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The Simultaneous Expression of Peroxisome Proliferator-Activated Receptor Delta and Cyclooxygenase-2 May Enhance Angiogenesis and Tumor Venous Invasion in Tissues of Colorectal Cancers

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Abstract

We conducted this study to evaluate the impact of the expression of peroxisome proliferator-activated receptor delta on angiogenesis in tissue samples of colorectal cancer. We examined 52 samples of primary human colorectal carcinomas and matched normal adjacent tissues to evaluate the expression of peroxisome proliferator-activated receptor delta, cyclooxygenase-2, vascular endothelial growth factor-A, and CD34 through immunohistochemical analysis. Peroxisome proliferator-activated receptor delta was expressed in 25 (48.1%), and cyclooxygenase-2 was expressed in 26 (50.0%) of total colorectal cancer tissues. Tissue samples were divided into four groups, according to the expression of peroxisome proliferator-activated receptor delta and cyclooxygenase-2. The positive rate of vascular endothelial growth factor-A, the levels of microvascular density, and the incidence of venous vessel invasion in peroxisome proliferator-activated receptor delta (+)/cyclooxygenase-2 (+) samples exceeded significantly those in the other three groups of tissue samples (P < 0.05). The results suggest that the axis of the cyclooxygenase-2/peroxisome proliferator-activated receptor delta signal pathway might play a crucial role in the development of colorectal cancers by enhancing angiogenesis.

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References

  1. Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000;43:527–550. doi:10.1021/jm990554g.

    Article  PubMed  CAS  Google Scholar 

  2. Kliewer SA, Forman BM, Blumberg B, et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA. 1994;91:7355–7359. doi:10.1073/pnas.91.15.7355.

    Article  PubMed  CAS  Google Scholar 

  3. Kliewer SA, Lehmann JM, Milburn MV, Willson TM. The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways. Recent Prog Horm Res. 2000;54:345–367.

    Google Scholar 

  4. Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998;47:507–514. doi:10.2337/diabetes.47.4.507.

    Article  PubMed  CAS  Google Scholar 

  5. Peters JM, Cattley RC, Gonzalez FJ. Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. Carcinogenesis. 1997;18:2029–2033. doi:10.1093/carcin/18.11.2029.

    Article  PubMed  CAS  Google Scholar 

  6. Reddy JK, Chu R. Peroxisome proliferator-induced pleiotropic responses: pursuit of a phenomenon. Ann NY Acad Sci. 1996;804:176–201. doi:10.1111/j.1749-6632.1996.tb18616.x.

    Article  PubMed  CAS  Google Scholar 

  7. Tontonoz P, Singer S, Forman BM, et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci USA. 1997;94:237–241. doi:10.1073/pnas.94.1.237.

    Article  PubMed  CAS  Google Scholar 

  8. Mueller E, Sarraf P, Tontonoz P, et al. Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell. 1998;1:465–470. doi:10.1016/S1097-2765(00)80047-7.

    Article  PubMed  CAS  Google Scholar 

  9. Sarraf P, Mueller E, Jones D, et al. Differentiation and reversal of malignant changes in colon cancer through PPAR gamma. Nat Med. 1998;4:1046–1052. doi:10.1038/2030.

    Article  PubMed  CAS  Google Scholar 

  10. Brockman JA, Gupta RA, DuBois RN. Activation of PPAR gamma leads to inhibition of anchorage-independent growth of human colorectal cancer cells. Gastroenterology. 1998;115:1049–1055. doi:10.1016/S0016-5085(98)70072-1.

    Article  PubMed  CAS  Google Scholar 

  11. He TC, Chan TA, Vogelstein B, Kinzler KW. PPARd is an APC regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999;99:335–345. doi:10.1016/S0092-8674(00)81664-5.

    Article  PubMed  CAS  Google Scholar 

  12. Gupta RA, Wang D, Katkuri S, Wang H, Dey SK, DuBois RN. Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-d accelerates intestinal adenoma growth. Nat Med. 2004;10:245–247. doi:10.1038/nm993.

