Association between Helicobacter spp.infections and hepatobiliary malignancies:A review

Hepatobiliary cancers are highly lethal cancers that comprise a spectrum of invasive carcinomas originating in the liver hepatocellular carcinoma,the bile ducts intrahepatic cholangiocarcinoma and extrahepaticcholangiocarcinoma,the gallbladder and the ampulla of Vater(collectively known as biliary tract cancers).These tumors account for approximately 13% of all annual cancer-related deaths worldwide and for 10%-20% of deaths from hepatobiliary malignancies.Cholangiocarcinoma(CCA) is a devastating disease that displays a poor survival rate for which few therapeutic options are available.Population genetics,geographical and environmental factors,cholelithiasis,obesity,parity,and endemic infection with liver flukes have been identified as risk factors that influence the development of biliary tract tumors.Other important factors affecting the carcinogenesis of these tumors include chronic inflammation,obstruction of the bile ducts,and impaired bile flow.It has been suggested that CCA is caused by infection with Helicobacter species,such as Helicobacter bilis and Helicobacter hepaticus,in a manner that is similar to the reported role of Helicobacter pylori in distal gastric cancer.Due to the difficulty in culturing these Helicobacter species,molecular methods,such as polymerase chain reaction and sequencing,or immunologic assays have become the methods of choice for diagnosis.However,clinical studies of benign or malignant biliary tract diseases revealed remarkable variability in the methods and the findings,and the use of uniform and validated techniques is needed.     

Cholangiocarcinoma--controversies and challenges

Cholangiocarcinomas are a diverse group of tumors that are presumed to originate from the biliary tract epithelium either within the liver or the biliary tract. These cancers are often difficult to diagnose, their pathogenesis is poorly understood, and their dismal prognosis has resulted in a nihilistic approach to their management. The two major clinical phenotypes are intrahepatic, mass-forming tumors and large ductal tumors. Among the ductal cancers, lesions at the liver hilum are most prevalent. The risk factors, clinical presentation, natural history and management of these two types of cholangiocarcinoma are distinct. Efforts to improve outcomes for patients with these diseases are affected by several challenges to effective management. For example, designations based on anatomical characteristics have been inconsistently applied, which has confounded analysis of epidemiological trends and assessment of risk factors. The evaluation of therapeutic options, particularly systemic therapies, has been limited by a lack of appreciation of the different phenotypes. Controversies exist regarding the appropriate workup and choice of management approach. However, new and emerging tools for improved diagnosis, expanded indications for surgical approaches, an emerging role for locoregional and intrabiliary therapies and improved systemic therapies provide optimism and hope for improved outcomes in the future.     

Role of epigenetic alterations in cholangiocarcinoma

Intrahepatic cholangiocarcinomas are rare malignant epithelial liver tumors arising from intrahepatic bile ducts. The prognosis of affected patients is poor. Several risk factors, including hepatolithiasis, liver fluke infection, and anatomical abnormalities associated with inflammation of the biliary tract have been described. At present, little is known about the cellular and molecular mechanisms leading to the development of cholangiocarcinoma. In recent years, in addition to genetic alterations, epigenetic inactivation of (tumor suppressor) genes by promoter CpG island hypermethylation has been recognized as an important and alternative mechanism in tumorigenesis. This review discusses the epi-genetic inactivation of different tumor suppressor genes in cholangiocarcinoma.     

Current approaches to the diagnosis and treatment of cholangiocarcinoma

Malignancies arising from biliary tract epithelia, or cholangiocarcinoma, are rare tumors that have a poor prognosis. The incidence of these tumors is gradually increasing in many countries. Recent advances have been made in identifying some of the risk factors, and the need for appropriate classification is emerging. The diagnosis of cholangiocarcinoma is often difficult and requires multiple complementary studies. The use of molecular approaches may improve the diagnostic utility of biliary cytology. Treatment of these tumors is complex, and there are many different treatment options. Although surgical resection can be curative, many patients with cholangiocarcinoma are diagnosed at an advanced stage when only palliative approaches can be used. Photodynamic therapy is emerging as a useful modality.     

Biological characteristics of cancers in the gallbladder and biliary tract and targeted therapy

Adenocarcinomas of the gallbladder (GBC) and bile ducts (cholangiocarcinoma) (combined as biliary tract cancers, BTC) are uncommon tumors in the United States, but are endemic in parts of South America and Asia. BTC are aggressive tumors with poor survival. Published response rates to chemotherapy are less than 30% and no survival benefit has been demonstrated from palliative systemic therapy. Improved understanding of the biological characteristics and molecular carcinogenic mechanisms of these malignancies may lead to improved therapeutic regimens for patients.     

Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma

Aberrant expression and signaling of epidermal growth factor receptor （ErbB） family receptor tyrosine kinases, most notably that of ErbB2 and ErbB1, have been implicated in the molecular pathogenesis of intrahepatic cholangiocarcinoma. Constitutive overexpression of ErbB2 and/or ErbB1 in malignant cholangiocytes has raised interest in the possibility that agents which selectively target these receptors could potentially be effective in cholangiocarcinoma therapy. However, current experience with such ErbB- directed therapies have at best produced only modest responses in patients with biliary tract cancers. This review provides a comprehensive and critical analysis of both preclinical and clinical studies aimed at assessing the role of altered ErbB2 and/or ErbB1 expression, genetic modifications, and dysregulated signaling on cholangiocarcinoma development and progression. Specific limitations in experimental approaches that have been used to assess human cholangiocarcinoma specimens for ErbB2 and/or ErbB1 overexpression and gene amplification are discussed. In addition, current rodent models of intrahepatic cholangiocarcinogenesis associated with constitutive ErbB2 overexpression are reviewed. Select interactive relationships between ErbB2 or ErbB1 with other relevant molecular signaling pathways associated with intrahepatic cholangiocarcinoma development and progression are also detailed, including those linking ErbB receptors to bile acid, cyclooxygenase-2,interleukin-6/gp130, transmembrane mucins, hepatocyte growth factor/Met, and vascular endothelial growth factor signaling. Lastly, various factors that can limit therapeutic efficacy of ErbB-targeted agents against cholangiocarcinoma are considered.     

Mechanisms of biliary carcinogenesis and growth

Cholangiocarcinoma is a rare cancer originating from the neoplastic transformation of the epithelial cells （i.e. cholangiocytes） that line the biliary tract. The prognosis for patients with cholangiocarcinoma is grim due to lack of viable treatment options. The increase in world-wide incidence and mortality from cholangiocarcinoma highlights the importance of understanding the intracellular mechanisms that trigger the neoplastic transformation of cholangiocytes and the growth of biliary cancers. The purpose of the following review is to address what has been learned over the past decade concerning the molecular basis of cholangiocarcinogenesis. The material presented is divided into two sections：（1） mechanisms regulating neoplastic transformation of cholangiocytes; and （2） factors regulating cholangiocarcinoma growth. An understanding of the growth regulatory mechanisms of cholangiocarcinoma will lead to the identification of therapeutic targets for this devastating cancer.     

Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC)represents 90%of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV),hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins.DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.     

Cholangiocarcinoma

Cholangiocarcinomas are rare malignant tumors composed of cells that resemble those of the biliary tract. On the basis of their anatomic location, cholangiocarcinomas can be classified as intrahepatic, extrahepatic and hilar tumors. For reasons that are not clear, the incidence of cholangiocarcinoma is increasing globally. Established risk factors, including conditions associated with chronic biliary tract inflammation, account for a small proportion of cases. Additional risk factors such as cirrhosis, infection with hepatitis B virus and hepatitis C virus are now becoming recognized. The diagnosis of cholangiocarcinoma requires the integration of clinical information, imaging studies of the hepatic parenchyma and biliary tract, tumor markers, and histology. In terms of the treatment options for cholangiocarcinoma, surgery can be curative, although few patients are candidates for surgery. Palliative biliary decompression can provide symptomatic relief. Advances in MRI and positron-emission tomography scanning, identification of new tumor markers, improved utility of biliary cytology, and the use of photodynamic therapy for adjunct treatment are all expected to enhance the diagnosis, evaluation and management of cholangiocarcinoma.     

Genomic investigations into acute inflammatory lung injury

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome, are complex illnesses involving the interplay of both environmental (such as mechanical ventilation) and genetic factors. To understand better the underlying mechanisms of pathogenesis associated with ALI, we recently identified several candidate genes by global expression profiling in preclinical models of ALI and relevant single-nucleotide polymorphisms. We summarize here several strategies successfully used to identify novel ALI candidate genes and detail the validation of variants in these genes as contributing factors to ALI pathobiology, conclusions based on functional analyses, and specific genetic association studies conducted in ALI cohorts. Continued insights into ALI pathogenesis and identification of genetic variants, which confer ALI risk and severity, promise to reveal novel molecular therapeutic targets that can be translated into personalized treatments to reduce the very high, unacceptable mortality of this disorder.     

