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Departments of Medicine [R. A. G., J. D. M., R. N. D.], Cell and Developmental Biology [R. A. G., S. K. Dey., R. N. D.], Pediatrics [L. V. T., S. K. Das., S. K. Dey.], and Pharmacology [J. D. M.], Vanderbilt University School of Medicine, Nashville, Tennessee 37232
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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In addition, treatment options for patients diagnosed with advanced disease remain inadequate. Thus, ovarian cancer represents a potential candidate to target for chemoprevention. The results of epidemiological studies examining whether NSAIDs can prevent or delay the development of ovarian cancer have been mixed. Several population- and hospital-based case control studies have documented that exposure to several NSAIDs is associated with a time- and dose-dependent decrease in the risk for the development of ovarian cancer (4, 5, 6) , whereas other studies detected either no statistically significant association or found the reduction in risk to be associated only with the use of particular NSAIDs (7 , 8) . There are also conflicting data available describing the expression of COX isotypes in ovarian cancer; Dore et al. (9) found COX-1 to be the predominant COX isoform expressed, whereas two other groups reported finding high levels of COX-2 (10 , 11) . However, these latter two expression studies did not specifically rule out samples that had undergone cytoreductive therapy, a treatment that is common in patients presenting with advanced ovarian malignancy. Because many compounds used in this type of therapy induce COX-2 (12 , 13) , it is unclear if COX-2 was found to be elevated because of the malignant process itself or simply secondary to the use of cytotoxic agents for treatment of primary disease. To investigate the role of the cyclooxygenase pathway in the pathogenesis of ovarian cancer and determine whether a scientific rationale exists for the use of COX inhibitors in the prevention and/or treatment of the disease, we evaluated COX-1 and COX-2 expression in ovarian cancer samples taken specifically from patients who had not undergone cytoreductive therapy.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Tissue Samples.
Tissue samples of 11 epithelial ovarian cancers that had not undergone cytoreductive therapy and nine normal human ovaries were obtained immediately after surgery from surgical pathology specimens (University of Kansas Medical Center and Vanderbilt University). The tissues obtained from the pathologist were flash frozen in liquid Histo-freeze (Fisher) and stored at -80°C.
RNA Isolation and Northern Blot Analysis.
Total RNA was extracted from the tissue specimens using TRIzol Kit (Life Technologies, Inc.). Total RNA (20 µg) was denatured, separated by formaldehyde-agarose gel electrophoresis, transferred, and cross-linked to nylon membranes by UV irradiation. Northern blots were prehybridized, hybridized, and washed as described previously (14
, 15)
. For Northern hybridization, antisense 32P-labled cRNA probes for mouse COX-1, human COX-2, and ß-actin were generated. After hybridization, the blots were washed under stringent conditions, and the hybrids were detected by autoradiography. Stripping of the hybridized probe before subsequent rehybridization was achieved. Each blot was hybridized sequentially to COX-2, COX-1, and ß-actin probes.
In Situ Hybridization.
In situ hybridization followed the protocol described previously (14)
. Frozen sections (10 µM) from each tissue specimen were mounted onto poly-L-lysine-coated slides and stored at -80°C until used. Serial sections were obtained to detect localization of gene expression in similar areas. Sections were brought to room temperature, fixed in cold 4% paraformaldehyde solution in PBS, acetylated, and hybridized at 45°C for 4 h in 50% formamide buffer containing 35S-labeled antisense or sense cRNA probes specific to mouse cRNA to COX-1 and human-specific cRNAs to COX-2, HIF-1
, VEGF, and Flk-1. After hybridization and washing, the slides were incubated with RNase A (20 µg/ml) at 37°C for 20 min, and RNase A-resistant hybrids were detected by autoradiography using Kodak NTB-2 liquid emulsion. Parallel sections hybridized with the sense probes served as negative controls. Slides were poststained with H&E.
Immunohistochemistry.
Immunocolocalization of COX-1 and COX-2 was performed in 2% paraformaldehyde-fixed frozen sections using a Zymed-Histostain SP kit (Zymed). Rabbit antipeptide antibodies to mouse COX-1 and COX-2 were used as described previously (15)
. These antibodies were found to cross-react with human tissues. After immunostaining, sections were lightly counterstained with hematoxylin or fast green. Red deposits indicate the site of immunoreactive proteins.
Preparation of Tissue Lysates.
Tissue samples were homogenized in lysis buffer [1% Triton X-100, 1% deoxycholate, 10 mM Tris (pH 7.2), 150 mM NaCl, 1 mM sodium vanadate, 50 mM sodium fluoride, 1 mM phenylmetheysulfonyl fluoride, 50 mg/ml aprotinin, and 50 mg/ml leupeptin]. The samples were transferred to eppendorf tubes and centrifuged at 14,000 x g for 15 min in the cold. The supernatants were transferred to fresh tubes, and protein concentrations were determined. These extracts were used for Western blot analysis.
Western Blot Analysis.
