Journal of Gastroenterology

, Volume 49, Issue 3, pp 436–445 | Cite as

The prognostic significance of peroxisome proliferator-activated receptor β expression in the vascular endothelial cells of colorectal cancer

  • Jin Zhou
  • Lie Yang
  • Yuan Li
  • Gunnar Arbman
  • Ke-Ling Chen
  • Bin Zhou
  • Yong-Yang Yu
  • Cun Wang
  • Xian-Ming Mo
  • You Lu
  • Zong-Guang Zhou
  • Xiao-Feng Sun
Original Article—Alimentary Tract



Currently, little is known regarding the role of peroxisome proliferator-activated receptor-β (PPAR β) in the vascular endothelial cells (VECs) of colorectal cancers (CRCs). The aim of this study was to investigate the relationship of PPAR β expression in the VECs of CRCs in terms of the prognosis and clinicopathological features of CRC patients.


The expression and localization of PPAR β in the primary cancers and the matched normal mucosal samples of 141 Swedish CRC patients were analyzed in terms of its correlation with clinicopathological features and the expression of angiogenesis-related genes. This study also included 92 Chinese CRC patients.


PPAR β was predominantly localized in the cytoplasm and was significantly downregulated in the VECs of CRC compared to that of the normal mucosa. The low expression levels of PPAR β in the VECs of CRC were statistically correlated with enhanced differentiation, early staging and favorable overall survival and were associated with the increased expression of VEGF and D2-40. The patients exhibiting elevated expression of PPAR β in CRC cells but reduced expression in VECs exhibited more favorable survival compared with the other patients, whereas the patients with reduced expression of PPAR β in CRC cells but increased expression in VECs exhibited less favorable prognosis.


PPAR β might play a tumor suppressor role in CRC cells in contrast to a tumor promoter role in the VECs of CRCs.


Peroxisome proliferator-activated receptor-β Colorectal cancer Prognosis Vascular endothelial cells Angiogenesis 


