Perioperative cyclooxygenase 2 inhibition to reduce tumor cell adhesion and metastatic potential of circulating tumor cells in non–small cell lung cancer
Surgical manipulation of lung cancers may increase circulating tumor cells and contribute to metastatic recurrence after resection. Cyclooxygenase 2 is overexpressed in most non–small cell lung cancer and upregulates the cell adhesion receptor CD44. Our goal was to examine the effects of perioperative cyclooxygenase blockade on the metastatic potential of circulating tumor cells, CD44 expression, and adhesion of cancer cells to extracellular matrix.
Methods
Human non–small cell lung cancer cells (A549) were injected through the lateral tail vein in an in vivo murine model of tumor metastasis with three random treatment groups: no treatment, perioperative selective cyclooxygenase 2 inhibition (celecoxib) only, and continuous celecoxib. Lung metastases were assessed at 6 weeks by a blinded observer. For in vitro experiments, cells were treated with celecoxib, and expression of CD44 was determined by Western blotting. Extracellular matrix adhesion was assessed by Matrigel (BD Labware, Bedford, Mass) assay.
Results
In vivo lung metastases were significantly decreased relative to control by both perioperative and continuous celecoxib (P = .0135). There was no significant difference in number of metastases between continuous and perioperative treatment groups. In vitro adhesion to the extracellular matrix was significantly inhibited by celecoxib in a dose-dependent manner (P < .01). A549 cells expressed high levels of CD44, upregulated by interleukin 1β and downregulated by celecoxib.
Conclusion
Celecoxib significantly reduced establishment of metastases by circulating tumor cells in a murine model. It also inhibited CD44 expression and extracellular matrix adhesion in vitro. Perioperative modulation of cyclooxygenase 2 may be a novel strategy to minimize metastases from circulating tumor cells during this high-risk period.
CTSNet classification
9
10
Abbreviations and Acronyms
COX
cyclooxygenase
CTC
circulating tumor cell
ECM
extracellular matrix
IL
interleukin
NSCLC
non–small cell lung cancer
Tris
tris(hydroxymethyl)aminomethane
Cited by (0)
L.M.B. is a recipient of the Los Angeles Heart and Lung Research Grant. R.M.B. is a recipient of the Robert E. Gross Research Grant from the Graham Education and Research Foundation of the American Association for Thoracic Surgery. Supported in part by a grant from the Hastings Foundation.
Read at the Thirty-first Annual Meeting of the Western Thoracic Surgical Association, Victoria, BC, Canada, June 22-25, 2005.