Precursor Lesions of Pancreatic Cancer

Yonezawa, Suguru; Higashi, Michiyo; Yamada, Norishige; Goto, Masamichi

doi:10.5009/gnl.2008.2.3.137

Cited by 73 publications

(73 citation statements)

References 99 publications

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“…However, neither the myeloproliferative disease observed in Mx1-Cre;LSL-Kras G12D mice, nor the lung tumors seen in M-Cre;LSL-Kras G12D animals are genetically or histologically faithful to the analogous diseases seen in humans. In contrast, the neoplastic transformation and disease progression observed in the pancreas of Pdx1-Cre;LSL-Kras G12D mice faithfully mimics the progression of human pancreatic ductal adenocarcinoma (PDA) through a series of precursor lesions known as pancreatic intraepithelial neoplasias (PanINs) (11,12). Moreover, not only is PDA among the human cancers most frequently associated with oncogenic mutations in the KRAS gene (13), but activating mutations in the KRAS proto-oncogene have been found in patients with early PanIN lesions (14), suggesting that KRAS mutations may be an initiating genetic event for PDA.…”

Section: Introductionmentioning

confidence: 99%

Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

Court¹,

Amoyel²,

Hackman³

et al. 2013

J. Clin. Invest.

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RAS is the most frequently mutated oncogene in human cancers. Despite decades of effort, anti-RAS therapies have remained elusive. Isoprenylcysteine carboxylmethyltransferase (ICMT) methylates RAS and other CaaX-containing proteins, but its potential as a target for cancer therapy has not been fully evaluated. We crossed a Pdx1-Cre;LSL-Kras G12D mouse, which is a model of pancreatic ductal adenocarcinoma (PDA), with a mouse harboring a floxed allele of Icmt. Surprisingly, we found that ICMT deficiency dramatically accelerated the development and progression of neoplasia. ICMT-deficient pancreatic ductal epithelial cells had a slight growth advantage and were resistant to premature senescence by a mechanism that involved suppression of cyclin-dependent kinase inhibitor 2A (p16 INK4A ) expression. ICMT deficiency precisely phenocopied Notch1 deficiency in the Pdx1-Cre;LSL-Kras G12D model by exacerbating pancreatic intraepithelial neoplasias, promoting facial papillomas, and derepressing Wnt signaling. Silencing ICMT in human osteosarcoma cells decreased Notch1 signaling in response to stimulation with cell-surface ligands. Additionally, targeted silencing of Ste14, the Drosophila homolog of Icmt, resulted in defects in wing development, consistent with Notch loss of function. Our data suggest that ICMT behaves like a tumor suppressor in PDA because it is required for Notch1 signaling.Introduction RAS is the most frequently mutated oncogene in human cancer (1). This has made RAS the target of drug discovery efforts for more than three decades, but effective anti-RAS therapies have remained elusive (2). RAS is a prototypical small GTPase that functions as a binary molecular switch to regulate a number of signaling pathways including those that control growth and differentiation. RAS is inactive when GDP bound and is active when it binds GTP. The GDP/GTP cycle is controlled by guanine nucleotide exchange factors (GEFs) that activate RAS and by GTPase-activating proteins (GAPs) that dramatically accelerate the rate of GTP hydrolysis catalyzed by RAS, thereby limiting RAS activity (3). The oncogenic mutations found in human cancer are one of several single nucleotide changes in codons 12, 13, or 61 that render RAS insensitive to GAPs and reduce the intrinsic rate of GTP hydrolysis, thus allowing the accumulation of GTP-bound, activated RAS (1, 4). Attempts to devise therapeutic agents that reverse the accumulation of GTP-bound RAS have failed. Accordingly, investigators have taken an alternate approach driven by another hallmark of RAS biology: its regulation of signaling pathways only when associated with cellular membranes (5).RAS is a peripheral membrane protein that gains affinity for membranes as a consequence of a series of posttranslational modifications of a C-terminal CaaX motif (6). The CaaX sequence is first modified by farnesyltransferase (FTase), which adds a farnesyl lipid to the cysteine. Next, RAS-converting enzyme 1 (RCE1) removes the aaX amino acids. Finally, isoprenylcysteine carboxylmethyltransferas...