Lysates (50 µg of protein/lane) were analyzed by SDS-PAGE on 10% Tris-glycine gels. Protein was electrotransferred to nitrocellulose membranes and blocked with a solution of PBS containing 5% milk and 0.1% Tween 20. Bands were detected using chemiluminescent detection reagents (Pierce). Blots were probed with a goat polyclonal antibody against COX-1 or COX-2 (Santa Cruz Biotechnology) followed by a peroxidase-conjugated antigoat (Sigma) or donkey-antigoat (Jackson ImmunoResearch Laboratories), respectively. After incubation, antibodies were washed in PBS and 0.1% Tween 20. Bands were detected using chemiluminescent detection reagents (Pierce).
PG Measurements.
PG profiles for the OVCAR-3 cells were measured and quantified using a gas chromatography/negative ion chemical ionization mass spectrometric assay and a PGE2 immunoassay kit (R&D Systems).
Cell Growth Measurements.
Cells were plated at a density of 
20%, and treatment was initiated the following day with 0.1% DMSO or the indicated dose of COX inhibitor. Fresh media and drug was added every 48 h, and the number of viable cells was determined using a Coulter counter after 7 days of treatment.
VEGF Measurements.
VEGF concentrations in the media of OVCAR-3 cells treated with the indicated dose of AA, COX inhibitor, and PGE2 were measured using the Quantikine Human VEGF Immunoassay kit (R&D Systems) according to manufacturer instructions.
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Results and Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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. However, dramatic elevations of COX-1, not COX-2, protein and mRNA were detected in a majority of the ovarian cancer samples tested. In colorectal and other cancers, COX-1 and COX-2 protein levels have been determined in multiple cell types, including epithelial, fibroblast, macrophage, and endothelial cells. In situ hybridization and immunohistochemistry analysis were done to determine the cellular localization of COX-1 and COX-2 protein in ovarian cancer. A significant elevation in COX-1, not COX-2, mRNA was observed by in situ hybridization, and COX-1 mRNA was localized to the epithelial compartment of the tumors (Fig. 2, A and B)
. Immunohistochemical analysis of sections of both normal human ovary and ovarian epithelial cancers confirmed the elevated expression of COX-1, not COX-2, protein in ovarian tumors, and the immunoreactivity detected with a COX-1-specific antibody was localized primarily to ovarian carcinoma cells within the tumor (Fig. 2C)
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is a dominant regulator of VEGF gene transcription and induces significant increases in VEGF mRNA copy number in response to various stimuli by binding to a hypoxia-responsive element within the VEGF promoter (20)
. There is also a strong link between the COX pathway and angiogenesis. Data from multiple groups suggest that a major mechanism by which COX-derived PGs promote polyp growth in the colon is through the stimulation of new blood vessel growth. To determine whether regions within ovarian tumors demonstrating high COX-1 expression correlate with foci of prominent angiogenic activity, in situ hybridization was done probing for COX-1, VEGF, Flk-1, and HIF-1 in serial sections. Regions of ovarian epithelial cells exhibiting high COX-1 also expressed significant levels of HIF-1 and VEGF (Figs. 2A
and 3, A and B
). High levels of flk-1 were seen in the endothelial cells located in the stroma adjacent to ovarian epithelial cells expressing COX-1, HIF-1, and VEGF (Fig. 3C)
. The above data suggest that elevations in COX-1 expression are enhanced in regions of ovarian epithelial tumors undergoing extensive angiogenesis.
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. No reports have been published documenting the types of PGs synthesized by ovarian carcinoma cells. Levels of the five major PG metabolites were measured in these cells in response to stimulation with AA, and significant levels of PGF2, PGI2, PGE2, and PGD2 were detected (Fig. 4B)
. Although most NSAIDs inhibit the enzymatic activity of both COX-1 and COX-2, isoform selective COX inhibitors have been developed. SC-560 is 700 times more selective for inhibiting COX-1 compared with COX-2, whereas celecoxib is 3000-fold more selective for COX-2 versus COX-1 (21)
. The ability of increasing doses of either SC-560 or celecoxb to inhibit AA-induced PGE2 formation in OVCAR-3 cells was evaluated. SC-560, but not celecoxib, inhibited PGE2 formation in a dose-dependent manner (Fig. 4C)
. These data confirmed our expression studies, indicating that COX-1 is the major source of PG production in these cells.
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. Biological effects seen at such high drug concentrations are unlikely to be caused by inhibition of COX catalytic activity and have limited clinical relevance, because these levels are 50–100 times greater than the concentration of COX inhibitors that can be achieved in vivo (22)
. In contrast, treatment of OVCAR-3 cells with a low dose of SC-560, but not celecoxib, significantly inhibited AA-induced VEGF secretion, and this effect could be partially reversed by cotreatment with PGE2 (Fig. 4E)
. Neoplasms of the ovary rarely produce symptoms that lead to prompt medical attention until the disease is highly advanced and often incurable. Currently, no effective detection strategies exist to identify patients at high risk or who have localized lesions that can be effectively treated. These facts make ovarian cancer account for a disproportionate number of lethal cancers and thus a primary candidate to target for prevention. Given the effectiveness of NSAID therapy in the chemoprevention of colorectal cancer, as well as several other types of solid tumors, it is important to determine the role, if any, that NSAID treatment may have in the management of ovarian cancer. Our results here suggest that: (a) the COX-1 enzyme is overexpressed in a significant number of ovarian cancers; (b) COX-1 may promote ovarian cancer development via stimulation of angiogenesis; and (c) COX-1 or non-COX selective inhibitors should be further evaluated for their ability to inhibit ovarian cancer cell growth.