  1. 1.
    Molnar F, Matilainen M, Carlberg C. Structural determinants of the agonist-independent association of human peroxisome proliferator-activated receptors with coactivators. J Biol Chem. 2005;280:26543–56.PubMedCrossRefGoogle Scholar
  2. 2.
    Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, Orahilly S, Palmer CN, Plutzky J, Reddy JK, Spiegelman BM, Staels B, Wahli W. International union of pharmacology. LXI peroxisome proliferator-activated receptors. Pharmacol Rev. 2006;58:726–41.PubMedCrossRefGoogle Scholar
  3. 3.
    Desvergne B, Michalik L, Wahli W. Transcriptional regulation of metabolism. Physiol Rev. 2006;86:465–514.PubMedCrossRefGoogle Scholar
  4. 4.
    Kostadinova R, Wahli W, Michalik L. PPARs in diseases: control mechanisms of inflammation. Curr Med Chem. 2005;12:2995–3009.PubMedCrossRefGoogle Scholar
  5. 5.
    Kilgore KS, Billin AN. PPARβ/δ ligands as modulators of the inflammatory response. Curr Opin Investig Drugs. 2008;9:463–9.PubMedGoogle Scholar
  6. 6.
    Kim DJ, Bility MT, Billin AN, Willson TM, Gonzalez FJ, Peters JM. PPAR beta/delta selectively induces differentiation and inhibits cell proliferation. Cell Death Differ. 2006;13:53–60.PubMedCrossRefGoogle Scholar
  7. 7.
    Nadra K, Anghel SI, Joye E, Tan NS, Basu-Modak S, Trono D, Wahli W, Desvergne B. Differentiation of trophoblast giant cells and their metabolic functions are dependent on peroxisome proliferator-activated receptor beta/delta. Mol Cell Biol. 2006;26:3266–81.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Varnat F, Heggeler BB, Grisel P, Boucard N, Corthesy-Theulaz I, Wahli W, Desvergne B. PPAR beta/delta regulates paneth cell differentiation via controlling the hedgehog signaling pathway. Gastroenterology. 2006;131:538–53.PubMedCrossRefGoogle Scholar
  9. 9.
    Brusselbach SM, Komhoff M, Rieck M, Meissner W, Kaddatz K, Adamkiewicz J, Keil B, Klose KJ, Moll R, Burdick AD, Peters JM, Muller R. Deregulation of tumor angiogenesis and blockade of tumor growth in PPAR beta-deficient mice. EMBO J. 2007;26:3686–98.CrossRefGoogle Scholar
  10. 10.
    Wang DZ, Wang HB, Guo Y, Ning W, Katkuri S, Wahli W, Desvergne B, Dey SK, Dubois RN. Crosstalk between peroxisome proliferator-activated receptor-delta and VEGF stimulates cancer progression. PNAS. 2006;103:19069–74.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Rohrl C, Kaindl U, Koneczny I, Hudec X, Baron DM, Konig JS, Marian B. Peroxisome-proliferator-activated receptors γ and β/δ mediate vascular endothelial growth factor production in colorectal tumor cells. J Cancer Res Clin Oncol. 2011;137:29–39.PubMedCrossRefGoogle Scholar
  12. 12.
    Harman FS, Nicol CJ, Marin HE, Ward JM, Gonzalez FJ, Peters JM. Peroxisome proliferator-activated receptor-δ attenuates colon carcinogenesis. Nat Med. 2004;10:481–3.PubMedCrossRefGoogle Scholar
  13. 13.
    He TC, Chan TA, Vogelstein B, Kinzler KW. PPAR δ is an APC regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999;99:335–45.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Gupta RA, Wang D, Katkuri S, Wang H, Dey SK, DuBois RN. Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-δ accelerates intestinal adenoma growth. Nat Med. 2004;10:245–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Barak Y, Liao D, He W, Ong ES, Nelson MC, Olefsky JM, Boland R, Evans RM. Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer. Proc Natl Acad Sci USA. 2002;99:303–8.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Wang D, Wang H, Shi Q, Katkuri S, Walhi W, Desvergne B, Das SK, Dey SK, DuBois RN. Prostaglandin E2 promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor δ. Cancer Cell. 2004;6:285–95.PubMedCrossRefGoogle Scholar
  17. 17.
    Yang L, Zhang H, Zhou ZG, Yan H, Adell G, Sun XF. Biological function and prognostic significance of peroxisome proliferator-activated receptor δ in rectal cancer. Clin Cancer Res. 2011;17:3760–70.PubMedCrossRefGoogle Scholar
  18. 18.
    Yang L, Olsson B, Pfeifer D, Jonsson JI, Zhou ZG, Jiang X, Fredriksson BA, Zhang H, Sun XF. Knockdown of peroxisome proliferator-activated receptor-δ induces less differentiation and enhances cell fibronectin adhesion of colon cancer cells. Oncogene. 2010;29:516–26.PubMedCrossRefGoogle Scholar
  19. 19.
    Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438:932–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353–64.PubMedCrossRefGoogle Scholar
  21. 21.
    Abdoll A, Schwager C, Kleeff J, Esposito I, Domhan S, Peschke P, Hauser K, Hahnfeldt P, Hlatky L, Debus J, Peters JM, Friess H, Folkman J, Huber PE. Transcriptional network governing the angiogenic switch in human pancreatic cancer. PNAS. 2007;104:12890–5.CrossRefGoogle Scholar
