Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical management of pancreatic disease is often hampered by a lack of tissue diagnosis. Endoscopic pancreatography offers the opportunity to investigate exfoliated cells. However, the significance of mere cytological investigation is compromised by an insufficient sensitivity. The evaluation of the molecular background of carcinogenesis hopefully is capable of providing more sensitive diagnostic markers. The p16INK4a-/retinoblastoma tumour-suppressive pathway has been shown to be involved in the development of near to all pancreatic neoplasms. p14ARF is another tumour suppressor located in the immediate neighbourhood of p16INK4a. Promoter methylation has been demonstrated to be a major inactivating mechanism of both genes. We sought to further evaluate the role of the gene locus INK4a methylation status in the endoscopic differentiation of chronic inflammatory and neoplastic pancreatic disease. Pancreatic fluid specimens of 61 patients with either pancreatic carcinoma (PCA: 39), chronic pancreatitis (CP: 16) or a normal pancreatogram (NAD: 6) were retrieved. In order to detect methylation of either the p14ARF or the p16INK4a promoter a methylation-specific PCR protocol was applied. While 19 out of 39 patients with PCA showed p16 promoter methylation (49%), none of the 16 patients with CP revealed p16 promoter methylation. p14ARF methylation was found in a lower percentage of PCA specimens and in none of the samples of patients with CP. These results suggest a specific significance of INK4a for the development of malignant pancreatic disease. Our data further indicate a potential role for INK4a methylation as a diagnostic marker in the endoscopic differentiation of benign and malignant pancreatic disease.
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PMID:Methylation status of p14ARF and p16INK4a as detected in pancreatic secretions. 1261 May 6

Aberrant c-Src protein kinase activation has been identified as one of the molecular alterations involved in human pancreatic carcinogenesis. It has been postulated that c-Src may induce transformation by causing the overexpression of the insulinlike growth factor-1 receptor (IGF-1R) in pancreatic tumor cell lines. To further study the interaction between c-Src and IGF-1R proteins in human pancreatic cancer, we examined their coexpression in 47 human pancreatic ductal adenocarcinomas (PDA). Formalin-fixed, paraffin-embedded sections from 47 cases of PDA were stained using the immunohistochemical avidin-biotin-peroxidase method. We used an anti-human IGF-1R mouse monoclonal antibody (dilution 1:100 with antigen retrieval), and an anti-c-Src mouse monoclonal antibody (dilution 1:100 with antigen retrieval). The stains were semiquantitatively evaluated using the Allred score system, assessing intensity of stain and percentage of positive tumor cells. High cytoplasmic c-Src expression (Allred score 7-8) was seen in 33/47 (70%) tumors. In only 4 cases was c-Src either negative or low (Allred score 3). Strong and diffuse membranous IGF-1R stain (Allred score 7-8) was identified in 30/47 (64%) tumors. IGF-1R staining was low (Alled score 2-4) in 2 cases and negative in 1. Interestingly, in 40/47 (85%) cases c-Src and IGF-1R stains had similar scores. An inverse staining pattern was detected in only 6/47 (13%) tumors. Normal pancreatic ducts as well as areas of chronic pancreatitis were negative for IGF-1R. In conclusion, our data support the role of IGF-1R and c-Src in human pancreatic carcinogenesis; the coexpression of both these molecules may play an important role in transformation of pancreatic ductal cells.
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PMID:Coexpression of IGF-1R and c-Src proteins in human pancreatic ductal adenocarcinoma. 1462 43

