Clinical Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention
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Clinical Cancer Research Vol. 9, 1577-1578, May 2003
© 2003 American Association for Cancer Research

Editorial

Evaluation of the Whole Prostaglandin Biosynthetic Pathway in Lung Cancer1

Raymond N. DuBois2

Departments of Medicine, Cancer Biology and Cell/Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232

Ermert et al. (1) report in this issue the expression patterns of COX-1,3 COX-2, PGE2 synthase, prostaglandin D2 synthase, PGI-S, and thromboxane A2 synthase in a variety of lung tumors. Over the past 10 years, an enormous amount of information has been published characterizing the enzymatic pathway responsible for the production of prostaglandins and other bioactive lipid mediators (Fig. 1)Citation . This has led to the development of new drugs, such as the selective COX-2 inhibitors (Celecoxib, Rofecoxib, and Valdecoxib), which are mainly prescribed for arthritis and acute pain relief. These drugs are sometimes referred to as Coxibs. The prostaglandin receptor signaling pathways have also been characterized during this time period, and numerous other targets for inhibition of prostaglandin signaling/biosynthesis are under development. An amazing interest in the role of this pathway in cancer biology has surfaced as well, mainly because of reports that COX inhibitors and/or genetic manipulation of this cascade results in dramatic effects on cancer biology and/or progression of metastatic disease. A recent National Cancer Institute-supported NSAID and cancer workshop report describes some of the advances and controversies in this field (2 , 3) .



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  		Fig. 1. Arachidonic acid pathway for production of prostaglandins and other bioactive lipids.

 
For over a decade, we have known that there is a significant reduction in risk of colorectal cancer and other cancers in persons who take NSAIDs (COX inhibitors) on a regular basis (4) . COX-2 levels were first reported to be elevated in human colon carcinomas in 1994 (5) , and to my knowledge, this was the first report making an association between COX-2 and colon cancer. Since then, several groups have reported that COX-2 levels are increased in the majority of colorectal cancers (6, 7, 8, 9) and many other cancers as well (10) . Now it has been well documented that COX-2 has pro-neoplastic effects in a number of contexts. A recent study by Liu et al. (11) is the first to demonstrate that overexpression of COX-2 in transgenic mice is sufficient for the induction of cellular transformation in the breast. This group developed transgenic mice in which the murine mammary tumor virus promoter/enhancer controls COX-2 expression. Multiparous female mice showed significant increases in mammary gland carcinomas compared with age-matched controls. Treatment of these animals with COX inhibitors led to a significant reduction in breast cancer. Muller-Decker et al. (12) have reported that transgenic mice programmed to overexpress COX-2 in skin tissue develop skin cancer at a much higher rate than control animals. However, another group saw opposite effects in their COX-2 transgenic mice (13) . Overexpression of COX-2 in intestinal epithelial cells is known to result in a pro-neoplastic phenotype in which there is a resistance to undergo programmed cell death (14) , an increase in expression of matrix metalloproteinase enzymes (15) , and alterations in colony morphology (15) . The most direct and compelling evidence implicating a role for COX-2 in colorectal cancer has come from genetic studies in mice. Oshima et al. (16) determined intestinal polyp number in Apc{Delta}716 mice (a mouse model similar to the APCMin but in which there is a target truncation in the APC gene) in both wild-type and homozygous null COX-2 genetic backgrounds. The number and size of polyps were reduced in the COX-2 null mice compared with COX-2 wild-type mice. Treatment of the Apc{Delta}716 COX-2 wild-type mice with a COX-2 selective inhibitor or the NSAID sulindac also reduced polyp number. Other types of solid malignancies have also been reported to have elevated levels of COX-2, such as skin, lung, breast, prostate, bladder, and uterine (reviewed in Ref. 10 ).

