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J Thorac Cardiovasc Surg 2006;132:297-303
© 2006 The American Association for Thoracic Surgery

General Thoracic Surgery

Perioperative cyclooxygenase 2 inhibition to reduce tumor cell adhesion and metastatic potential of circulating tumor cells in non–small cell lung cancer

Leah M. Backhus, MD, Eric Sievers, MD, Gloria Y. Lin, MD, Roberto Castanos, Robert D. Bart, MD, Vaughn A. Starnes, MD, Ross M. Bremner, MD, PhD *

Department of Cardiothoracic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California

Received for publication June 20, 2005; revisions received October 12, 2005; accepted for publication October 20, 2005.

* Address for reprints: Ross M. Bremner, MD, PhD, Heart and Lung Institute, St. Joseph's Hospital and Medical Center, 500 W. Thomas Road, Suite 500, Phoenix, AZ 85013. (Email: ross.bremner{at}chw.edu).

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 1ß 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.

Abbreviations and Acronyms COX = cyclooxygenase; CTC = circulating tumor cell; ECM = extracellular matrix; IL = interleukin; NSCLC = non–small cell lung cancer; Tris = tris(hydroxymethyl)aminomethane






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