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Growth Stimulation of COX-2–Negative Pancreatic Cancer by a Selective COX-2 Inhibitor

¹ Section of Gastrointestinal Surgery, ² Division of Endocrinology, Diabetes and Hypertension, and ³ Harbor-University of California at Los Angeles Research and Education Institute, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California

Requests for reprints: Guido Eibl, Section of Gastrointestinal Surgery, David Geffen School of Medicine at University of California at Los Angeles 72-215 CHS, 10833 LeConte Avenue, Los Angeles, CA 90095-6904. Phone: 310-794-9577; Fax: 310-206-2472; E-mail: Geibl{at}mednet.ucla.edu.

Cyclooxygenase 2 (COX-2) inhibitors are promising antiangiogenic agents in several preclinical models. The aim of the present study was to evaluate the effect of selective COX-2 inhibitors on vascular endothelial growth factor (VEGF) production in vitro and angiogenesis and growth of pancreatic cancer in vivo, focusing on putative differences between COX-2–negative and COX-2–positive tumors. VEGF production and angiogenesis in vitro were determined by ELISA and endothelial cell migration assay. To determine whether the effect of COX-2 inhibitors was mediated by peroxisome proliferator–activated receptor (PPAR-), we used a dominant-negative PPAR- and a pharmacologic inhibitor. In vitro findings were validated in a pancreatic cancer animal model. Microvessel density was assessed by CD31 immunostaining. Intratumoral prostaglandin and VEGF levels were measured by mass spectroscopy and ELISA. Selective COX-2 inhibitors had a concentration-dependent effect on VEGF production in vitro. Higher concentrations increased VEGF levels and stimulated angiogenesis by activating PPAR-. In vivo, nimesulide increased VEGF production by cancer cells in COX-2–positive and COX-2–negative pancreatic tumors. In COX-2–negative pancreatic cancer, this effect was associated with an increase in angiogenesis and growth. In COX-2–positive pancreatic cancer, the nimesulide-induced increase of VEGF production by the cancer cells was offset by a decrease in VEGF production by the nonmalignant cell types leading to reduced tumor angiogenesis and growth. Selective COX-2 inhibitors had opposite effects on growth and angiogenesis in pancreatic cancer depending on COX-2 expression. These findings imply that assessing the COX-2 profile of the pancreatic tumor is mandatory before initiating therapy with a selective COX-2 inhibitor.

Key Words: COX-2 inhibitor • pancreatic cancer • PPAR- • VEGF • angiogenesis

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