PDF
ePub
Citation
Print
Abstract
Purpose
Angiogenesis plays a key role in the growth and metastasis of malignant tumor. Angiogenesis is reportedly enhanced by prostaglandins (PGs). Cyclooxygenase (COX)-2 is an inducible enzyme that catalyzes the formation of PGs from arachidonic acid. The COX enzyme system is composed of two isoenzymes, COX-1 and COX-2. Recent sources of experimental and epidemiological evidence suggest a significant role for the COX enzymes, particularly COX-2, in the pathogenesis of breast cancer. COX-2 overexpression in a murine mammary gland is sufficient to cause tumor formation. We performed our study to determine the effect of COX-2 inhibitor in a in vivo mouse mammary tumor (MMT) cell line.
Methods
In order to test our study, 24 C57BL/6 type mice (Jackson Laboratory, Bar Harbor, USA) were randomized to receive 35 days of either placebo supplemented diet (n=11) or a 1,500ppm celecoxib (CELEBREX®, Pfizer Inc. St. Louis, USA) supplemented diet (n=13) beginning at day 0. At 14 days after the beginning day, 30 ㎕ of a 1% India ink solution that contained 500,000 of MMT cells or dye alone (control) was intradermally inoculated at each flank (day 14). The animals were sacrificed 21 days later (day 35) and skin specimens were harvested/processed for quantification of the microvessel density (MVD) that was associated with each inoculated site. The aortas that were isolated according to each treatment group at the time of animal sacrifice were used to create identical aortic ring angiogenesis assays (media 199 supplemented with 20% FBS). Explants were evaluated for 14 days in culture to determine both the rate of angiogenesis initiation (% of explants exhibiting the angiogenic phenotype) and the neovessel growth rate (using a subjective angiogenic index score for the wells exhibiting initiation). Analysis of variance (ANOVA) was used to evaluate the differences between groups for each assay.
Results
According to the immunohistochemical staining, celecoxib administration resulted in a parallel decrease in the MVD at both the control and MMT inoculated sites (22% and 21%, p = 0.025 and p = 0.010 respectively). On the aortic ring assay, the dietary treatment group was not significantly inhibited compared with the placebo group (75% and 63.3%, respectively, p = NS). However, dietary celecoxib administration significantly inhibited the angiogenic index of the neovessel growth rate (5.0 ± 2.38 and 8.9 ± 3.44, respectively, p < 0.001).
References
1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971. 285:1182–1186.
2. Cavallaro U, Christofori G. Molecular mechanisms of tumor angiogenesis and tumor progression. J Neurooncol. 2000. 50:63–70.
3. Bronstein JC, Bull AW. The correlation between 13-hydroxyoctadecadienoate dehydrogenase (13-HODE dehydrogenase) and intestinal cell differentiation. Prostaglandins. 1993. 46:387–395.
4. Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci USA. 1992. 89:7384–7388.
5. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994. 107:1183–1188.
6. Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA. 1997. 94:3336–3340.
7. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 1998. 93:705–716.
8. Smalley WE, DuBois RN. Colorectal cancer and nonsteroidal anti-inflammatory drugs. Adv Pharmacol. 1997. 39:1–20.
9. Thun MJ, Namboodiri MM, Heath CW Jr. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med. 1991. 325:1593–1596.
10. Howe LR, Subbaramaiah K, Patel J, Masferrer JL, Deora A, Hudis C, et al. Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2(HER-2)/neu-induces breast cancer. Cancer Res. 2002. 62:5405–5407.
11. Youn HS. Nationwide Korean breast cancer data of 2002. J Korean Breast Cancer Soc. 2004. 7:72–83.
12. Scheiman JM. NSAIDs, gastrointestinal injury, and cytoprotection. Gastroenterol Clin North Am. 1996. 25:279–298.
13. Wallace JL. Prostaglandins, NSAIDs, and cytoprotection. Gastroenterol Clin North Am. 1992. 21:631–641.
14. Picot D, Loll PJ, Garavito RM. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature. 1994. 367:243–249.
15. Hla T, Bishop-Bailey D, Liu CH, Schaefers HJ, Trifan OC. Cyclooxygenase-1 and -2 isoenzymes. Int J Biochem Cell Biol. 1999. 31:551–557.
16. Herschman HR. Prostaglandin synthase 2. Biochim Biophys Acta. 1996. 1299:125–140.
17. Appleby SB, Ristimaki A, Neilson K, Narko K, Hla T. Structure of the human cyclo-oxygenase-2 gene. Biochem J. 1994. 302:723–727.
18. Robertson FM, Parrett ML, Joarder FS, Ross M, Abou-Issa HM, Alshafie G, et al. Ibuprofen-induced inhibition of cyclooxygenase isoform gene expression and regression of rat mammary carcinomas. Cancer Lett. 1998. 122:165–175.