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Section: Introductionmentioning

confidence: 99%

Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

Court¹,

Amoyel²,

Hackman³

et al. 2013

J. Clin. Invest.

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“…MUC6 was positive in 31.3% of dysplasias, and 18.2% in CC. Several authors demonstrated higher expression of these mucins in both CC and dysplastic epithelium, emphasizing that they are important in characterizing biliary and pancreatic pre-neoplastic lesions (7,11,15,20,21,24) . Although these results apparently substantiate the usefulness of mucins 5 and 6 in the characterization of preneoplastic lesions, we observed that both were also expressed in reactive epithelium in 40.3% and 11.9%, respectively.…”

Section: Discussionmentioning

confidence: 99%

Mucins and NCAM (CD56) in intrahepatic cholangiocarcinogenesis

Esperança¹,

Camacho²,

Monteiro³

et al. 2014

Jornal Brasileiro De Patologia E Medicina Laboratorial

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Introduction: Cholangiocarcinoma is the second most common malignant neoplasm of the hepatobiliary system. During cholangiocarcinogenesis phenotypic changes occur in the ductal epithelium, including the expression of mucins (MUC). However, the evaluating studies of the expression of mucins in the different stages of cholangiocarcinogenesis are scarce. CD56 has also contributed in differentiating benign ductal proliferation and cholangiocarcinoma; however, its expression has not been evaluated in dysplastic epithelium of the bile duct yet. Objective: To assess immunohistochemical profile of (MUC) 1, 2, 5, 6, and CD56 in cholangiocarcinoma, pre-neoplastic and reactive lesions in the epithelium of intrahepatic bile ducts. Material and methods: Immunohistochemical expression of MUC 1, 2, 5, 6, and CD56 were studied for 11 cases of cholangiocarcinoma and 83 intrahepatic bile ducts (67 reactive and 16 dysplastic). Variables were considered significant when p < 0.05. Results: The expression of MUC1 occurred in about 90% of the cholangiocarcinomas, contrasting with the low frequency of positive cases in reactive and dysplastic bile ducts (p < 0.001). However, there was no statistically significant difference in the expression of MUC5, MUC6 and CD56 between the reactive or dysplastic lesions and cholangiocarcinoma. The anti-MUC2 antibody was negative in all cases. Conclusions: MUC1 contributed for the differential diagnosis between cholangiocarcinoma and pre-neoplastic and reactive/regenerative lesions of intrahepatic bile ducts, and it should compose the antibodies panel aiming at improvement of these differential diagnoses. In contrast, MUC2, MUC5, MUC6 and CD56 were not promising in differentiating all the phases of cholangiocarcinogenesis.

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“…Pancreatic ductal adenocarcinoma (PDAC) is known as pancreatic cancer, is the most well-known exocrine-based pancreatic tumor. Scientific studies indicated that the progression of this malignancy is not solely dictated by the tumor cells themselves, but rather there is melodious synergy between tumor stromal cells with multiple signaling pathways [20].…”

Section: Epidemiology Of Pancreatic Cancermentioning

confidence: 99%

Role of Probiotics in Pancreatic Cancer Prevention: The Prospects and Challenges

Singhal¹,

Mukherjee²

2016

ABB

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Pancreatic cancer is expressed as a disorder of chaos that leads to impairment in biochemical and metabolic physiology of pancreas. It is considered as the most intractable and fatal among all gastrointestinal (GI) cancers. The early occurrence of metastatic spread and the development of intrinsic and acquired resistance during drug treatment limit its prognosis at the right time. The universalized treatment involves surgical resection in which only a minority (<20%) of patients qualify due to advanced stage of disease at the time of diagnosis. Despite the rigorous technological developments in understanding the molecular mechanism of pancreatic cancer, no significant advances in efficacy of chemotherapeutic treatment have been arisen till date and still present challenges to overcome. That leads to the scientists to undergo exhaustive research to find an alternative treatment and increasing focus have been given on the studies of symbiotic relationships between microbiota and host which confers benefits to the host in many key aspects of life and form a synergistic harmony so called "super-organism". The perturbations in the regulatory circuits of the host that control homeostasis, or alterations of the microbiome, through environmental changes (infection, diet or lifestyle), may disturb this symbiotic relationship and favors carcinogenesis in the pancreas. Research studies speculating convincing evidence that, among the gut microbiota, probiotics have demonstrated their potential role in the prevention of all stages of cancer development, but the critical question has been arisen that Can probiotics be used as preventive targets for pancreatic cancer? Thus, the efforts have been directed towards to summarize the prospective and challenging role of probiotics as preventive approach for pancreatic cancer. Though prospects of probiotics in prevention of pancreatic cancer are being great challenge among research community therefore, more rigorous and well-designed in vitro, animal and clinical studies are required for worthy manifestations.

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Precursor Lesions of Pancreatic Cancer

Cited by 73 publications

References 99 publications

Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

Mucins and NCAM (CD56) in intrahepatic cholangiocarcinogenesis

Role of Probiotics in Pancreatic Cancer Prevention: The Prospects and Challenges

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