Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediatedby CD44

Elevated tumor cyclooxygenase (COX-2) expression is associated with increas ed angiogenesis, tumor invasion, and suppression of host immunity. We have previously shown that genetic inhibition of tumor COX-2 expression reverses the immunosuppression induced by nonsmall cell lung cancer (NSCLC). To ass ess the impact of COX-2 expression in lung cancer invasiveness, NSCLC cell lines were transduced with a retroviral vector expressing the human COX-2 c DNA in the sense (COX-2-S) and antisense (COX-2-AS) orientations. COX-2-S c lones expressed significantly more COX-2 protein, produced 10-fold more pro staglandin E-2, and demonstrated an enhanced invasive capacity compared wit h control vector-transduced or parental cells. CD44, the cell surface recep tor for hyaluronate, was overexpressed in COX-2-S cells, and specific block ade of CD44 significantly decreased tumor cell invasion. In contrast, COX-2 -AS clones had a very limited capacity for invasion and showed diminished e xpression of CD44. These findings suggest that a COX-2-mediated, CD44-depen dent pathway is operative in NSCLC invasion. Because tumor COX-2 expression appears to have a multifaceted role in conferring the malignant phenotype, COX-2 may be an important target for gene or pharmacologic therapy in NSCL C.