19. Nakatsugi S, Ohta T, Kawamori T, Mutoh M, Tanigawa T, Watanabe K, et al. Chemoprevention by nimesulide, a selective cyclooxygenase-2 inhibitor, of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP)-induced mammary gland carcinogenesis in rats. Jpn J Cancer Res. 2000. 91:886–892.
20. Howe LR, Crawford HC, Subbaramaiah K, Hassell JA, Dannenberg AJ, Brown AM. PEA3 is up-regulated in response to Wnt1 and activates the expression of cyclooxygenase-2. J Biol Chem. 2001. 276:20108–20115.
21. Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem. 2001. 276:18563–18569.
22. Soslow RA, Dannenberg AJ, Rush D, Woerner BM, Khan KN, Masferrer J, et al. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer. 2000. 89:2637–2645.
23. Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, et al. Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res. 2002. 62:632–635.
24. Subbaramaiah K, Telang N, Ramonetti JT, Araki R, DeVito B, Weksler BB, et al. Transcription of cyclooxygenase-2 is enhanced in transformed mammary epithelial cells. Cancer Res. 1996. 56:4424–4429.
25. Sheng H, Williams CS, Shao J, Liang P, DuBois RN, Beauchamp RD. Induction of cyclooxygenase-2 by activated Ha-ras oncogene in Rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway. J Biol Chem. 1998. 273:22120–22127.
26. Vadlamudi R, Mandal M, Adam L, Steinbach G, Mendelsohn J, Kumar R. Regulation of cyclooxygenase-2 pathway by HER2 receptor. Oncogene. 1999. 18:305–314.
27. Mestre JR, Subbaramaiah K, Sacks PG, Schantz SP, Tanabe T, Inoue H, et al. Retinoids suppress epidermal growth factor-induced transcription of cyclooxygenase-2 in human oral squamous carcinoma cells. Cancer Res. 1997. 57:2890–2895.
28. Xie W, Herschman HR. v-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. J Biol Chem. 1995. 270:27622–27628.
29. Xie W, Herschman HR. Transcriptional regulation of prostaglandin synthase 2 gene expression by platelet-derived growth factor and serum. J Biol Chem. 1996. 271:31742–31748.
30. Subbaramaiah K, Altorki N, Chung WJ, Mestre JR, Sampat A, Dannenberg AJ. Inhibition of cyclooxygenase-2 gene expression by p53. J Biol Chem. 1999. 274:10911–10915.
31. Yamamoto K, Arakawa T, Ueda N, Yamamoto S. Transcriptional roles of nuclear factor kappa B and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells. J Biol Chem. 1995. 270:31315–31320.
32. Nolan RD, Danilowicz RM, Eling TE. Role of arachidonic acid metabolism in the mitogenic response of BALB/c 3T3 fibroblasts to epidermal growth factor. Mol Pharmacol. 1988. 33:650–656.
33. Goin M, Pignataro O, Jimenez de Asua L. Early cell cycle diacylglycerol (DAG) content and protein kinase C (PKC) activity enhancement potentiates prostaglandin F2 alpha (PGF2 alpha) induced mitogenesis in Swiss 3T3 cells. FEBS Lett. 1993. 316:68–72.
34. Bandyopadhyay GK, Imagawa W, Wallace D, Nandi S. Linoleate metabolites enhance the in vitro proliferative response of mouse mammary epithelial cells to epidermal growth factor. J Biol Chem. 1987. 262:2750–2756.
35. Huang M, Sharma S, Mao JT, Dubinett SM. Non-small cell lung cancer-derived soluble mediators and prostaglandin E2 enhance peripheral blood lymphocyte IL-10 transcription and protein production. J Immunol. 1996. 157:5512–5520.
36. Sharma S, Stolina M, Yang SC, Baratelli F, Lin JF, Atianzar K, et al. Tumor cyclooxygenase 2-dependent suppression of dendritic cell function. Clin Cancer Res. 2003. 9:961–968.
37. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996. 86:353–364.
38. Daly JM, Bertagnolli M, DeCosse JJ, Morton DL. Schwarz SI, editor. Oncology. Principle of surgery. 1999. 7th ed. Singapore: McGraw-Hill;297–360.
39. Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992. 267:10931–10934.
40. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 1998. 93:705–716.
41. Gately S. The contributions of cyclooxygenase-2 to tumor angiogenesis. Cancer Metastasis Rev. 2000. 19:19–27.
42. Kirkpatrick K, Ogunkolade W, Elkak A, Bustin S, Jenkins P, Ghilchik M, et al. The mRNA expression of cyclo-oxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in human breast cancer. Curr Med Res Opin. 2002. 18:237–241.
43. Williams CS, Tsujii M, Reese J, Dey SK, DuBois RN. Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest. 2000. 105:1589–1594.
44. Sawaoka H, Tsuji S, Tsujii M, Gunawan ES, Sasaki Y, Kawano S, et al. Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo. Lab Invest. 1999. 79:1469–1477.
XML Download