Immunohistochemical validation of a novel epithelial and a novel stromal marker of pancreatic ductal adenocarcinoma identified by global expression microarrays: sea urchin fascin homolog and heat shock protein 47.
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We extended the results of a previous microarray analysis by immunohistochemical validation of differential protein expression in a series of 57 surgically resected infiltrating ductal pancreatic adenocarcinomas. Two representative genes were examined: sea urchin fascin homolog (overexpressed in both cell lines and primary tumors) and heat shock protein 47 (HSP47; overexpressed in primary tumors only). Protein expression also was evaluated in the precursor lesions of pancreatic cancer pancreatic intraepithelial neoplasia (PanIN), and normal ductal epithelium. Fascin expression was seen in the neoplastic cells of 54 (95%) of 57 ductal adenocarcinomas but not in 49 (94%) of 52 adjacent nonneoplastic epithelium. In the multistep pathogenesis of ductal adenocarcinomas, fascin expression seemed to be a late event, usually present in PanINs 2 and 3. HSP47 expression was almost universal and most intense in the ductal adenocarcinoma-associated stromal desmoplasia (57/57), although 37 cases (65%) also expressed HSP47 in the neoplastic epithelium. HSP47 expression was absent in the majority of nonneoplastic pancreata (46 [88%]). Fascin and HSP47 are novel tumor markers with potential diagnostic and therapeutic implications for pancreatic carcinoma. These results establish the usefulness of global expression platforms to identify novel tumor markers. (+info)
Clinicopathological significance of abnormalities in Gadd45 expression and its relationship to p53 in human pancreatic cancer.
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PURPOSE: The growth arrest and DNA damage-inducible 45 gene (GADD45a) is one of the downstream mediators of the p53 gene that stimulates DNA excision repair. The present study was designed to assess the clinicopathological significance of GADD45a and p53 in resectable invasive ductal carcinomas (IDCs) of the pancreas. EXPERIMENTAL DESIGN: This study included 72 pancreatic IDC patients who received surgery between 1982 and 2001. Point mutations in exons 1 and 4 of GADD45a and the expression of the GADD45a gene product (Gadd45) and p53 protein were analyzed by direct DNA sequencing and immunohistochemistry. RESULTS: Point mutations were found in exon 4 of GADD45a in eight cases (13.6%). Gadd45 and p53 were expressed in 54.2% (39 of 72) and 47.2% (34 of 72) of the patients. The expression of Gadd45 did not necessarily correlate with that of p53. However, Gadd45 expression correlated significantly with the grade of the pT factor of the tumors. Coexpression analysis of Gadd45 and p53 indicated that in patients with p53(+) IDC, the Gadd45(+) group had a significantly lower survival rate than the Gadd45(-) group. Furthermore, Gadd45 expression had no effect on the efficacy of the adjuvant chemotherapy. Multivariate analysis indicated that pTNM (tumor-node-metastasis) stage, grade, and adjuvant chemotherapy were significant variables for survival. Furthermore, in the p53(-) group, there were no significant variables. In contrast, in the p53(+) group, pTNM stage, histological grade, and Gadd45 expression were significant variables. CONCLUSIONS: The frequency of GADD45a mutation is appreciable in human pancreatic IDC, and the expression of Gadd45, combined with that of p53, significantly affects the survival of patients with resectable IDCs of the pancreas. (+info)
Clinicopathological significance of galectin-3 expression in ductal adenocarcinoma of the pancreas.
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PURPOSE: Galectin-3, a member of the beta-galactoside-binding lectin family, has multiple biological functions including cell-cell interactions and cell-extracellular matrix adhesion, cellular proliferation, cellular differentiation, and apoptosis. The aim of this study was to determine the relationship of galectin-3 expression to clinicopathological findings and patient prognosis in ductal adenocarcinoma of the pancreas. EXPERIMENTAL DESIGN: We examined galectin-3 expression in 104 surgically resected pancreatic ductal adenocarcinoma cases with stages I through IV using immunohistochemistry and investigated the relationship of it to overall survival. RESULTS: Patients were divided into two groups: a low expression group, where <60% of tumor cells were positive; and a high expression group, where > or =60% of tumor cells were positive. Cases in the low expression group had a significant tendency to be at later stages, to have distant metastasis, and to have less differentiated tumors, compared with cases in the high expression group (P = 0.001 for stage, P = 0.001 for metastasis, and P = 0.006 for differentiation). Postoperative overall survival was worse in the low galectin-3 expression group than in the high galectin-3 expression group (P = 0.004). Multivariate analysis showed that the risk ratio of prognosis was 2.06 among patients in the low galectin-3 expression group compared with the high galectin-3 expression group (P = 0.006). CONCLUSIONS: Decreased expression of galectin-3 was associated with advanced stage, tumor de-differentiation, and metastasis in ductal adenocarcinoma of the pancreas. Galectin-3 expression might be a useful prognostic marker for survival in ductal adenocarcinoma of the pancreas. (+info)
Intraductal papillary and mucinous pancreatic tumour: a new extracolonic tumour in familial adenomatous polyposis.