The role of COX-2 and prostaglandins in lung cancer is now attracting a considerable amount of attention from cancer biologists and the public. Lung cancer is by far the leading cause of cancer-related deaths, and the clinical outcome of patients with advanced disease is fairly dismal. The current study by Ermert et al. (1) evaluated 48 cases of human lung tumors, which consisted of 15 adenocarcinomas, 31 squamous cell carcinomas, 2 benign lung tumors, and 10 normal lung specimens. Unfortunately, no clinical data were provided concerning the treatment status of the patients involved in this study before resection of their tumors. This is a critical issue because it has been documented that certain chemotherapeutic agents (taxanes and others; Ref. 17 ) and hypoxia (18) can induce the expression of some of these enzymes, especially COX-2. Hence, increased expression levels may be related to treatment regimen that these patients have undergone before surgery or tissue hypoxia during surgery and not be related to the primary disease process. The immunostaining techniques used by the investigators in the current study is difficult to assess because most of the data are presented in tabular form. The specificity and sensitivity of immunostaining for COX-1 and COX-2 are crucial and should be standardized for clinical use before it will be possible to compare results from different studies. There are some published COX-2 immunostaining studies that are misleading because of poor antibody specificity and false positive staining.

One of the most intriguing results from this study may lie in the observation that no significant levels of PGI-S were found in any of the lung tumors. This may be significant in light of recently reported results of Keith et al. (19) demonstrating that manipulation of PGI-S in mice leads to a marked reduction of murine lung cancers. Hence, modulating pathways downstream of COX-2 may be well worth exploring in lung cancer. We and others have shown a pro-neoplastic role for PGE2 in colorectal and ovarian cancer (20) . Other prostaglandins, like prostacyclin, may have different effects because of activation of different downstream signaling pathways or the context in which they are produced. Is prostacyclin synthase good for lung cancer and PGE2 bad? More work is needed to carefully explore all of the downstream effects after activation by each of these bioactive lipid molecules. Using gene microarray and proteomic technologies, it should not be too difficult to differentiate the effects of these prostaglandins on lung biology and come up with an answer.

FOOTNOTES

1 Supported by NIH Grants DK-47297, CA-77839, and CA 68485 (Vanderbilt-Ingram Cancer Center). Back

2 To whom requests for reprints should be addressed, at Department of Medicine/GI; MCN C-2104, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 27232-2279. Phone: (615) 343-5200; Fax: (615) 343-6229; E-mail: raymond.dubois{at}vanderbilt.edu Back

3 The abbreviations used are: COX, cyclooxygenase; PGE2, prostaglandin E1; NSAID, nonsteroidal anti-inflammatory drug; PGI-S, prostacyclin synthase. Back

Received 1/ 8/03; accepted 1/15/03.

