Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease

Tada, Minoru; Ohashi, Makoto; Shiratori, Yasushi; Okudaira, Takehito; Komatsu, Yutaka; Kawabe, Takao; Yoshida, Haruhiko; Machinami, Rikuo; Kishi, Kazuhisa; Omata, Masao

doi:10.1053/gast.1996.v110.pm8536861

Cited by 258 publications

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“…Although there is no established tumor progression model for pancreatic cancer, such as the adenoma-carcinoma sequence of colorectal carcinoma, 41 it is generally accepted that K-ras and p16 mutations occur relatively early in pancreatic carcinogenesis, whereas p53 mutations occur late in this process. 37,[41][42][43] Increased Id expression may contribute to malignant transformation of cultured cell lines in vitro 11 and has been linked to cell invasion in a murine mammary epithelial cell line. 44 In view of the current findings that Id-1, Id-2, and Id-3 are overexpressed in pancreatic cancer and in dysplastic/ metaplastic ducts in CP, these observations raise the possibility that elevated levels of Id-1, Id-2, and, to a lesser extent, Id-3 may represent relatively early markers of pancreatic malignant transformation and may contribute to the pathobiology of pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Id-1 and Id-2 Are Overexpressed in Pancreatic Cancer and in Dysplastic Lesions in Chronic Pancreatitis

Maruyama

Kleeff

Wildi

et al. 1999

The American Journal of Pathology

138

113

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Id proteins antagonize basic helix-loop-helix proteins , inhibit differentiation , and enhance cell proliferation. In this study we compared the expression of Id-1 , Id-2 , and Id-3 in the normal pancreas , in pancreatic cancer , and in chronic pancreatitis (CP). Northern blot analysis demonstrated that all three Id mRNA species were expressed at high levels in pancreatic cancer samples by comparison with normal or CP samples. Pancreatic cancer cell lines frequently coexpressed all three Ids , exhibiting a good correlation between Id mRNA and protein levels , as determined by immunoblotting with highly specific anti-Id antibodies. Immunohistochemistry using these antibodies demonstrated the presence of faint Id-1 and Id-2 immunostaining in pancreatic ductal cells in the normal pancreas , whereas Id-3 immunoreactivity ranged from weak to strong. In the cancer tissues, Basic helix-loop-helix (bHLH) proteins play an important role as transcription factors in cellular development, proliferation, and differentiation. 1,2 The basic domain of the bHLHs is required for binding to an E-box DNA sequence, thus promoting transcription of specific target genes. The HLH domain promotes dimer formation with various members of the bHLH protein family. 1,2 Homodimers of the class B family of bHLH proteins, including MyoD, NeuroD, and numerous other proteins, are known to activate tissue-specific genes. 3-5 These tissuespecific bHLHs typically form heterodimers with widely expressed class A bHLHs, which include proteins encoded by E2A, E2-2, HEB, and other genes (also termed E-proteins). 6 -9 These heterodimers activate transcription of genes that are associated with differentiation.Id genes encode a family of four HLH proteins that lack the basic DNA binding domain. 1,10 They act as dominantnegative HLH proteins by forming high affinity heterodimers with other bHLH proteins, thereby preventing them from binding to DNA and inhibiting transcription of differentiation-associated genes. 10 -12 Id gene expression is down-regulated on differentiation in many cell types in vitro and in vivo. [13][14][15][16][17][18] In addition, Id proteins seem to be required for cell cycle progression through G 1 /S phase in certain cell types, and interaction between Id-2 and pRB is associated with enhanced proliferation in some cell lines in vitro. 19 -23 Pancreatic cancer is the fifth leading cause of cancer death in the United States, with a mortality rate that virtually equals its incidence rate. 24 This malignancy is often associated with the overexpression of a variety of mitogenic growth factors and their receptors, and by oncogenic mutations of K-ras and inactivation of the p53 tumor suppressor gene. 25 We have recently reported that pancreatic cancers overexpress the HLH protein Id-2, and that enhanced expression of this protein is evident in the cytoplasm of the cancer cells within the pancreatic tumor mass. 26 It is not known, however, whether the expression of other Id proteins is altered in this malignancy, or whether their expressio...

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Section: Discussionmentioning

confidence: 99%

Id-1 and Id-2 Are Overexpressed in Pancreatic Cancer and in Dysplastic Lesions in Chronic Pancreatitis