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Familial adenomatous polyposis (FAP) is characterised by the development of numerous colorectal adenomatous polyps. Other extracolonic benign or malignant lesions have been reported previously in association with FAP but precancerous lesions in the pancreas have never been described. We report the first case of intraductal papillary and mucinous pancreatic tumour (IPMT) in a patient with FAP. A 48 year old man with a well documented past history of FAP was admitted for epigastric pain, weight loss, and new onset diabetes mellitus. Spiral computed tomography scan revealed a large tumour in the pancreatic head with upstream main pancreatic duct dilatation. Endoscopic ultrasonography confirmed these data. Mucous secretion was seen at duodenoscopy and a lesion in the main pancreatic duct was confirmed by retrograde pancreatography. The patient underwent a pancreaticoduodenectomy for suspected IPMT. Histological examination of the resected specimen confirmed an IPMT with in situ carcinoma. Twelve months after resection, the patient remained free of tumour relapse. Genetic analysis showed loss of the wild allele of the adenomatous polyposis coli gene in IPMT, causing inactivation of both alleles and demonstrating that IPMT was not incidental in this patient. IPMT should be included in the extracolonic localisation of FAP. (+info)
Silencing of secretin receptor function by dimerization with a misspliced variant secretin receptor in ductal pancreatic adenocarcinoma.
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Secretin receptors that are key for regulation of healthy pancreatic ductal epithelial cells have been reported to be functionally absent on ductal pancreatic adenocarcinomas. Here, we examine the possible presence and function of molecular forms of the secretin receptor in pancreatic cancer cell lines and in primary tumors. Surprisingly, reverse transcription-PCR and sequencing demonstrated wild-type secretin receptor mRNA in each of four cell lines and three primary tumors. Lack of biological response to nanomolar concentrations of secretin was best explained by the demonstrated coexpression of a second and predominant transcript in each of the cell lines and tumors. This represented a variant of the secretin receptor in which the third exon was spliced out to eliminate residues 44-79 from the NH(2)-terminal tail. This spliceoform has only recently been recognized in a rare gastrinoma, where it was incapable of binding secretin or signaling, and possessed dominant-negative activity to suppress hormone action at the wild-type secretin receptor (1). Overexpression of wild-type secretin receptor in Panc-1 cells driven by transfection of fully processed cDNA resulted in normal responsiveness to low concentrations of secretin, establishing the ability of these cells to produce a receptor capable of normal biosynthesis, trafficking, and signaling. Bioluminescence resonance energy transfer demonstrated that the variant receptor could form a heterodimer with wild-type receptor, providing a molecular mechanism for its dominant-negative activity. This suggests that missplicing is responsible for expression of a secretin receptor variant having the ability to suppress the function of wild-type receptor by a direct interaction. In 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays in receptor-bearing Chinese hamster ovary cells, the secretin receptor was shown to have growth-inhibitory effects. Suppression of this activity in pancreatic carcinoma might, therefore, facilitate tumor growth and progression of this aggressive neoplasm. (+info)
The desmoplastic response to infiltrating breast carcinoma: gene expression at the site of primary invasion and implications for comparisons between tumor types.
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The gene expression patterns of desmoplasia are becoming exposed through the application of global gene expression technologies such as cDNA microarrays or serial analysis of gene expression (SAGE). These patterns represent the sum of the many cellular components of the host stromal response to an infiltrating carcinoma. In studies of human neoplasms, it would be useful to identify those prototypical genes that characteristically indicate the recognizable forms of the responses to individual tumor types. Such genes may offer clues to better understand the process of invasion itself, the interactions between tumor and host cells, and tumor-specific differences in invasion. We used SAGE-defined genes and in situ transcript labeling to characterize the desmoplastic stroma induced by infiltrating ductal carcinomas of the breast. Principal component analysis identified 103 SAGE tags as specific for invasive breast carcinomas, in comparison with in situ duct carcinomas or normal breast epithelium. Of these, 68 tags corresponded to known genes. Six of the 68 genes from this breast cancer "invasion-specific" cluster were further characterized by in situ hybridization to breast cancer tissues. Results of in situ hybridization demonstrated that each gene was expressed within one of five distinct regions of the invasive tumors (neoplastic epithelium; angioendothelium; inflammatory, panstromal, and juxtatumoral stroma), reflecting a defined architectural structure to the transcriptome of invasive breast cancers. Two of these 6 genes were specifically expressed by the stromal cells within the invasive carcinoma; however, 1 (collagen 1alpha1) was expressed throughout the stromal response (panstromal expression), whereas the second (osteonectin) was specifically expressed within the juxtatumoral stromal cells, indicating a critical "regionality" of gene expression within the stromal response itself. A comparison of the gene expression profiles of the juxtatumoral stroma in breast and pancreatic carcinomas indicated important differences between the two, suggesting tumor-specific or organ-specific differences in the desmoplastic responses. Some of the genes presented are novel markers of the invasive process, imply communication at the host/tumor interface, and suggest potential therapeutic targets. (+info)
Prognosis of malignant intraductal papillary mucinous tumours of the pancreas after surgical resection. Comparison with pancreatic ductal adenocarcinoma.
