Dr. Guido Eibl studies the role of cyclooxygenase enzymes in pancreatic cancer. Cyclooxygenases convert certain fatty acids to biologically active products called prostaglandins, which have a variety of effects on cancer cells. They can stimulate pancreatic cancer growth and spread and increase the resistance to chemotherapeutic agents. Inhibiting the production of prostaglandins is therefore a promising therapeutic approach in pancreatic cancer.
Eibl and his colleagues have demonstrated that cyclooxygenase products, in particular PGE2, stimulate pancreatic cancer cell proliferation, invasion and metastasis. PGE2 also increases angiogenesis in pancreatic cancer by upregulation of VEGF production. On the other hand, COX inhibitors induce pancreatic cancer cell apoptosis and decrease invasion and angiogenesis.
Eibl and other researchers have found that COX-2 is expressed only in a subset of pancreatic cancer. About 10 to 40 percent of human pancreatic cancers are considered to be COX-2 negative. Selective COX-2 inhibitors, however, also have some effects in COX-2 negative cells. Eibl and his colleagues have shown that some of these effects are mediated by activation of the nuclear receptor PPAR.
Interestingly, COX-2 inhibitors seem to have a concentration-dependent effect on VEGF production in pancreatic cancer cells. At higher concentrations, they stimulate the production of VEGF, which is mediated by PPAR. The increase in VEGF levels translates to a stimulation of angiogenesis and growth in an orthotopic pancreatic cancer animal model.
Eibl is interested in elucidating the complex interactions between the cyclooxygenase and PPAR system in vitro and in vivo with special emphasis on putative differences between COX-2 negative and positive pancreatic cancers. For these studies, researchers use cultured pancreatic cancer cells as well as xenograft and transgenic animal models.
Selected Cancer-Related Publications:
Nitsche C, Edderkaoui M, Moore RM, Eibl G, Kasahara N, Treger J, Grippo PJ, Mayerle J, Lerch MM, Gukovskaya AS. The Phosphatase PHLPP1 Regulates Akt2, Promotes Pancreatic Cancer Cell Death, and Inhibits Tumor Formation. Gastroenterology. 2011 Oct 29. [Epub ahead of print]
Takahashi H, Chen MC, Pham H, Angst E, King JC, Park J, Brovman EY, Ishiguro H, Harris DM, Reber HA, Hines OJ, Gukovskaya AS, Go VL, Eibl G. Baicalein, a component of Scutellaria baicalensis, induces apoptosis by Mcl-1 down-regulation in human pancreatic cancer cells. Biochim Biophys Acta. 2011 Aug;1813(8):1465-74. Epub 2011 May 10.
Funahashi H, Satake M, Dawson D, Huynh NA, Reber HA, Hines OJ, Eibl G. Delayed progression of pancreatic intraepithelial neoplasia in a conditional Kras(G12D) mouse model by a selective cyclooxygenase-2 inhibitor. Cancer Res. 2007 Aug 1;67(15):7068-71. Epub 2007 Jul 24.
Eibl G, Takata Y, Boros LG, Liu J, Okada Y, Reber HA, Hines OJ. Growth stimulation of COX-2-negative pancreatic cancer by a selective COX-2 inhibitor. Cancer Res. 2005; 65(3): 982-90.
Sawai H, Okada Y, Kazanjian K, Kim J, Hasan S, Hines OJ, Reber HA, Hoon DS, Eibl G. The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res. 2005; 65(24): 11536-44.