Findings obtained from numerous prospective cohort and case-control studies on alcohol consumption and pancreatic cancer risk have been inconsistent, with many confounding variables present in various investigations. However, heavy alcohol consumption has been known to be a major cause of chronic pancreatitis and a risk factor for type 2 diabetes mellitus, both of which are linked to pancreatic cancer. It has been established that an extensive normal interaction exists between the exocrine and endocrine pancreas, as well as in inflammatory processes and carcinogenesis. Alcohol and its metabolites (acetaldehyde and fatty acid ethyl esters) can alter metabolic pathways involved in the inflammatory response and carcinogenesis, and they are mediated by one or more of the following mechanisms: (1) premature activation of zymogens; (2) induction of the inflammatory response through activation of nuclear transcription factors, including nuclear factor-kappa and activation protein 1; (3) increased production of reactive oxygen species, resulting in oxidative DNA damage and altered effect of dietary antioxidants; (4) activation of pancreatic stellate cells, which leads to fibrosis; (5) gene mutation in enzymes related to cytochrome P450, glutathione S-transferase, aldehyde dehydrogenase, cationic trypsinogen, and pancreatic secretory trypsin inhibitor; (6) synergistic effects of ethanol and tobacco carcinogen on NNK [nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] metabolism; and (7) dysregulation of proliferation and apoptosis. These various metabolic effects of alcohol can lead to or interact with other risk factors (genetic, dietary, environmental, and lifestyle factors) that result in acute and chronic pancreatitis and diabetes mellitus and, ultimately, affect the multistep process of carcinogenesis toward the development of pancreatic cancer.
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PMID:Alcohol and pancreatic cancer. 1605 82

Tobacco smoke, with its complexity of constituents, damages the pancreatic organ in multiple ways. Smoke not only affects pancreatic secretion patterns via its nicotine content but induces inflammatory reactions and exerts carcinogenic effects by several other constituents. Smoke enhances ethanol-induced pancreatic injury and accelerates the development and progression of chronic pancreatitis independent of etiology. Through the process of inflammation, smoking contributes to pancreatic carcinogenesis. The experiment of Wittel and colleagues published in this issue of the American Journal of Gastroenterology sheds further light on this topic by reporting in great detail two different kinds of pancreatic damage in rats exposed to high doses of smoke.
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PMID:Smoking--a trigger for chronic inflammation and cancer development in the pancreas. 1640 48

Intraductal papillary mucinous neoplasms (IPMNs) are common cystic tumours of the pancreas. Sonic hedgehog (SHH) is involved in gastric epithelial differentiation and pancreatic carcinogenesis. However, a comprehensive analysis of SHH expression in IPMN has not yet been performed. In the present study, one-step quantitative real-time reverse transcription-polymerase chain reaction with gene-specific priming was used to examine mRNA levels in various types of clinical samples. SHH expression in IPMN was measured and the possible association of gastric epithelial differentiation with development of IPMN was evaluated. In bulk tissue analyses (IPMNs, 11 pancreatic cancer, and 20 normal pancreatic tissues), IPMN expressed significantly higher levels of SHH than did normal pancreas (IPMN versus normal pancreas, p = 0.0025; pancreatic cancer versus normal pancreas, p = 0.0132), but SHH expression did not differ between IPMN and pancreatic cancer (p = 0.3409). In microdissection analyses (infiltrating ductal carcinoma cells from 20 sections, IPMN cells from 20 sections, pancreatitis-affected epithelial cells from 11 sections, and normal epithelial cells from 12 sections), IPMN cells expressed significantly higher levels of SHH than did cancer cells, normal cells, or pancreatitis-affected ductal cells (all comparisons, p < 0.008). Pancreatic juice analyses (20 samples from pancreatic cancers, 31 samples from IPMNs, and 27 samples from chronic pancreatitis) revealed that SHH expression differed significantly between IPMN juice and pancreatitis juice (p < 0.0001), and between cancer juice and pancreatitis juice (p = 0.0125). Receiver operating characteristic curve analyses revealed that SHH measurement in pancreatic juice was useful for discriminating IPMN from chronic pancreatitis (area under the curve = 0.915; 95% confidence interval: 0.796-0.976). The data suggest that overexpression of SHH is an early event in the development of IPMN and that SHH measurement in pancreatic juice may provide some advantages for the treatment or follow-up of a subset of patients with IPMN or chronic pancreatitis.
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PMID:Sonic hedgehog is an early developmental marker of intraductal papillary mucinous neoplasms: clinical implications of mRNA levels in pancreatic juice. 1679 90

