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

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An Editorial to this article was published on 26 November 2013

Abstract

Objective

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.

Design

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.

Results

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.

Conclusions

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

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References

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  3. Desvergne B, Michalik L, Wahli W. Transcriptional regulation of metabolism. Physiol Rev. 2006;86:465–514.

    Article  CAS  PubMed  Google Scholar 

  4. Kostadinova R, Wahli W, Michalik L. PPARs in diseases: control mechanisms of inflammation. Curr Med Chem. 2005;12:2995–3009.

    Article  CAS  PubMed  Google Scholar 

  5. Kilgore KS, Billin AN. PPARβ/δ ligands as modulators of the inflammatory response. Curr Opin Investig Drugs. 2008;9:463–9.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  19. Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438:932–6.

    Article  CAS  PubMed  Google Scholar 

  20. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353–64.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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. 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. 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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Natural Science Foundation of China (Grant No. 30801332), the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 200806100058), the Foundation for the Author of National Excellent Doctoral Dissertation of PR China (No. 2007B66), and the Swedish Cancer Foundation, Swedish Research Council and the Health Research Council in the South-East of Sweden.

Conflict of interest

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 and Xiao-Feng Sun declare no conflicts of interest relevant to this manuscript.

Author information

Authors and Affiliations

  1. Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Jin Zhou, Lie Yang, Yuan Li, Ke-Ling Chen, Bin Zhou, Yong-Yang Yu, Cun Wang, Zong-Guang Zhou & Xiao-Feng Sun

  2. Department of Surgery, Vrinnevi Hospital, Norrköping, Sweden

    Gunnar Arbman

  3. Laboratory of Stem Cell Biology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Xian-Ming Mo

  4. Department of Oncology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    You Lu

  5. Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Country Council of Östergötland, Linköping, Sweden

    Xiao-Feng Sun

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  1. Jin Zhou
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  2. Lie Yang
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Corresponding authors

Correspondence to Zong-Guang Zhou or Xiao-Feng Sun.

Additional information

J. Zhou and L. Yang contributed equally to this study.

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Zhou, J., Yang, L., Li, Y. et al. The prognostic significance of peroxisome proliferator-activated receptor β expression in the vascular endothelial cells of colorectal cancer. J Gastroenterol 49, 436–445 (2014). https://doi.org/10.1007/s00535-013-0845-7

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  • DOI: https://doi.org/10.1007/s00535-013-0845-7

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