Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44.
Elevated tumor cyclooxygenase (COX-2) expression is associated with increased 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 non-small cell lung cancer (NSCLC). To assess the impact of COX-2 expression in lung cancer invasiveness, NSCLC cell lines were transduced with a retroviral vector expressing the human COX-2 cDNA in the sense (COX-2-S) and antisense (COX-2-AS) orientations. COX-2-S clones expressed significantly more COX-2 protein, produced 10-fold more prostaglandin E(2), and demonstrated an enhanced invasive capacity compared with control vector-transduced or parental cells. CD44, the cell surface receptor for hyaluronate, was overexpressed in COX-2-S cells, and specific blockade of CD44 significantly decreased tumor cell invasion. In contrast, COX-2-AS clones had a very limited capacity for invasion and showed diminished expression of CD44. These findings suggest that a COX-2-mediated, CD44-dependent 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 NSCLC.
Dohadwala
M
M
Lung Cancer Research Program of the UCLA Jonsson Comprehensive Cancer Center, Division of Pulmonary Medicine, Department of Medicine, UCLA, School of Medicine, Los Angeles California 90095-1690, USA.
Luo
J
J
Zhu
L
L
Lin
Y
Y
Dougherty
G J
GJ
Sharma
S
S
Huang
M
M
Pold
M
M
Batra
R K
RK
Dubinett
S M
SM
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D015703:Antigens, CD / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000502:physiology*; D006820:Hyaluronic Acid / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins; D009361:Neoplasm Invasiveness; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D008565:Membrane Proteins; D011994:Recombinant Proteins; D006820:Hyaluronic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone