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Editorial |
Department of Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [J. M. K.], and Departments of Medicine and Cell Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 [R. N. D.]
COX-2 in Epithelial Cancer
COX-12 and -2 metabolize AA and other 20-carbon polyunsaturated fatty acids into PGs, which have a wide array of biological roles that are tissue-specific (1) . A variety of exogenous stimuli increase the expression of COX-2 but not COX-1 as a consequence of their distinct transcriptional and translational regulation. Although the enzymatic reaction they catalyze is the same, COX-1 and -2 exhibit different substrate specificities (2) . With its distinct properties, it was not surprising that COX-2 was found to play a unique role in epithelial tumorigenesis.
A large body of genetic and biochemical evidence supports a role for COX-2 in human CRC. COX-2 expression and enzymatic activity are increased in colonic epithelial premalignancy and invasive disease (3) . Treatment of CRC cells with PGE2 or PGJ2, which are COX-induced AA metabolites, induces cellular proliferation (4) . Rat intestinal epithelial cells that overexpress COX-2 take on phenotypic changes that could enhance their tumorigenic potential (5) . Conversely, carcinogen-induced CRC is reduced in mice that are COX-2-null and by cotreatment with COX-2 enzymatic inhibitors (6, 7, 8) . Most interestingly, recently completed clinical trials demonstrated that chronic administration of a COX-2 inhibitor reduced the formation of adenomatous colonic polyps in patients at high risk (9) .
Additional studies support a role for COX-2 in a variety of other epithelial cancers including lung cancer. NSCLCs and premalignant bronchial and alveolar lesions express increased levels of COX-2 (10
, 11)
. COX-2 has pleitrophic effects on the bronchial epithelium that culminate in malignancy, including proangiogenesis, epithelial mitogenesis and antiapoptosis, and local immune suppression (Fig. 1
; Refs. 5
, 12
, 13
). Supporting a role for COX-2 in lung carcinogenesis, COX-2 inhibitors reduced lung tumor formation in carcinogen-treated animal models (14
, 15)
. In addition to its direct effects on the bronchial epithelium, COX-2 may indirectly promote lung cancer by stimulating the formation of carcinogenic metabolites of cigarette smoke (16)
. In turn, components of tobacco smoke activate COX-2 and increase the conversion of phospholipids to AA, a COX-2 substrate (17
, 18)
. Thus, cigarette consumption creates a feed-forward loop involving activation of COX-2 and tobacco smoke metabolism.
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Whereas the evidence supporting a role for COX-2 in epithelial cancer is strong, the mechanisms responsible for the carcinogenic effect of COX-2 have not been fully defined. COX enzymes catalyze the formation of PGH2, the unstable bicycloendoperoxide intermediate, which undergoes additional metabolism to the parent eicosanoids PGD2, PGE2, PGF2, PGI2, and thromboxane A2 (Fig. 2)
. Of these, PGE2 is most clearly implicated in lung cancer. PGE2 levels are elevated in the bronchial fluid of NSCLC patients, and it induces local immune suppression, which may be important in malignant progression (12
, 19
, 20)
. A role for PGE2 is supported by data reported by Yoshimatsu et al. (21)
who investigated the expression of PGES, a glutathione-dependent, membrane-bound enzyme that converts PGH2 into PGE2 (22)
. Yoshimatsu et al. (21)
demonstrated that PGES levels were increased in NSCLCs relative to normal tissue, and mutant ras, which is found in 30–50% of lung adenocarcinomas, activated PGES gene transcription. Interestingly, PGES and COX-2 were frequently coexpressed in tumor tissue.
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COX-2 and PGES are inducible enzymes that are components of the same pathway. Several tumors expressed COX-2 at much higher levels than PGES, which is consistent with genetic evidence from in vitro models in which COX-2 overexpression alone is sufficient to induce a transformed phenotype (5) . However, Yoshimatsu et al. (21) found that COX-2 and PGES are frequently coexpressed in NSCLC tumors. Alterations of two molecules involved in a common pathway are not consistent with the expected pattern of genetic or biochemical alterations in human cancer, which usually involves alterations of a single pathway component. For example, the retinoblastoma pathway is blocked through either inactivation of a tumor suppressor (retinoblastoma or the p16 cyclin-dependent kinase inhibitor) or overexpression of an oncoprotein (cyclin D1 or cyclin dependent kinase-4; Ref. 25 ).
One possible explanation for this apparent inconsistency is that COX-2 and PGES act synergistically to drive PGE2 production. This hypothesis is consistent with previous reports that COX-2 and PGES are coregulated, and PGE2 biosynthesis may depend on the presence of both of these enzymes (22) . If PGE2 is an important mediator of COX-2 transformation, coexpression could be advantageous from the standpoint of clonal evolution. In this setting, COX-2 and PGES coexpression may be important from the standpoint of the natural history of the disease and response to treatment. Elucidating this will require prospective evaluation of NSCLC patients in clinical trials.
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom requests for reprints should addressed, at: Department of Thoracic/Head and Neck Medical Oncology, Box 432, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard Houston, TX 77030. 
2 The abbreviations used are: COX, cyclooxygensase; AA, arachidonic acid; PG, prostaglandin; CRC, colorectal cancer; NSCLC, non-small cell lung cancer; PGES, prostaglandin E synthase.
Received 6/ 7/01; accepted 6/ 8/01.
REFERENCES
12,14-prostaglandin J2 induce proliferation of cyclooxygenase-depleted colorectal cancer cells. Cancer Res., 59: 2739-2746, 1999.716 knockout mice by inhibition of cyclooxygenase 2 (Cox-2). Cell, 87: 803-809, 1996.[CrossRef][Medline]
B. Carcinogenesis (Lond.), 21: 1745-1751, 2000.B. J. Biol. Chem., 275: 4949-4955, 2000.Key Article
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