Our results indicate that COX-1, not COX-2, mRNA and protein levels are elevated in ovarian cancers from patients not exposed previously to cytotoxic chemotherapy. Similar results were obtained by Dore et al. (9) , who used immunohistochemistry to demonstrate strong expression of COX-1, not COX-2, protein in human ovarian cancer specimens. Both of these results are in contradiction to data generated by two other groups that report elevated COX-2 levels in ovarian cancer (10 , 11) . However, neither of these two groups determined the status of COX-1 expression in their samples. The reason for the discrepancy with regard to COX-2 expression is not known but may be related to differences in clinical treatment regimens of patients before tissue collection, detection methods, tissue processing, and/or antibody cross-reactivity.
A majority of epithelial-derived tumors with elevated PG levels overexpresses COX-2 and not COX-1. This is consistent with the hypothesis that COX-1 is constitutively expressed and responsible for basal PG production, whereas COX-2 is highly inducible and responsible for the elevations in PG production that occur in response to pro-inflammatory cytokines and growth factors, both of which are likely to be highly concentrated within the microenvironment of a tumor. The basis for the divergent expression patterns of COX-1 and COX-2 in ovarian cancer is not known. The simplest explanation may be that the development of ovarian cancer is associated with the dysregulation of a unique combination of signaling pathways not found in other tumor types that converge to cause activation of COX-1, not COX-2, gene transcription. The COX-1 promoter is relatively uncharacterized, and transfection experiments using COX-1 and COX-2 promoter–reporter constructs in the OVCAR-3 cells may help determine the molecular basis for why COX-1 and not COX-2 is up-regulated ovarian cancer.
The role of COX-1 in neoplasia is not clear. COX-1 and COX-2 catalyze identical biochemical reactions. It is thus possible that the elevated COX-2 seen in many types of cancer is selected to simply increase total PG levels within the tumor microenvironment. Alternatively, COX-2 may exhibit unique substrate utilization, cellular or subcellular localization, and/or coupling with downstream PG synthases, resulting in a pro-oncogenic effect that cannot be substituted by COX-1. There are published reports using genetically modified mice to support both theories. Chulada et al. (23) demonstrated an equivalent reduction in intestinal polyposis in Min/+ mice with a genetic disruption of COX-1 or COX-2, and both genes were found to contribute equally to PGE2 levels within polyps. In contrast, Williams et al. (24) found that xenografts of Lewis lung carcinoma cells grew more slowly only in mice genetically null for COX-2 but not COX-1. Future experiments using the OVCAR-3 cells may help clarify whether COX-1 has a unique pro-tumorigenic role in ovarian cancer or if it is simply an issue of generating a threshold level of PGs that can be derived from either COX isotype, e.g., mRNA antisense or RNAi could be used to inhibit COX-1 expression (and hence VEGF secretion) in these cells and rescue experiments performed to determine whether transfection with COX-2 can substitute for COX-1 to stimulate angiogenic growth factor production.
Our results imply that PGE2 positively regulates VEGF production in ovarian epithelial cells perhaps via the H1F1- pathway. Future experiments designed to determine the expression levels of all four PGE2 receptor (EP) subtypes in human ovarian cancer, as well as the ability of EP receptor subtype-specific agonists to stimulate angiogenic growth factor production, will be important.
In summary, our current results suggest that use of COX-1 or non-COX isotype selective NSAIDs may be more plausible than COX-2 inhibitor therapy in either the primary or secondary prevention of ovarian cancer or as a component of a cancer treatment for advanced tumors. However, it will be important to test this hypothesis in vivo using COX inhibitors that preferentially inhibit COX-1 or COX-2, and such experiments using preclinical models of ovarian cancer cell growth are currently underway.
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FOOTNOTES |
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1 Supported in part from USPHS Grants HD37830 (S. K. D.), HD12304, and HD33994 and Mellon Foundation (S. K. D.) Grants DK 47297, DK 62112, and PO1CA-77839 (R. N. D.). S. K. D. is a recipient of an National Institute of Child Health and Human Development/NIH MERIT Award. R. N. D. is the Mina C. Wallace Professor of Cancer Prevention. 
2 R. A. G. and L. V. T. contributed equally to this work.
3 Present address: Heartland Women’s Health Care, 200 North East 54th Street, Kansas City, MO 64118.
4 To whom correspondence should be addressed, at sk.dey{at}vanderbilt.edu (S. K. D.) or raymond.dubois{at}vanderbilt.edu (R. N. D.).
5 The abbreviations used are: COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug; PG, prostaglandin; AA, arachidonic acid; HIF, hypoxia-inducible factor; VEGF, vascular endothelial growth factor.
Received 11/20/02. Accepted 1/20/03.
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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