Overexpression of cyclooxygenase-2 in carcinoma of the pancreas

Okarni, Jiro; Shoji, Nobuyuki; Sakon, Masato; Yamamoto, Hirofumi; Kondo, Motoi; Shiozaki, Ken; Oshima, Satoshi; Aoki, Taro; Nagano, Hiroaki; Dono, Keizo; Umeshita, K; Monden, Morito

doi:10.1016/s0016-5085(00)82293-3

Cited by 88 publications

(109 citation statements)

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“…Experiments using COX-2 inhibitors may allow a better understanding of the possible role of COX-2 in pancreatic islet physiology and the pathogenesis of diabetes mellitus because prostaglandin E 2 negatively regulates pancreatic islet function, i.e., glucose-induced insulin secretion. 9 Fukutake et al 19 reported that nimesulide exerts a suppressive effect on azoxymethane-induced colon carcinogenesis in ICR mice without significant influence on liver and lung tumor development, which is in line with our data in the present study. Organ speci- ficity of NSAIDs was also encountered in a rat multiorgan carcinogenesis model, in which the chemopreventive effect of indomethacin was investigated, 36 lung carcinogenesis being inhibited but not hepatocarcinogenesis.…”

Section: Discussionsupporting

confidence: 92%

“…3,4 COX-2 has been closely associated with carcinogenesis, especially the growth and progression of a number of human cancers, including those in the colon, 5 stomach, 6 liver, 7 lung 8 and pancreas. 9,10 In addition, selective COX-2 inhibitors prevent growth of cancer cells. 4 It is now clear that COX-2 is an inducible immediate early gene, 11 involved not only in inflammation and cell proliferation 11 but also in differentiation, 12 apoptosis, 13 metastasis, 14 immunologic surveillance 15 and angiogenesis.…”

mentioning

confidence: 99%

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A cyclooxygenase‐2 inhibitor, nimesulide, inhibits postinitiation phase of N‐nitrosobis(2‐oxopropyl)amine‐induced pancreatic carcinogenesis in hamsters

Furukawa

Nishikawa

Lee

et al. 2003

Intl Journal of Cancer

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The modification effects of nimesulide, a cyclooxygenase (COX)-2 inhibitor, administration during the postinitiation phase of pancreatic carcinogenesis were investigated in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Male Syrian hamsters were given 4 weekly s.c. injections of BOP at a dose of 10 mg/kg and thereafter administered 0, 100 or 400 ppm nimesulide in the diet for 36 weeks. Additional groups of hamsters were fed 400 ppm nimesulide without prior BOP initiation or nontreated. At week 40, all surviving animals were killed and development of neoplastic and preneoplastic lesions was assessed histopathologically. The incidence of pancreatic adenocarcinomas was significantly (p < 0.05) decreased in the BOP/400 ppm nimesulide group compared to the BOP alone group. The multiplicity of total lesions of pancreatic adenocarcinoma plus atypical hyperplasia was also significantly (p < 0.05) lowered. Immunohistochemically, COX-2 was clearly expressed in pancreatic and lung tumor cells, whereas expression was not remarkably affected by the 400 ppm nimesulide treatment. Proliferating cell nuclear antigen labeling indices of pancreatic ducts were significantly (p < 0.01) reduced by nimesulide. The incidence and multiplicity of neoplastic lesions in other organs did not significantly differ among the BOP-treated groups, though only the multiplicity of lung tumors showed a tendency to decrease. No neoplastic lesions were detected in animals receiving nimesulide alone. Our results clearly indicate that nimesulide protects against BOP-induced pancreatic tumors in hamsters.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

A cyclooxygenase‐2 inhibitor, nimesulide, inhibits postinitiation phase of N‐nitrosobis(2‐oxopropyl)amine‐induced pancreatic carcinogenesis in hamsters

Furukawa

Nishikawa

Lee

et al. 2003

Intl Journal of Cancer

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“…The nearly universal expression of COX-2 protein in carcinoma cells also suggests that this protein might play an important role in the progression of this cancer. As described in several previous reports, [14][15][16][17][19][20][21][22][23][24]76,77 the strong COX-2 expression was observed in several cancer cells, and some expression levels were reported to correlate to several clinicopathological stages. 78 In some cases, especially in colon cancer cells, overexpression of COX-2 gene is considered to induce matrix metalloproteinases (MMPs) 32 and angiogenic factors 33 by preventing the tumor cell death and apoptosis, 31 an important requirement for tumor growth and metastasis.…”