Ductal adenocarcinoma of the pancreas is characterized by extremely aggressive behavior, with an overall 5-year survival of <4%. Because conventional and specifically tailored therapeutic regimens have little impact on patient survival, epidemiological and molecular research aims at identifying and reducing risk factors. Cigarette smoking, obesity, diabetes mellitus, and chronic pancreatitis are amenable to medical prevention or therapy. Heavy alcohol consumption is an inconsistent single risk factor for pancreatic cancer but may promote carcinogenesis by increasing the risk of diabetes mellitus or chronic pancreatitis. For various agents, the key carcinogenic effect is probably an inflammatory response in the pancreatic tissue. On the molecular level, mutations of oncogenes and tumor suppressor genes, as well as various epigenetic alterations, such as overexpression of growth factors and their receptors, are important in tumorigenesis. Complete and safe surgical resection, together with adjuvant therapy, offers prolonged survival, with 5-year survival rates of approximately 25%. However, for unresectable or disseminated disease, which constitutes the vast majority of cases, treatment is palliative. Despite increasing knowledge about the molecular pathology of pancreatic cancer and despite advances in treatment, the overall course of the disease is dismal, and reinforced efforts to reduce incidence and improve outcome are needed desperately.
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PMID:Update on pancreatic cancer and alcohol-associated risk. 1695 77

Inflammatory injury to the pancreas results in regeneration of normal tissue and formation of metaplastic lesions of a ductal phenotype. These metaplastic ductal lesions (MDL) are called tubular complexes (TC), mucinous metaplasia, or pancreatic intraepithelial neoplasia. Because they are regularly found in chronic pancreatitis and pancreatic cancer, their formation is thought to represent a step in inflammation-mediated carcinogenesis. Despite these lesions' ductal character, their origin is controversial. All known pancreatic cell lineages have been suggested as the origin. In vitro studies suggest that differentiated cells in the pancreas remain highly plastic and can transdifferentiate as a mechanism of regeneration and metaplasia. In vivo studies suggest that islets, specifically beta cells, may be the cell of origin. However, in vitro studies are subject to ductal cell contamination, and previous in vivo studies interpret static data rather than direct evidence. Using genetic lineage tracing in vivo, we investigate whether transdifferentiation of beta cells contributes to regeneration or metaplasia in pancreatitis. RIP-CreER;Z/AP mice were used to heritably tag beta cells in the adult pancreas. Injury by cerulein pancreatitis resulted in regeneration of normal tissue and metaplasia with formation of two distinct types of TC and mucinous lesions. Lineage tracing revealed that none of these MDL are of beta cell origin; nor do beta cells contribute to regeneration of normal acinar and ductal tissue, which indicates that the plasticity of differentiated pancreatic islet cells, suggested by earlier static and in vitro studies, plays no role in regeneration, metaplasia, and carcinogenesis in vivo.
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PMID:Beta cell transdifferentiation does not contribute to preneoplastic/metaplastic ductal lesions of the pancreas by genetic lineage tracing in vivo. 1736 May 39