  22. 22.
    Piqueras L, Reynolds AR, Hodivala-Dilke KM, Alfranca A, Redondo JM, Hatae T, Tanabe T, Warner TD, Bishop-Bailey D. Activation of PPAR beta/delta induces endothelial cell proliferation and angiogenesis. Arterioscler Thromb Vasc Biol. 2007;27:63–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Gao J, Arbman G, Rearden A, Sun XF. Stromal staining for PINCH is an independent prognostic indicator in colorectal cancer. Neoplasia. 2004;6:796–801.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Gao J, Knutsen A, Arbman G, Carstensen J, Franlund B, Sun XF. Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer. Dig Liver Dis. 2009;41:116–22.PubMedCrossRefGoogle Scholar
  25. 25.
    Muller R, Rieck M, Brusselbach SM. Regulation of cell proliferation and differentiation by PPAR β. PPAR Res. 2008. doi:10.1155/2008/614852.
  26. 26.
    Hollingshead HE, Morimura K, Adachi M, Kennett MJ, Billin AN, Willson TM, Gonzalez FJ, Peters JM. PPAR beta/delta protects against experimental colitis through a ligand-independent mechanism. Dig Dis Sci. 2007;52:2912–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Sun XF, Zhang H. Clinicopathological significance of stromal variables: angiogenesis, lymphangiogenesis, inflammatory infiltration, MMP and PINCH in colorectal carcinomas. BMC Mol Cancer. 2006;5:43.CrossRefGoogle Scholar
  28. 28.
    Glienke J, Schmitt AO, Pilarsky C, Hinzmann B, Weiss B, Rosenthal A, Thierauch KH. Differential gene expression by endothelial cells in distinct angiogenic states. Eur J Biochem. 2000;267:2820–30.PubMedCrossRefGoogle Scholar
  29. 29.
    Zhang ZY, Tian YF, Wang YY, Zhang LJ, Zhao ZR, Sun XF. PINCH mRNA overexpression in colorectal carcinomas correlated with VEGF and FAS mRNA expression. Anticancer Res. 2011;31:4127–33.PubMedGoogle Scholar
  30. 30.
    Romero S, Szafranska J, Cabrera E, Gonzalez A, Peiro A, Llauger J, Ortega L, Bague S, Canet B, Espinosa I, Prat J. Role of tumor-associated macrophages and angiogenesis in desmoids-type fibromatosis. Virchows Arc. 2012;461:117–22.Google Scholar
  31. 31.
    Moon HS, Liu X, Nagel JM, Chamberland JP, Diakopoulos KN, Brinkoetter MT, Hatziapostolou M, Wu Y, Robson SC, Iliopoulos D, Mantzoros CS. Salutary effects of adiponectin on colon cancer: in vivo and in vitro studies in mice. Gut. 2013;62:561–71.Google Scholar
  32. 32.
    Jakob C, Aust DE, Liebscher B, Baretton GB, Datta K, Muders MH. Lymphangiogenesis in regional lymph nodes is an independent prognostic marker in rectal cancer patients after neoadjuvant treatment. PLoS ONE. 2011;6:327402.Google Scholar
  33. 33.
    Cimpean AM, Poenaru Sava M, Raica M, Ribatti D. Preliminary evidence of the presence of lymphatic vessels immunoreactive for D2-40 and Prox-1 in human pterygium. Oncol Rep. 2011;26:1111–3.PubMedGoogle Scholar
  34. 34.
    Takayama O, Yamamoto H, Damdinsuren B, Sugita Y, Ngan CY, Xu X, Tsujino T, Takemasa I, Ikeda M, Sekimoto M, Matsuura N, Monden M. Expression of PPAR delta in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology. Br J Cancer. 2006;95:889–95.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Yoshinaga M, Kitamura Y, Chaen T, Yamashita S, Tsuruta S, Hisano T, Ikeda Y, Sakai H, Nakamura K, Takayanagi R, Muto Y. The simultaneous expression of peroxisome proliferator-activated receptor delta and cyclooxygenase-2 may enhance angiogenesis and tumor venous invasion in tissues of colorectal cancer. Dig Dis Sci. 2009;54:1108–14.PubMedCrossRefGoogle Scholar
  36. 36.
    Girroir EE, Hollingshead HE, He P, Zhu B, Perdew GH, Peters JM. Quantitative expression patterns of peroxisome proliferator-activated receptor-β (PPAR β) protein in mice. BBRC. 2008;371:456–61.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Japan 2013

Authors and Affiliations

  • Jin Zhou
    • 1
  • Lie Yang
    • 1
  • Yuan Li
    • 1
  • Gunnar Arbman
    • 2
  • Ke-Ling Chen
    • 1
  • Bin Zhou
    • 1
  • Yong-Yang Yu
    • 1
  • Cun Wang
    • 1
  • Xian-Ming Mo
    • 3
  • You Lu
    • 4
  • Zong-Guang Zhou
    • 1
  • Xiao-Feng Sun
    • 1
    • 5
  1. 1.Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
  2. 2.Department of SurgeryVrinnevi HospitalNorrköpingSweden
  3. 3.Laboratory of Stem Cell Biology and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
  4. 4.Department of Oncology, West China HospitalSichuan UniversityChengduChina
  5. 5.Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health SciencesLinköping University, Country Council of ÖstergötlandLinköpingSweden

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