Cyclooxygenase 2 Expression in Pancreatic Adenocarcinoma and Pancreatic Intraepithelial Neoplasia

Maitra, Anirban; Ashfaq, Raheela; Gunn, Carla R.; Rahman, Asifur; Yeo, Charles J.; Sohn, Taylor A.; Cameron, John L.; Hruban, Ralph H.; Wilentz, Robb E.

doi:10.1309/tpg4-ck1c-9v8v-8awc

Cited by 155 publications

(106 citation statements)

References 25 publications

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“…Maitra et al (2002) reported that COX-2 is overexpressed in 65% of PanIN lesions and suggested the use of COX-inhibitors for chemoprevention in patients at high risk. However, COX-2 is not expressed in all PanIN lesions and is also expressed in islets (Maitra et al, 2002). BLT2 may prove to be a superior target, because of the consistent and selective expression in PanINs and IPMNs.…”

Section: Discussionmentioning

confidence: 99%

“…A recent review pointed out the important role of cyclooxygenase and lipoxygenase pathways in fat metabolism and in the regulation of pancreatic cancer cell proliferation and survival (Ding et al, 2003). Cyclooxygenase-2 (COX-2) plays an important role in carcinogenesis, is upregulated in 56 -90% of pancreatic adenocarcinomas and 65% of PanINs and frequent use of aspirin seems to decrease the risk of pancreatic cancer (Hitt, 2002;Maitra et al, 2002;Ding et al, 2003). The 5-lipoxygenase (5-LOX) pathway seems to have an even more important function in pancreatic carcinogenesis (Ding et al, 2003).…”

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confidence: 99%

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BLT2 is expressed in PanINs, IPMNs, pancreatic cancer and stimulates tumour cell proliferation

et al. 2008

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Pancreatic cancer has an abysmal prognosis. Targets for early detection, prevention and therapy are desperately needed. Inflammatory pathways have an important impact on tumour growth and progression. Expression of BLT2 (the second leukotriene B 4 receptor) was investigated by real-time RT -PCR and immunohistochemistry. Cell proliferation was studied after stable transfection with BLT2, after treatment with siRNA and Compound A as an agonist. BLT2 is expressed in all pancreatic cancer cell lines. Results from real-time RT -PCR revealed significant overexpression of BLT2 in malignant intraductal papillary mucinous neoplasias (IPMNs) and pancreatic adenocarcinoma. Intense staining was evident in IPMNs, infiltrating tumour cells and advanced pancreatic intraepithelial neoplasias (PanINs) but not in normal ductal cells. Overexpression of BLT2 as well as stimulation of Colo357, Panc-1 and AsPC1 cells with Compound A caused a significant increase in tumour cell proliferation, an effect reversed after siRNA treatment. This study demonstrates for the first time the expression of BLT2 in the pancreas and overexpression in pancreatic cancers and malignant IPMNs in particular. Upregulation of BLT2 is already evident in precursor lesions (PanINs, IPMNs). Overexpression of this receptor leads to significant growth stimulation. Therefore, we suggest BLT2 as a new target for chemoprevention and therapy for pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

BLT2 is expressed in PanINs, IPMNs, pancreatic cancer and stimulates tumour cell proliferation

et al. 2008

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“…Two observers, LZ and SC, scored the sections independently for agreement. (46) Statistical analysis…”

Section: Immunohistochemistrymentioning

confidence: 99%

Blockage of Src by Specific siRNA as a Novel Therapeutic Strategy to Prevent Destructive Repair in Steroid-Associated Osteonecrosis in Rabbits