    Article  PubMed  CAS  Google Scholar 

  13. Takayama O, Yamamoto H, Damdinsuren B, et al. Expression of PPARd in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology. Br J Cancer. 2006;95:889–895. doi:10.1038/sj.bjc.6603343.

    Article  PubMed  CAS  Google Scholar 

  14. Harman FS, Nicol CJ, Marin HE, Ward JM, Gonzalez FJ, Peters JM. Peroxisome proliferator-activated receptor-d attenuates colon carcinogenesis. Nat Med. 2004;10:481–483. doi:10.1038/nm1026.

    Article  PubMed  CAS  Google Scholar 

  15. Reed KR, Sansom OJ, Hayes AJ, et al. PPAR delta status and Apc-mediated tumorigenesis in the mouse intestine. Oncogene. 2004;23:8992–8996. doi:10.1038/sj.onc.1208143.

    Article  PubMed  CAS  Google Scholar 

  16. Park BH, Vogelstein B, Kinzler KW. Genetic disruption of PPARd decreases the tumorigenicity of human colon cancer cells. Proc Natl Acad Sci USA. 2001;98:2598–2603. doi:10.1073/pnas.051630998.

    Article  PubMed  CAS  Google Scholar 

  17. Bergsland EK. Vascular endothelial growth factor as a therapeutic target in cancer. Am J Health Syst Pharm. 2004;61:S4–S11.

    PubMed  CAS  Google Scholar 

  18. Wang D, Wang H, Guo Y, et al. Crosstalk between peroxisome proliferator-activated receptor delta and VEGF stimulates cancer progression. Proc Natl Acad Sci USA. 2006;103:19069–19074. doi:10.1073/pnas.0607948103.

    Article  PubMed  CAS  Google Scholar 

  19. Cutler NS, Graves-Deal R, LaFleur BJ, et al. Stromal production of prostacyclin confers an antiapoptotic effect to colonic epithelial cells. Cancer Res. 2003;63:1748–1751.

    PubMed  CAS  Google Scholar 

  20. Wang D, Mann JR, DuBois RN. WNT and cyclooxygenase-2 crosstalk accelerates adenoma growth. Cell Cycle. 2004;3:1512–1515.

    PubMed  CAS  Google Scholar 

  21. Wang D, Wang H, Shi Q, et al. Prostaglandin E(2) promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor delta. Cancer Cell. 2004;6:285–295. doi:10.1016/j.ccr.2004.08.011.

    Article  PubMed  CAS  Google Scholar 

  22. Gupta RA, Tan J, Krause WF, et al. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. Proc Natl Acad Sci USA. 2000;97:13275–13280. doi:10.1073/pnas.97.24.13275.

    Article  PubMed  CAS  Google Scholar 

  23. Piqueras L, Reynolds AR, Hodivala-Dilke KM, et al. Activation of PPAR beta/delta induces endothelial cell proliferation and angiogenesis. Arterioscler Thromb Vasc Biol. 2007;27:63–69. doi:10.1161/01.ATV.0000250972.83623.61.

    Article  PubMed  CAS  Google Scholar 

  24. Yonenaga Y, Mori A, Onodera H, et al. Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology. 2005;69:159–166. doi:10.1159/000087840.

    Article  PubMed  Google Scholar 

  25. Onogawa S, Tanaka S, Oka S, et al. Clinical significance of angiogenesis in rectal carcinoid tumors. Oncol Rep. 2002;9:489–494.

    PubMed  Google Scholar 

  26. Takebayashi Y, Aklyama S, Yamada K, Akiba S, Aikou T. Angiogenesis as an unfavorable prognostic factor in human colorectal carcinoma. Cancer. 1996;78:226–231. doi :10.1002/(SICI)1097-0142(19960715)78:2<226::AID-CNCR6>3.0.CO;2-J.

    Google Scholar 

  27. Rmali KA, Puntis MC, Jiang WG. Prognostic values of tumor endothelial markers in patients with colorectal cancer. World J Gastroenterol. 2005;11:1283–1286.

