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BACKGROUND:
Surgical manipulation of lung cancers may increase circulating tumor cells and contribute to metastatic recurrence following resection. The cyclooxygenase-2 enzyme is over-expressed in most NSCLC’s and up-regulates the cell adhesion receptor, CD44. Our objective was to examine the effects of COX-2 inhibition on CD44 expression and cancer cell to extracellular matrix(ECM) adhesion in vitro, and the effect on metastatic potential of circulating tumor cells in vivo.
METHODS:
Human NSCLC cells(A549) were treated with the selective COX-2 inhibitor celecoxib. Expression of COX-2 and CD44 were determined by western blotting. Cell to ECM adhesion was assessed by a matrigel adhesion assay. A murine metastasis model was utilized for in vivo experiments. Mice were randomized to three treatment groups: no treatment, continuous celecoxib, and peri-operative celecoxib only. Lung metastases were assessed at six weeks by a blinded observer.
RESULTS:
A549 expressed COX-2 and CD44. CD44 was down-regulated by selective COX-2 inhibition. In vitro cell to ECM adhesion was inhibited in a dose-dependent manner(p<0.001). In vivo, number of lung metastases were significantly decreased by both peri-operative and continuous treatment with celecoxib compared to control (figure).
CONCLUSIONS:
Celecoxib significantly inhibits CD44 expression and tumor cell to ECM adhesion in vitro and reduces lung cancer metastases in vivo. Peri-operative modulation of COX-2 may be a novel treatment strategy to minimize metastases from circulating tumor cells during this high risk period.