Cao

Chen

et al. 2015

Journal of Bone and Mineral Research

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Vascular hyperpermeability and highly upregulated bone resorption in the destructive repair progress of steroid-associated osteonecrosis (SAON) are associated with a high expression of VEGF and high Src activity (Src is encoded by the cellular sarcoma [c-src] gene). This study was designed to prove our hypothesis that blocking the VEGF-Src signaling pathway by specific Src siRNA is able to prevent destructive repair in a SAON rabbit model. Destructive repair in SAON was induced in rabbits. At 2, 4, and 6 weeks after SAON induction, VEGF, anti-VEGF, Src siRNA, Src siRNAþVEGF, control siRNA, and saline were introduced via intramedullary injection into proximal femora for each group, respectively. Vascularization and permeability were quantified by dynamic contrast-enhanced (DCE) MRI. At week 6 after SAON induction, proximal femurs were dissected for micro-computed tomography (mCT)-based trabecular architecture with finite element analysis (FEA), mCT-based angiography, and histological analysis. Histological evaluation revealed that VEGF enhanced destructive repair, whereas anti-VEGF prevented destructive repair and Src siRNA and Src siRNAþVEGF prevented destructive repair and enhanced reparative osteogenesis. Findings of angiography and histomorphometry were consistent with those determined by DCE MRI. Src siRNA inhibited VEGF-mediated vascular hyperpermeability but preserved VEGF-induced neovascularization. Bone resorption was enhanced in the VEGF group and inhibited in the anti-VEGF, Src siRNA, Src siRNAþVEGF groups as determined by both 3D mCT and 2D histomorphometry. FEA showed higher estimated failure load in the Src siRNA and Src siRNAþVEGF groups when compared to the vehicle control group. Blockage of VEGF-Src signaling pathway by specific Src siRNA was able to prevent steroid-associated destructive repair while improving reconstructive repair in SAON, which might become a novel therapeutic strategy.

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“…[6][7][8] With regards to pancreatic cancer, COX-2 is overexpressed in human pancreatic neoplasms, suggesting that it may play a role in tumor progression. [9][10][11][12] Furthermore, prostaglandin synthesis antagonists (NSAIDs) inhibited the development of tumors in a hamster model of chemically-induced pancreatic cancer, 13 and epidemiological data suggest that aspirin dramatically decreases the risk of developing pancreatic cancer. 14 Although accumulating evidence implicates COX-2 in tumor progression, its mechanisms of action remain poorly characterized and controversial.…”

Section: Introductionmentioning

confidence: 99%

Celecoxib inhibits angiogenesis by inducing endothelial cell apoptosis in human pancreatic tumor xenografts

Raut

Nawrocki

Lashinger

et al. 2004

Cancer Biology & Therapy

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Previous studies suggest that antagonists of cyclooxygenases 1 and 2 (COX-1, -2) inhibit angiogenesis in tumor xenografts, but the molecular mechanisms involved remain unclear. Here we characterized the effects of non-selective (indomethacin) and selective (NS398, celecoxib) cyclooxygenase inhibitors on parameters of angiogenesis in human pancreatic adenocarcinoma cells. COX-1 expression was constitutive in 9/9 pancreatic cancer cell lines, whereas COX-2 and cytosolic phospholipase A 2 (cPLA 2 ) expression were observed in 4/9 cell lines (BxPC3, Capan2, Cfpac1 and L3.6 pl). Production of the COX product, prostaglandin E2, correlated with expression of cPLA 2 and COX-2 and was blocked by non-steroidal anti-inflammatory drugs (NSAIDs, indomethacin or NS398). In contrast to the findings of others, neither indomethacin nor NS398 affected tumor cell secretion of angiogenic factors (VEGF, bFGF, IL-8) at concentrations that produced maximal inhibition of PGE 2 production, and higher concentrations increased angiogenic factor production. We also studied the effects of celecoxib in orthotopic L3.6 pl xenografts. Immunofluorescence analysis revealed high-level expression of COX-2 in endothelial cells in L3.6 pl xenografts that increased following therapy with celecoxib, whereas the tumor cells expressed uniformly low levels of COX-2. Celecoxib did not decrease tumor-associated VEGF levels in orthotopic human L3.6 pl xenografts, but the drug did decrease tumor microvessel density (MVD) and increase apoptosis in tumor-associated endothelial cells in a dose-dependent fashion. Together, our results demonstrate that the anti-angiogeneic effects of NSAIDs in human pancreatic cancer cells are exerted via direct effects on endothelial cells.

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Cyclooxygenase 2 Expression in Pancreatic Adenocarcinoma and Pancreatic Intraepithelial Neoplasia

Cited by 155 publications

References 25 publications

BLT2 is expressed in PanINs, IPMNs, pancreatic cancer and stimulates tumour cell proliferation

BLT2 is expressed in PanINs, IPMNs, pancreatic cancer and stimulates tumour cell proliferation

Blockage of Src by Specific siRNA as a Novel Therapeutic Strategy to Prevent Destructive Repair in Steroid-Associated Osteonecrosis in Rabbits

Celecoxib inhibits angiogenesis by inducing endothelial cell apoptosis in human pancreatic tumor xenografts

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