    PubMed  CAS  Google Scholar 

  28. Choi HJ, Hyun MS, Jung GJ, Kim SS, Hong SH. Tumor angiogenesis as a prognostic predictor in colorectal carcinoma with special reference to mode of metastasis and recurrence. Oncology. 1998;55:575–581. doi:10.1159/000011915.

    Article  PubMed  CAS  Google Scholar 

  29. Acikalin MF, Oner U, Topcu I, Yasar B, Kiper H, Colak E. Tumor angiogenesis and mast cell density in the prognostic assessment of colorectal carcinomas. Dig Liver Dis. 2005;37:162–169. doi:10.1016/j.dld.2004.09.028.

    Article  PubMed  CAS  Google Scholar 

  30. Engel CJ, Bennett ST, Chambers AF, Doig GS, Kerkvliet N, O’Malley FP. Tumor angiogenesis predicts recurrence in invasive colorectal cancer when controlled for Dukes staging. Am J Surg Pathol. 1996;20:1260–1265. doi:10.1097/00000478-199610000-00012.

    Article  PubMed  CAS  Google Scholar 

  31. Frank RE, Saclarides TJ, Leurgans S, Speziale NJ, Drab EA, Rubin DB. Tumor angiogenesis as a predictor of recurrence and survival in patients with node-negative colon cancer. Ann Surg. 1995;222:695–699. doi:10.1097/00000658-199512000-00002.

    Article  PubMed  CAS  Google Scholar 

  32. Jubb AM, Hurwitz HI, Bai W, et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol. 2006;24:217–227. doi:10.1200/JCO.2005.01.5388.

    Article  PubMed  CAS  Google Scholar 

  33. Bossi P, Viale G, Lee AK, Alfano R, Coggi G, Bosari S. Angiogenesis in colorectal tumors: microvessel quantitation in adenomas and carcinomas with clinicopathological correlations. Cancer Res. 1995;55:5049–5053.

    PubMed  CAS  Google Scholar 

  34. Gunther K, Radkow T, Reymond MA, et al. Angiogenesis and dendritic cell density are not correlated with metachronous distant metastasis in curatively operated rectal cancer. Int J Colorectal Dis. 2003;18:300–308.

    PubMed  CAS  Google Scholar 

  35. Masunaga R, Kohno H, Dhar DK, et al. Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients. Clin Cancer Res. 2000;6:4064–4068.

    PubMed  CAS  Google Scholar 

  36. Liang P, Nakada I, Hong JW, et al. Prognostic significance of immunohistochemically detected blood and lymphatic vessel invasion in colorectal carcinoma: its impact on prognosis. Ann Surg Oncol. 2007;14:470–477. doi:10.1245/s10434-006-9189-3.

    Article  PubMed  Google Scholar 

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Acknowledgment

The authors thank the pathology technicians in both Beppu Medical Center (Beppu, Japan) and Kyodo Byori, Inc. (Kobe, Japan) for their excellent assistance.

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Authors and Affiliations

  1. Department of Gastroenterology, Hepathology, and Nutrition, National Hospital Organization Beppu Medical Center, 1473 Uchikamado, Beppu, Oita, 874-0011, Japan

    Masahiro Yoshinaga, Yosuke Kitamura, Tomohito Chaen, Shinsaku Yamashita, Satoru Tsuruta, Teruaki Hisano & Hironori Sakai

  2. Department of Surgery, National Hospital Organization Beppu Medical Center, Beppu, Oita, Japan

    Yoichi Ikeda & Yoichi Muto

  3. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Kazuhiko Nakamura & Ryoichi Takayanagi

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  1. Masahiro Yoshinaga
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  2. Yosuke Kitamura
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Correspondence to Masahiro Yoshinaga.

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Yoshinaga, M., Kitamura, Y., Chaen, T. et al. The Simultaneous Expression of Peroxisome Proliferator-Activated Receptor Delta and Cyclooxygenase-2 May Enhance Angiogenesis and Tumor Venous Invasion in Tissues of Colorectal Cancers. Dig Dis Sci 54, 1108–1114 (2009). https://doi.org/10.1007/s10620-008-0465-x

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  • DOI: https://doi.org/10.1007/s10620-008-0465-x

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