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BACKGROUND: Although the prognosis in malignant resectable intraductal papillary mucinous tumours of the pancreas (IPMT) is often considered more favourable than for ordinary pancreatic ductal adenocarcinoma, the long term outcome remains ill defined. AIMS: To assess prognostic factors in patients with malignant IPMT after surgical resection, and to compare long term survival rates with those of patients surgically treated for ductal adenocarcinoma. METHODS: Seventy three patients underwent surgery for malignant IPMT in four French centres. Clinical, biochemical, and pathological features and follow up after resection were recorded. Patients with invasive malignant IPMT were matched with patients with pancreatic ductal adenocarcinoma, according to age and TNM stages; survival rates after resection were compared. RESULTS: Surgical treatment for IPMT were pancreaticoduodenectomy (n=46), distal (n=14), total (n=11), or segmentary (n=2) pancreatectomy. The operative mortality rate was 4%. IPMT corresponded to in situ (n=22) or invasive carcinoma (n=51). In the latter group, 17 had lymph node metastases. Overall median survival was 47 months. Five year survival rates in patients with in situ and invasive carcinoma were 88% and 36%, respectively. On univariate analysis, abdominal pain, preoperative high serum carbohydrate antigen 19.9 concentrations, caudal localisation, invasive carcinoma, lymph node metastases, peripancreatic extension, and malignant relapse were associated with a fatal outcome. Using multivariate analysis, lymph node metastases were the only prognostic factor (OR 7.5; 95% CI: 3.4 to 16.4). Overall five year survival rate was higher in patients with malignant invasive IPMT compared with those with pancreatic ductal carcinoma (36 v 21%, p=0.03), but was similar in the subset of stage II/III tumours. CONCLUSIONS: The prognosis of patients with resected in situ/invasive stage I malignant IPMT is excellent. In contrast, prognosis of locally advanced forms is as poor as in patients with pancreatic ductal adenocarcinoma. (+info)
The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas: differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis.
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Emerging evidence suggests a dichotomy in the dysplasia-CIS-invasive carcinoma sequence in the pancreas. Pancreatic intraepithelial neoplasms (PanINs; small, incidental duct lesions) progress to invasive ductal adenocarcinomas (5-y survival of < 15%), whereas intraductal papillary mucinous neoplasms (large, intraductal tumors with ductal dilatation) are often associated with colloid carcinoma (5-y survival of > 55%). We explored the relationship of these lesions by examining the expression of MUC1 and MUC2, glycoproteins reportedly reflecting "aggressive" and "indolent" phenotypes in pancreas cancer, respectively. Immunohistochemical labeling with MUC1 (clone Ma695) and MUC2 (clone Ccp58) antibodies was performed on PanINs (n = 43), intraductal papillary mucinous neoplasms (n = 74), ductal adenocarcinomas (n = 136), and colloid carcinomas (n = 15). Fifty-four percent of the intraductal papillary mucinous neoplasms expressed MUC2, whereas none of the PanINs did. In contrast, PanINs, especially higher grade lesions, were often positive for MUC1 (61% of PanIN 3), whereas the expression of this glycoprotein was infrequent in intraductal papillary mucinous neoplasms (20%). This dichotomy was further accentuated in the invasive carcinomas with which these two preinvasive pathways are respectively associated: all colloid carcinomas were MUC2+ (100%) and MUC1- (0%), whereas the labeling pattern was the reverse for ductal adenocarcinomas: 63% were MUC1+ and only 1% were MUC2+. These results support a dichotomy in the dysplasia-CIS sequence in the pancreas. Because these two pathways often lead to different types of invasive carcinomas, this is an invaluable model for the study of carcinogenesis. The findings here also support the previous impression that MUC2 (the mucin associated with gel formation) is a marker of the "indolent" pathway (intraductal papillary mucinous neoplasm and colloid carcinoma), whereas MUC1 (the glycoprotein known to have an inhibitory role in cell-cell and cell-stroma interactions as well as in immunoresistance of tumor cells) is a marker of the "aggressive" pathway (PanIN to ductal adenocarcinoma). (+info)