Maruyama

Kleeff

Wildi

et al. 1999

The American Journal of Pathology

138

113

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“…K-ras abnormalities, most often mutations in Codon 12, have been demonstrated in neoplastic ductal epithelium isolated from patients with a history of pancreatic cancer as well as from those with no history of pancreatic neoplasia and from autopsy specimens (33)(34)(35)(36). Overexpression of p53 is found most commonly in invasive pancreatic carcinoma; however, it may also be overexpressed in PanIN, especially HG PanIN (34,(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Neoplasms of the Ampulla of Vater with Concurrent Pancreatic Intraductal Neoplasia: A Histological and Molecular Study

et al. 2001

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Adenoma and adenocarcinoma of the ampulla of Vater are uncommon neoplasms of the gastrointestinal tract that are found with increased frequency in familial adenomatous polyposis syndrome (1-3). Ampullary adenoma represents the precursor lesion to adenocarcinoma, and a coexistent adenoma can be identified frequently in patients with ampullary adenocarcinoma (1, 2). Because of their premalignant nature, ampullary adenomas are often resected either by polypectomy or, in the case of larger lesions, by pancreaticoduodenectomy (1,4,5). An association between adenomas of the ampullary region and pancreatic intraductal neoplasia has not been documented previously. Adenocarcinoma of the pancreas is often associated with pancreatic intraductal neoplasia (PanIN), which is thought to represent the precursor lesion for this cancer (6 -12). Several case reports documenting progression of high-grade (HG) PanIN to invasive pancreatic adenocarcinoma over time (17 mo to 29 y) support the role of PanIN as a precursor of carcinoma (10,13,14).The relationship between ampullary adenoma and PanIN has not been investigated previously, and only one analysis of the relationship between

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“…Recently, Tada et al (1996) showed that Ki-RAS mutations occur in hyperplastic foci of the pancreatic duct, even when no pancreatic cancer or pancreatitis was demonstrable. Thus, mutation of Ki-RAS on its own cannot lead to pancreatic cancer -other genetic alterations have to occur.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of p53 protein during pancreatitis

Maacke

Kessler²,

Schmiegel³

et al. 1997

Br J Cancer

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Summary Overexpression of p53 correlates with neoplasia in many cytological specimens. To test the specificity of overexpressed p53 as a tumour marker for the detection of pancreatic cancer, we analysed cytological specimens of pancreatic juice samples from patients with pancreatitis or pancreatic carcinoma (n = 42) for p53 protein overexpression. p53 protein overexpression was found in 59% of patients with pancreatitis and 67% of patients with pancreatic carcinoma. Thus, Kalthoff et al, 1993), and more than 50% of pancreatic carcinomas express an altered p53 tumour-suppressor gene (Barton et al, 1991;Kalthoff et al, 1993). Deletions of cyclin kinase inhibitors pl6/MTS1 (Caldas et al, 1994) and pl5/MTS2 (Naumann et al, 1996) have been described, and a new tumour-suppressor gene, DPC4, has been found very recently (Hahn et al, 1996). In spite of this progress at the molecular level, the clinical outcome of patients with pancreatic cancer is still very poor. Thus, detection of early stages of pancreatic cancer is still crucial for a better prognosis.For many cytological specimens, the detection of p53 overexpression by immunocytochemistry strongly correlates with neoplasia (Dowell et al, 1994). Our aim was to establish whether the detection of p53 overexpression in cytological specimens from pancreatic juice samples, collected during ERCP (endoscopic retrograde cholangiopancreaticography), may be useful in detecting early stages of pancreatic carcinoma.p53 protein overexpression was detected in nearly 60% of cytological specimens from patients with pancreatitis but without any sign of pancreatic cancer for up to 5 years (median follow-up) after ERCP. This indicates that, in the case of pancreatic disease, p53 protein overexpression does not correlate with neoplasia. However p53 seems to play an important role during pancreatitis, as apoptotic cell death has been observed during chronic disease. This is in line with the function of p53 as an inductor of apoptotic cell death (Lane, 1992 MATERIALS AND METHODS Preparation of cytological specimens by cytospin of pancreatic juicePancreatic juice samples were collected during diagnostic ERCP from a total of 42 patients. One group comprised 27 patients suffering from chronic pancreatitis. The other group had 15 patients with pancreatic ductal adenocarcinomas, the vast majority of which were in stage II and III. Sample preparation was performed exactly as described previously (Schmiegel et al, 1990). Median follow-up was 5 years in the group of pancreatitis patients. During this period, no pancreatic cancer cases were observed. Antibodies and immunoperoxidase studiesThe p53-specific monoclonal antibodies PAbl801, PAb240 and PAbl620 were obtained from Oncogene Sciences (Dianova, Hamburg). The polyclonal antiserum against recombinant human p53 (CM-1) was purchased from Medac (Hamburg). Immunoperoxidase studies were performed exactly as described previously (Kalthoff et al, 1993). Samples were scored positive when at least 5% of the cells from the investigated cytospin were...

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Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease

Cited by 258 publications

References 0 publications

Id-1 and Id-2 Are Overexpressed in Pancreatic Cancer and in Dysplastic Lesions in Chronic Pancreatitis

Id-1 and Id-2 Are Overexpressed in Pancreatic Cancer and in Dysplastic Lesions in Chronic Pancreatitis

Neoplasms of the Ampulla of Vater with Concurrent Pancreatic Intraductal Neoplasia: A Histological and Molecular Study

Overexpression of p53 protein during pancreatitis

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