Clinical and biological significance of precursor lesions of intrahepatic cholangiocarcinoma

Cholangiocarcinoma(CC) is primarily a malignant tumor of older adults most prevalent in Southeast Asia,where liver fluke infestation is high.However the etiology in western countries is unknown.Although the incidence of extrahepatic cholangiocarcinoma has remained constant,incidence of intrahepatic CC(ICC) which differs inmorphology,pathogenesis,risk factors,treatment and prognosis is increasing.While this increase is associated with hepatitis C virus infection,chronic nonalcoholic liver disease,obesity,and smoking,the pathogenesis of ICC and molecular alterations underlying the carcinogenesis are not completely elucidated.Benign biliary lesions such as biliary intraepithelial neoplasia,intraductal papillary neoplasm of the bile duct,von Meyenburg complex or bile duct hamartoma,and bile duct adenoma have been associated with ICC.For each of these entities,evidence suggests or supports a role as premalignant lesions.This article summarized the important biological significance of the precursor lesions of ICC and the molecular mechanisms that may be involved in intrahepatic cholangiocarcinogenesis.     

Molecular mechanisms of hypertension and heart failure due to antiangiogenic cancer therapies

Targeted antiangiogenic cancer therapies have revolutionized the treatment of highly vascularized cancers such as metastatic renal cell carcinoma and gastrointestinal stromal tumors. Such agents act by inhibiting the actions of proangiogenic growth factors and their receptor tyrosine kinases, which are known to be overexpressed in cancer. However, these factors also play an important role in normal cardiovascular physiology. This article summarizes the incidences of cardiovascular toxicities (namely hypertension and heart failure) associated with the most commonly used antiangiogenic therapies, and then presents data from preclinical and clinical studies to provide some insight into the underlying molecular mechanisms.     

Surgical management of cholangiocarcinoma

Biliary tract cancer affects approximately 7500 Americans each year. Tumors arising from the gallbladder are the most common; those of bile duct origin, or cholangiocarcinoma, are less frequently encountered, constituting approximately 2% of all reported cancers. Although cholangiocarcinoma can arise anywhere within the biliary tree, tumors involving the biliary confluence (i.e., hilar cholangiocarcinoma) represent the majority, accounting for 40 to 60% of all cases. Twenty to 30% of cholangiocarcinomas originate in the lower bile duct, and approximately 10% arise within the intrahepatic biliary tree and will present as an intrahepatic mass. Complete resection remains the most effective and only potentially curative therapy for cholangiocarcinoma. For all patients with intrahepatic cholangiocarcinoma and nearly all patients with hilar tumors, complete resection requires a major partial hepatectomy. Distal cholangiocarcinomas, on the other hand, are treated like all periampullary malignancies and typically require pancreaticoduodenectomy. Most patients with cholangiocarcinoma present with advanced disease that is not amenable to surgical treatment, and even with a complete resection, recurrence rates are high. Adjuvant therapy (chemotherapy and radiation therapy) has not been shown clearly to reduce recurrence risk.     

Cholangiocarcinoma: modern advances in understanding a deadly old disease

Cholangiocarcinomas are tumors that arise anywhere in the biliary tract, presumably of cholangiocyte origin. The global incidence of this rare disease is on the rise. Several known risk factors exist, and link chronic biliary inflammation to the pathogenesis of cholangiocarcinoma. Among these, amplification of the epidermal growth factor receptor, the interleukin-6 signaling pathway, inducible nitric oxide, erb-2, and cyclooxygenase-2 are well defined. Most patients present late, with a median survival of months. Although, imaging studies and clinical context often indicate cholangiocarcinoma, pathologic and cytologic diagnosis is difficult to obtain. Advanced cytologic tests with fluorescence in situ hybridization or digital image analysis can increase diagnostic sensitivity. Surgical resection is the current therapy of choice for both intrahepatic and ductal cholangiocarcinomas. However, the 5-year survival is poor, with 60 to greater than 90% recurrence rates. In a single center experience, liver transplantation with neoadjuvant chemoirradiation, for highly selected patients, has a 5-year disease free survival of greater than 80%. Future targeted therapies will depend on a better understanding of the cellular and molecular biology of cholangiocarcinomas.     

Genomics of acute lung injury

Acute lung injury (ALI) is a complex syndrome involving the interplay of both environmental (such as the addition of mechanical ventilation) and genetic factors. Clinical models have identified risk factors for development and poor outcome but these strategies remain imprecise. To better understand the mechanisms of pathogenesis associated with mechanisms of ALI, candidate genes identified by global expression profiling or related literature searches are being explored for relevant polymorphisms (single base pair substitutions) that can affect both ALI susceptibility and outcome. This article summarizes several specific genetic association studies that have been conducted in ALI and reviews supporting data from in vitro and in vivo models of the disease and clinical observations. Although valuable information has been reported to date, intense analyses are needed in this developing discipline to assure significant clinical utility. The detailing of specific associated polymorphisms will continue to provide new insights in the understanding of disease pathogenesis, and promise to reveal novel molecular targets and personalized treatments to prevent the disease.     