Section: Discussionmentioning

confidence: 59%

Differential expression of cyclooxygenase-2 (COX-2) in human bile duct epithelial cells and bile duct neoplasm

et al. 2001

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“…42 Furthermore, NFAT-1 can also induce the expression of cyclooxygenase-2 43 which is known to be overexpressed in pancreatic tumors. 44 The association of the a6b4 integrin and known cooperating oncogenes such as Ras and c-Met and regulation of transcription factors, such as NFAT-1 in early tumor precursor lesions, suggests that integrin a6b4 could cooperate and/or activate these factors to drive the development and progression of pancreatic adenocarcinomas and contribute to the invasive and metastatic phenotype of these cancers. Therefore, we suggest that early expression of a6b4 in PanIN lesions can predispose pancreatic adenocarcinomas to become among the most invasive and metastatic cancers.…”

Section: Discussionmentioning

confidence: 99%

Upregulation and redistribution of integrin α6β4 expression occurs at an early stage in pancreatic adenocarcinoma progression

et al. 2007

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Pancreatic adenocarcinomas are highly invasive cancers for reasons that are currently unclear. Here we sought to determine if the proinvasive integrin a6b4 may be related to pancreatic adenocarcinoma tumor progression. Expression of integrin a6b4 was analyzed via immunohistochemistry for the b4 subunit in normal pancreas, pancreatic intraepithelial neoplasia (PanIN) lesions, pancreatic adenocarcinomas and chronic pancreatitis. In normal pancreatic ducts, integrin a6b4 was noted only at the cell's basal interface with the basement membrane. In pancreatic adenocarcinomas, 92% (104/113) demonstrated overexpression of integrin a6b4 and altered localization to the cytoplasm and membranous regions. This pattern of expression was observed in all PanIN lesions as early as PanIN-1A, and was evident in lesions that were juxtapositioned to normal epithelium. In contrast, 93% (13/14) of chronic pancreatitis samples resembled the staining pattern of normal pancreas. When cancer was present in areas of chronic pancreatitis, this altered expression of a6b4 integrin identified the cancer. We conclude that integrin a6b4 is expressed only on the basal surface of ductal cells in normal pancreas and chronic pancreatitis. During pancreatic adenocarcinoma progression, the a6b4 integrin is dramatically overexpressed and displays altered localization at the earliest stages of PanIN, thus representing an early event in pancreatic adenocarcinoma progression. Keywords: pancreatic intraepithelial neoplasia (PanINs); immunohistochemistry; precursor lesion; integrins; pancreatic cancer; chronic pancreatitis Pancreatic carcinoma is the fourth leading cause of cancer death in the US and has the highest death to incidence ratio of all cancers. 1 Poor prognosis of pancreatic cancer patients relates to a high incidence of tumor cell invasion and metastasis. Treatment options are limited and patients succumb to the disease shortly after diagnosis unless eligible for tumor resection. 2 Of those patients that undergo resection, only 15-20% will survive to 5 years. 1 Over 90% of pancreatic cancers are adenocarcinomas that are thought to arise from proliferative premalignant pancreatic intraepithelial neoplasia (PanIN) of the ductal epithelium. PanIN lesions start as low cuboidal epithelial cells that become columnar due to increased mucin production. Cells then present with nuclear atypia and enhanced proliferation, which lead to luminal shedding and/ or invasion into the stroma. 3 These morphological alterations correlate with increased genetic abnormalities such as the activation of K-ras, loss of tumor suppressors (eg p16, p53 and DPC4) and upregulation of telomerases. 4 Although PanIN-1A and PanIN-1B are considered early cancer precursor lesions, molecular studies have shown that PanIN-2 and PanIN-3 lesions represent a distinct step toward invasive carcinoma. 5 Moreover, PanIN lesions can be found in patients with chronic pancreatitis 6 and these patients have an increased risk of developing pancreatic cancer. 7,8 Infiltrating duct-like and tubul...

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Overexpression of cyclooxygenase-2 in carcinoma of the pancreas

Cited by 88 publications

References 0 publications

A cyclooxygenase‐2 inhibitor, nimesulide, inhibits postinitiation phase of N‐nitrosobis(2‐oxopropyl)amine‐induced pancreatic carcinogenesis in hamsters

A cyclooxygenase‐2 inhibitor, nimesulide, inhibits postinitiation phase of N‐nitrosobis(2‐oxopropyl)amine‐induced pancreatic carcinogenesis in hamsters

Differential expression of cyclooxygenase-2 (COX-2) in human bile duct epithelial cells and bile duct neoplasm

Upregulation and redistribution of integrin α6β4 expression occurs at an early stage in pancreatic adenocarcinoma progression

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