preceded by dysplastic and in situ lesions. Definition and clinical significance of precursor lesions, including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm, are discussed in this review. A main challenge in diagnosing cholangiocarcinoma is the fact that tumour tissue for histological examination is difficult to obtain. Thus, a major clinical obstacle is the establishment of the correct diagnosis at a tumour stage that is amenable to surgery which still represents the only curable therapeutic option. Current standards, methodology and criteria for diagnosis are discussed. Cholangiocarcinoma represents a heterogeneous tumour with regard to molecular alterations. In intrahepatic subtype, mainly two distinctive morpho‐molecular groups can currently be discriminated. Large‐duct type intrahepatic cholangiocarcinoma shows a high mutation frequency of oncogenes and tumour suppressor genes, such as KRAS and TP53 while Isocitrate Dehydrogenase 1/2 mutations and Fibroblast Growth Factor Receptor 2‐fusions are typically seen in small‐duct type tumours. It is most important to ensure the separation of the given anatomical subtypes and to search for distinct subgroups within the subtypes on a molecular and morphological basis.     

肝吸虫引发胆管细胞癌发病机制的研究进展

肝吸虫病是一种危害性极大的食源性寄生虫病.全世界感染肝吸虫的人数大约有3500万,约有11亿人存在感染风险.长期肝吸虫感染引起最严重的并发症是胆管细胞癌(CCA),世界卫生组织国际癌症研究署已经将肝吸虫列为CCA的Ⅰ类致癌性病原体.近年来,有许多学者对肝吸虫感染的致癌机制做了相应的临床及实验研究,但至今其致癌机制尚未明...