Non—AIDS–Defining cancers and HIV infection

With fewer patients now succumbing to infectious complications of AIDS, other HIV-related morbidities such as malignancies have become increasingly important. Apart from Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cervical cancer, which are considered as AIDS-defining, several additional cancers, referred to as non-AIDS-defining cancers, are also statistically increased in HIV-infected persons. These include Hodgkin’s disease, anal carcinoma, lung cancer, nonmelanomatous skin cancer, and testicular germ cell tumors, among others. However, the types of cancer observed at an increased frequency and the relative risks reported vary widely among studies. Although immunosuppression is consistently associated with an increased risk of AIDS-related malignancies, the role of immunosuppression in the pathogenesis of non-AIDSdefining cancers is controversial. Although data regarding the optimal management of these cancers are lacking, current studies suggest that patients with HIV-associated malignancies should be treated with similar approaches to those of their counterparts in the general population.     

Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy

Cholangiocarcinomas are devastating cancers that are increasing in both their worldwide incidence and mortality rates. The challenges posed by these often lethal biliary tract cancers are daunting, with conventional treatment options being limited and the only hope for long-term survival being that of complete surgical resection of the tumor. Unfortunately, the vast majority of patients with cholangiocarcinoma typically seek treatment with advanced disease, and often these patients are deemed poor candidates for curative surgery. Moreover, conventional chemotherapy and radiation therapy have not been shown to be effective in prolonging long-term survival, and although photodynamic therapy combined with stenting has been reported to be effective as a palliative treatment, it is not curative. Thus, there is a real need to develop novel chemopreventive and adjuvant therapeutic strategies for cholangiocarcinoma based on exploiting select molecular targets that would impact in a significant way on clinical outcome. This review focuses on potential preventive targets in cholangiocarcinogenesis, such as inducible nitric oxide synthase, cyclooxygenase-2, and altered bile acid signaling pathways. In addition, molecular alterations related to dysregulation of cholangiocarcinoma cell growth and survival, aberrant gene expression, invasion and metastasis, and tumor microenvironment are described in the context of various clinical and pathological presentations. Moreover, an emphasis is placed on the importance of critical signaling pathways and postulated interactions, including those of ErbB-2, hepatocyte growth factor/Met, interleukin-6/glycoprotein130, cyclooxygenase-2, vascular endothelial growth factor, transforming growth factor-beta, MUC1 and MUC4, beta-catenin, telomerase, and Fas pathways as potential molecular therapeutic targets in cholangiocarcinoma.     

The association between biliary tract cancers and cancers of other sites

OBJECTIVE: Cancers of the biliary tract, including cancers of the gallbladder and bile duct, generally carry a very poor prognosis. Little is known about their etiology. The pattern of co-occurrence of two cancers may give clues to shared etiological risk factors. We therefore investigated the association of biliary tract cancer with other cancers, especially with estrogen- and tobacco-related cancers. METHODS: We used data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Associations between biliary tract cancer and other cancers were evaluated using the standardized incidence ratio as an estimate of the relative risk of a second primary malignancy. RESULTS: Estrogen-related cancers of the breast and uterine corpus and smoking-related upper aerodigestive tract cancers were not associated with biliary tract cancer. The risk of gallbladder cancer was inversely related to the risk of prostate cancer in men, but positively related to the risk of cervical cancer in women. CONCLUSIONS: This study suggests that smoking and estrogen exposure have minimal roles in the pathogenesis of biliary tract cancer. Our finding of an inverse relationship between prostate cancer and gallbladder cancer requires confirmation by further studies.     

Hamartomatous polyposis syndromes

The hamartomatous polyposis syndromes are a heterogeneous group of disorders that share an autosomal-dominant pattern of inheritance and are characterized by hamartomatous polyps of the gastrointestinal tract. These syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome and the PTEN hamartoma tumor syndrome. The frequency and location of the polyps vary considerably among syndromes, as does the affected patient's predisposition to the development of gastrointestinal and other malignancies. Although the syndromes are uncommon, it is important for the clinician to recognize these disorders because they are associated with considerable morbidity and mortality, not only from malignancy but also from nonmalignant manifestations such as bleeding, intussusception, and bowel obstruction. Each hamartomatous polyposis syndrome has its own distinctive organ-specific manifestations and each requires a different surveillance strategy, which makes accurate diagnosis crucial for appropriate patient management. The availability of clinical genetic testing for these disorders means that appropriate recognition allows for timely referral for cancer genetic counseling, and often allows for predicative testing in at-risk family members. Promisingly, an understanding of the molecular pathogenesis of these disorders offers insights into the mechanisms underlying the development of sporadic malignancy, and enables rational selection of targeted therapies that warrant further investigation.