There are few reports describing the diagnostic significance of S100A6 expression in clinical samples obtained from patients with pancreatic disease. In the present study, we measured S100A6 expression in pancreatic tissues and juice to evaluate its involvement in pancreatic carcinogenesis. We did quantitative real-time reverse transcription-PCR to measure mRNA expression in microdissected cells and pancreatic juice samples. Microdissected invasive ductal carcinoma and intraductal papillary mucinous neoplasm (IPMN) cells expressed significantly higher levels of S100A6 than did microdissected pancreatitis-affected epithelial and normal cells (all comparison; P < 0.008). Median levels of S100A6 in invasive ductal carcinoma were higher than those in IPMN, and those in pancreatitis-affected epithelial cells tended to be higher than those in normal cells, although these differences were not statistically significant. In analyses of pancreatic juice, IPMN and pancreatic cancer samples expressed significantly higher levels of S100A6 than did chronic pancreatitis samples (both; P < 0.017), but levels in pancreatic cancer and IPMN samples did not differ form each other. Receiver operating characteristic (ROC) curve analysis revealed that measurement of S100A6 was useful for discriminating cancer (area under the ROC curve, 0.864) or IPMN (area under the ROC curve, 0.749) from chronic pancreatitis. The present data suggest that expression of S100A6 is increased in a stepwise manner during pancreatic carcinogenesis and may be a biomarker for evaluating malignant potential. Measurement of S100A6 in pancreatic juice may be useful to detect early pancreatic cancer or identify individuals with high-risk lesions that may progress to pancreatic cancer.
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PMID:S100A6 is increased in a stepwise manner during pancreatic carcinogenesis: clinical value of expression analysis in 98 pancreatic juice samples. 1741 53

Autoimmune pancreatitis (AIP) is responsive to steroid therapy, but some AIP patients improve spontaneously, or only improve after biliary drainage. Pancreatic enlargement and irregular narrowing of the main pancreatic duct usually improves in almost all patients, but marked atrophy of the pancreas develops in some patients. Biliary stenosis improves to various degrees, and a biliary drainage tube can be withdrawn. Other extrapancreatic lesions, including swelling of the salivary or lacrimal glands, lymphadenopathy, and retroperitoneal fibrosis also improve with steroid therapy. Pancreatic endocrine and exocrine function is frequently impaired in AIP patients, and steroid therapy is occasionally effective for these dysfunction. Deterioration of pancreatic exocrine function is rarely detected after steroid therapy. In the literature, the recurrence rate of AIP was reported to be about 17% (range 6% to 26%). AIP patients who relapse during maintenance steroid therapy or after stopping steroid medication should be re-treated with a high-dose steroid. Although AIP is rarely associated with pancreatic stones, stones are formed in some relapsing AIP patients. The long-term prognosis for AIP is unknown. As the pancreatic exocrine and endocrine functions as well as the morphological findings are reversible after steroid therapy, the prognosis for AIP seems better than that of chronic pancreatitis, which is usually followed by exocrine and endocrine pancreatic insufficiency with disease progression. Although carcinogenesis of AIP is unknown, some AIP patients developed a malignancy during follow-up. Since AIP occurs predominantly in the elderly, clinicians should pay attention to any complicating diseases in follow-up of AIP patients. Further studies are necessary to clarify the pathogenesis as well as the long-term prognosis of AIP.
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PMID:Prognosis of autoimmune pancreatitis. 1752 Feb 25

Late diagnosis and ineffective therapeutic options mean that pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer. The identification of genetic alterations facilitated the launch of the Pancreatic Intraepithelial Neoplasm nomenclature, a standardized classification system for pancreatic duct lesions, but the factors that contribute to the development of such lesions and their progression to high-grade neoplasia remain obscure. Age, smoking, obesity and diabetes confer increased risk of PDA, and the presence of chronic pancreatitis is a consistent risk factor for pancreatic cancer. It is hypothesized that chronic inflammation generates a microenvironment that contributes to malignant transformation in the pancreas, as is known to occur in other organs. Pancreatic stellate cells (PSCs) are the main mediator of fibrogenesis during chronic pancreatitis, but their contribution to the development of PDA has not been elucidated. Data now suggest that PSCs might assume a linking role in inflammation-associated carcinogenesis through their ability to communicate with inflammatory cells, acinar cells, and pancreatic cancer cells in a complicated network of interactions. In this Review, the role of PSCs in the process of inflammation-associated carcinogenesis is discussed and new potential treatment options evaluated.
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PMID:Mechanisms of disease: chronic inflammation and cancer in the pancreas--a potential role for pancreatic stellate cells? 1766 94


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