REFERENCES

  1. Ermert L., Dierkes C., Ermert M. Immunohistochemical expression of COX-isozymes and downstream enzymes in human lung tumors. Clin. Cancer Res., 9: 1604-1610, 2003.[Abstract/Free Full Text]
  2. Hwang D. H., Fung V., Dannenberg A. J. National Cancer Institute workshop on chemopreventive properties of nonsteroidal anti-inflammatory drugs: role of COX-dependent and -independent mechanisms. Neoplasia, 4: 91-97, 2002.[CrossRef][Medline]
  3. Marx J. Anti-inflammatories inhibit cancer growth–but how?. Science (Wash. DC), 291: 581-582, 2001.[Free Full Text]
  4. Marnett L. J. Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res., 52: 5575-5589, 1992.[Free Full Text]
  5. Eberhart C. E., Coffey R. J., Radhika A., Giardiello F. M., Ferrenbach S., DuBois R. N. Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology, 107: 1183-1188, 1994.[Medline]
  6. Chapple K. S., Cartwright E. J., Hawcroft G., Tisbury A., Bonifer C., Scott N., Windsor A. C., Guillou P. J., Markham A. F., Coletta P. L., Hull M. A. Localization of cyclooxygenase-2 in human sporadic colorectal adenoma. Am. J. Pathol., 156: 545-553, 2000.[Abstract/Free Full Text]
  7. Kargman S., O’Neill G., Vickers P., Evans J., Mancini J., Jothy S. Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res., 55: 2556-2559, 1995.[Abstract/Free Full Text]
  8. Sano H., Kawahito Y., Wilder R. L., Hashiramoto A., Mukai S., Asai K., Kimura S., Kato H., Kondo M., Hla T. Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res., 55: 3785-3789, 1995.[Abstract/Free Full Text]
  9. Kutchera W., Jones D. A., Matsunami N., Groden J., McIntyre T. M., Zimmerman G. A., White R. L., Prescott S. M. Prostaglandin H synthase-2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect. Proc. Natl. Acad. Sci. USA, 93: 4816-4820, 1996.[Abstract/Free Full Text]
  10. Anderson W. F., Umar A., Viner J. L., Hawk E. T. The role of cyclooxygenase inhibitors in cancer prevention. Curr. Pharm. Des., 8: 1035-1062, 2002.[CrossRef][Medline]
  11. Liu H. L., Chang S. H., Narko K., Trifan O. C., Wu M. T., Smith E., Haudenschild C., Lane T. F., Hla T. Over-expression o f cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J. Biol. Chem., 276: 18563-18569, 2001.[Abstract/Free Full Text]
  12. Muller-Decker K., Neufang G., Berger I., Neumann M., Marks F., Furstenberger G. Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis. Proc. Natl. Acad. Sci. USA, 99: 12483-12488, 2002.[Abstract/Free Full Text]
  13. Bol D. K., Rowley R. B., Ho C. P., Pilz B., Dell J., Swerdel M., Kiguchi K., Muga S., Klein R., Fischer S. M. Cyclooxygenase-2 overexpression in the skin of transgenic mice results in suppression of tumor development. Cancer Res., 62: 2516-2521, 2002.[Abstract/Free Full Text]
  14. Tsujii M., DuBois R. N. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase-2. Cell, 83: 493-501, 1995.[CrossRef][Medline]
  15. Tsujii M., Kuwano S., DuBois R. N. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc. Natl. Acad. Sci. USA, 94: 3336-3340, 1997.[Abstract/Free Full Text]
  16. Oshima M., Dinchuk J. E., Kargman S. L., Oshima H., Hancock B., Kwong E., Trzaskos J. M., Evans J. F., Taketo M. M. Suppression of intestinal polyposis in APC{Delta}716 knockout mice by inhibition of prostaglandin endoperoxide synthase-2 (COX-2). Cell, 87: 803-809, 1996.[CrossRef][Medline]
  17. Subbaramaiah K., Hart J. C., Norton L., Dannenberg A. J. Microtubule-interfering agents stimulate the transcription of cyclooxygenase-2. Evidence for involvement of ERK1/2 AND p38 mitogen-activated protein kinase pathways. J. Biol. Chem., 275: 14838-14845, 2000.[Abstract/Free Full Text]
  18. Schmedtje J. F., Jr., Ji Y. S., Liu W. L., DuBois R. N., Runge M. S. Hypoxia induces cyclooxygenase-2 via the NF-kappaB p65 transcription factor in human vascular endothelial cells. J. Biol. Chem., 272: 601-608, 1997.[Abstract/Free Full Text]
  19. Keith R. L., Miller Y. E., Hoshikawa Y., Moore M. D., Gesell T. L., Gao B., Malkinson A. M., Golpon H. A., Nemenoff R. A., Geraci M. W. Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. Cancer Res., 62: 734-740, 2002.[Abstract/Free Full Text]
  20. Sheng H., Shao J., Washington M. K., DuBois R. N. Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J. Biol. Chem., 276: 18075-18081, 2001.[Abstract/Free Full Text]

Key Article

Immunohistochemical Expression of Cyclooxygenase Isoenzymes and Downstream Enzymes in Human Lung Tumors
Leander Ermert, Christian Dierkes, and Monika Ermert
Clin. Cancer Res. 2003 9: 1604-1610. [Abstract] [Full Text] [PDF]



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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online