Expression of cancer testis antigens in pancreatic carcinoma cell lines, pancreatic adenocarcinoma and chronic pancreatitis
Boris KubuschokXiaoxiun XieRalf JesnowskiKlaus‐Dieter PreussBernd RomeikeFrank NeumannEvi RegitzG. PistoriusMartin SchillingP. ScheunemannJakob R. IzbickiMatthias LöhrMichael Pfreundschuh
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Abstract:
Abstract In order to define antigens that might be suitable as vaccines for pancreatic carcinoma, we investigated the composite expression of 10 cancer testis (CT) antigens (SCP‐1, NY‐ESO‐1, SSX‐1, SSX‐2, SSX‐4, GAGE, MAGE‐3, MAGE‐4, CT‐7 and CT‐8) by Reverse Transcriptase‐PCR (RT‐PCR) in fresh biopsies of human pancreatic adenocarcinoma, chronic pancreatitis and pancreatic carcinoma cell lines. While all CT genes were frequently expressed in cell lines derived from pancreatic cancer, no expression of MAGE‐3, SSX‐1, SSX‐2, NY‐ESO‐1 and CT‐7 was detected in fresh tumor biopsies, and MAGE‐4 (1/52), SSX‐4 (1/39) and CT‐8 (2/41) were only rarely expressed. In contrast, HOM‐TES‐14/SCP‐1 was expressed in 48% (29/61) and GAGE in 21% (13/61) of cases, respectively. One CT gene was expressed by 59% (75% in male, 46% in female patients; p = 0.05) and 2 or more CT genes by 15% of the samples. SCP‐1 protein expression correlated well with mRNA expression. While SCP‐1 and GAGE were absent in normal pancreas, they were found in 2/8 (SCP‐1) and 1/8 (GAGE) samples of chronic pancreatitis, respectively, supporting the concept of chronic pancreatitis as a premalignant condition. SCP‐1 and GAGE represent promising candidates for vaccine development in pancreatic carcinoma. Whether SCP‐1 and GAGE expression identify cases of chronic pancreatitis with a high risk of malignant transformation remains to be shown. © 2004 Wiley‐Liss, Inc.Keywords:
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Based on the relevant literature data and on personal experience, the author discusses the mechanisms of pancreatic function impairment in patients with pancreatic cancer, and the role of pancreatic function tests in the diagnosis of this disease. Although pancreatic function is reduced in the vast majority of patients with pancreatic cancer, at present pancreatic function tests are of limited value in the diagnostic approach to this tumor. This is mainly due to the fact that in most cases, patients with pancreatic cancer are seen when the cancer is in an advanced stage, and it can be rather easily diagnosed with currently available imaging techniques.
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Objectives: Pancreatitis is an inflammatory condition of the pancreas. However, it often shares many molecular features with pancreatic cancer. Biomarkers present in pancreatic cancer frequently occur in the setting of pancreatitis. The efforts to develop diagnostic biomarkers for pancreatic cancer have thus been complicated by the false-positive involvement of pancreatitis. Methods: In an attempt to develop protein biomarkers for pancreatic cancer, we previously use quantitative proteomics to identify and quantify the proteins from pancreatic cancer juice. Pancreatic juice is a rich source of proteins that are shed by the pancreatic ductal cells. In this study, we used a similar approach to identify and quantify proteins from pancreatitis juice. Results: In total, 72 proteins were identified and quantified in the comparison of pancreatic juice from pancreatitis patients versus pooled normal control juice. Nineteen of the juice proteins were overexpressed, and 8 were underexpressed in pancreatitis juice by at least 2-fold compared with normal pancreatic juice. Of these 27 differentially expressed proteins in pancreatitis, 9 proteins were also differentially expressed in the pancreatic juice from pancreatic cancer patient. Conclusions: Identification of these differentially expressed proteins from pancreatitis juice provides useful information for future study of specific pancreatitis-associated proteins and to eliminate potential false-positive biomarkers for pancreatic cancer.
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Pancreatic Disease
Exocrine pancreas
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Activated lymphocytes can release a soluble form of interleukin-2 receptor (sIL-2R) and abnormally high serum levels of sIL-2R have been reported in patients with advanced solid tumours and in those with chronic disease. We determined serum sIL-2R concentrations in 34 patients with chronic pancreatitis (8 in painful relapse), in 40 with pancreatic tumours in various stages, and in 40 healthy subjects as controls. Patients with pancreatic cancer and those with chronic pancreatitis had significantly higher serum concentrations of sIL-2R than healthy subjects (p < 0.001). In patients with Stage II pancreatic cancer, serum levels of soluble receptors were similar to those in patients with Stage III tumours, and these concentrations were significantly higher than in patients with resectable cancer (p < 0.01 and p < 0.05, respectively). In chronic pancreatitis patients, those studied during painful relapse of the disease had higher serum concentrations of sIL-2R than those studied during clinical remission (p < 0.05). The results of our study suggest an activation of the cellular immune system in pancreatic cancer and in chronic pancreatitis.
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The diagnostic role of serum and pancreatic juice CA 19-9 determination in discriminating surgically resectable pancreatic cancer from chronic pancreatitis was investigated. Only in about one third of cancer patients the serum assay was diagnostic versus subjects with chronic pancreatitis. None of 5 patients with 'early' pancreatic cancer had a diagnostic score [greater than 120 U/ml]. Conversely, the determination of CA 19-9 content in pure pancreatic juice, expressed as Units per microgram of protein, discriminated all the 15 patients with operable tumors, including those with early carcinoma, from subjects with chronic pancreatitis. The CA 19-9 assay of pancreatic juice is proposed as a reliable marker of cancer in those patients in whom the ERCP pattern is not definitive for malignancy.
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Three cases of chronic alcoholic pancreatitis associated with aberrant pancreas are reported. All three patients underwent laparotomy, and an aberrant pancreas was found in the jejunum of each of the three patients. Microscopic examination of the aberrant pancreas did not show any changes suggestive of chronic pancreatitis, despite severe chronic pancreatitis in the main pancreas.
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