Perioperative cyclooxygenase 2 inhibition to reduce tumor cell adhesion and metastatic potential of circulating tumor cells in non-small cell lung cancer.
OBJECTIVE
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 1beta and downregulated by celecoxib.


CONCLUSIONS
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.
Backhus
Leah M
LM
Department of Cardiothoracic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Sievers
Eric
E
Lin
Gloria Y
GY
Castanos
Roberto
R
Bart
Robert D
RD
Starnes
Vaughn A
VA
Bremner
Ross M
RM
D000230:Adenocarcinoma / Q000517:prevention & control / Q000556:secondary*; D000818:Animals; D015153:Blotting, Western; D000068579:Celecoxib; D002448:Cell Adhesion / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009360:Neoplastic Cells, Circulating / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D052246:Cyclooxygenase 2 Inhibitors; D018960:Hyaluronan Receptors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib