Expression of Inflammatory Modulator COX-2 in Pancreatic Ductal Adenocarcinoma and Its Relationship to Pathologic and Clinical Parameters

Abstract

Despite the exceedingly poor prognosis of pancreatic cancer, it is often histologically well to moderately differentiated. The apparent resistance to conventional therapeutic modalities is poorly understood and may be related to the molecules involved in its progression or its propensity for perineurial invasion. Cyclooxygenase-2 (COX-2) is an inducible enzyme homologous to COX-1 that is responsible for production of prostaglandins at sites of inflammation. It is activated by a variety of growth factors and tumor promoters, and it has been implicated in cancer progression. It may also have a role in the resistance to therapy. Anti-COX-2 agents have been documented to have antitumor activity, and some are now being tested in the therapy for various cancers, including those of the pancreas. Experience regarding the rate of COX-2 expression in pancreatic cancer and its relationship to the clinical and biologic parameters is very limited. In this study, immunohistochemical stains for COX-2 have been performed on 120 cases of pancreatic ductal adenocarcinoma. The stains were scored according to the percentage (0: no staining, 1: < 10%, 2: 10-50%, and 3: >50% of the cells staining) and intensity (0 for no staining, 1 for mild staining, and 2 for dark staining) of staining. Based on the combined score for each case, they were divided into low expressors (percentage and intensity < or =1) and high expressors (percentage or intensity >1). In addition to global scoring for each case, the glandular and solid (poorly differentiated) components, when present, were scored separately. The global scores were correlated with clinical and biologic parameters. Seventy-four percent of the cases exhibited expression of COX-2 and 53% were high expressors. No significant association was observed when comparing the global COX-2 expression to survival, tumor size, stage, and vascular invasion. Increased perineural invasion was found to be significantly associated with COX-2 expression (p < 0.05). Increased expression was also more common in the glandular component as compared with the solid component of the tumors (68% versus 35%, p < 0.05). Of the 34 patients who received radiotherapy, 9 were low expressor (median survival 19.5 months) and 25 were high expressors (median survival 14 months). The difference in survival was not statistically significant.

Resistance of cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells against γδ T cell cytotoxicity

“…[3][4][5] Cox-2 overexpression leads to an enhanced production of prostaglandin E2 (PGE2), which is involved in tumor progression as well as in tumor evasion of immunosurveillance. 6 The release of PGE2 by cancer cells induces and recruits regulatory T cells to the tumor site and suppresses immune responses of CD8 C ab T cells and natural killer (NK) cells as well as maturation of dendritic cells.…”

Prostaglandin E2 drives cyclooxygenase 2 expression via cyclic AMP response element activation in human pancreatic cancer cells

“…[7][8][9][10][11] Increased expression of COX-2 has also been observed in pancreatic cancer, irrespective of histological type and grade, but the mechanisms that control the constitutive and induced expression of COX-2 in human pancreatic carcinoma cells are not completely understood. [12][13][14][15][16][17] The transcriptional activation of COX-2 is mediated by the binding of transcription factors to regulatory elements in the COX-2 promoters, such as nuclear factor κB (NF-κB), CCAAT/enhancerbinding protein (C/EBP), cyclic AMP response element-binding protein (CREB) and nuclear factor-activated T-cell/AP-1, which are involved in COX-2 induction in response to a variety of stimuli in different species and cell types. [18][19][20][21][22][23] For example, the C/EBP family of transcription factors plays an important role in COX-2 induction by lipopolysaccharide and phorbol ester in human vascular endothelial cells, 18 by tumor necrosis factor-α in murine MC3T3-E1 osteoblastic cells, 19 and in mouse skin carcinoma cells.…”

A novel copper complex of 3‐benzoyl‐α methyl benzene acetic acid with antitumor activity mediated via cyclooxygenase pathway

“…12 Mounting evidence derived from clinically proven biopsy samples showed that COX-2 is upregulated in human pancreatic tumor tissues as compared with normal adjacent pancreatic tissues. [13][14][15] Moreover, COX-2 inhibitors inhibit cell growth with greater efficacy in cell lines with stronger COX-2 expression compared with weakly COX-2 expressing PC cell lines. 14,16 Further studies have shown that genetic deletion of COX-2 abrogates tumorigenesis as well as intestinal polyposis in mouse model of familial adenomatous polyposis APC D716 compared with wild type animal.…”

“…17,18 Studies from our laboratory have also shown over expression of COX-2 in pancreatic ductal adenocarcinoma, which was associated with increased perineural invasion. 15 Despite numerous advances in our understanding of the pathophysiology and molecular biology of PC, currently available standard therapeutic approach for PC show limited benefit in improving the survival of patients diagnosed with this deadly disease. NSAIDS are well studied class of chemopreventive agents and have been shown to act through both COX dependent 19,20 and independent pathways.…”