Annals of Surgical Oncology

, Volume 22, Supplement 3, pp 1587–1593 | Cite as

TGF Beta1 Expression Correlates with Survival and Tumor Aggressiveness of Prostate Cancer

  • Chun-Te Wu
  • Ying-Hsu Chang
  • Wei-Yu Lin
  • Wen-Cheng Chen
  • Miao-Fen Chen
Urologic Oncology



Although biopsy Gleason score and clinical stage can be used to inform treatment decisions for prostate cancer, identifying molecular markers of tumor aggressiveness could lead to a more tailored approaches to therapy. In the present study, we investigated the association of transforming growth factor (TGF)-β1 levels and various markers of tumor aggressiveness and explore some potential mechanisms underlying the associations.


We used human and murine prostate cancer cell lines and their respective hormone resistance sub-lines, in vitro and in vivo to examine the changes in tumor aggressiveness, as well as the pathway responsible for these changes. Furthermore, 105 prostate cancer biopsy specimens were analyzed to correlate the level of TGF-β1 with the clinical characteristics of patients.


Our data revealed that activated TGF-β1 signaling resulted in more aggressive tumor growth and augmented the epithelial–mesenchymal transition. Activated IL-6 signaling was associated with TGF-β1 levels and the aggressive tumor features noted in TGF-β1-positive prostate cancers in vitro and in vivo. Furthermore, the TGF-β1 levels significantly correlated with Tregs accumulation in vivo. The clinical data indicated that TGF-β1 immunoreactivity had a moderate positive correlation with IL-6 staining, advanced clinical stage, higher Gleason score, and pretreatment PSA in patients with prostate cancer.


TGF-β1 levels are significantly associated with aggressive prostate features. In vitro and in vivo alternations of TGF-β1 expression impacts tumor invasiveness, tumor growth rate and recruitment of immunosuppressive Treg cells in the tumor microenvironment. TGF-β1 expression may represent a clinical useful biomarker to guide prostate cancer treatment decisions.


Prostate Cancer Prostate Cancer Cell Gleason Score Hormone Resistance Aggressive Prostate Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The study was supported by National Science Council, Taiwan. Grant 101-2314-B-182-062-MY3.


There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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  1. 1.
    Murray NP, Reyes E, Tapia P, et al. Redefining micrometastasis in prostate cancer: a comparison of circulating prostate cells, bone marrow disseminated tumor cells and micrometastasis: implications in determining local or systemic treatment for biochemical failure after radical prostatectomy. Int J Mol Med. 2012;30:896–904.PubMedGoogle Scholar
  2. 2.
    National Comprehensive Cancer Network. Prostate Cancer (Version 1.2015). Accessed 23 June 2015.
  3. 3.
    Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Twillie DA, Eisenberger MA, Carducci MA, et al. Interleukin-6: a candidate mediator of human prostate cancer morbidity. Urology. 1995;45:542–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Drabsch Y, ten Dijke P. TGF-beta signalling and its role in cancer progression and metastasis. Cancer Metastasis Rev. 2012;31:553–68.PubMedCrossRefGoogle Scholar
  7. 7.
    Katsuno Y, Lamouille S, Derynck R. TGF-beta signaling and epithelial–mesenchymal transition in cancer progression. Curr Opin Oncol. 2013;25:76–84.PubMedCrossRefGoogle Scholar
  8. 8.
    Schroten C, Dits NF, Steyerberg EW, et al. The additional value of TGFbeta1 and IL-7 to predict the course of prostate cancer progression. Cancer Immunol Immunother. 2012;61:905–10.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Reis ST, Pontes-Júnior J, Antunes AA, et al. Tgf-β1 expression as a biomarker of poor prognosis in prostate cancer. Clinics (Sao Paulo). 2011;66:1143–7.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Cho KH, Jeong KJ, Shin SC, et al. STAT3 mediates TGF-beta1-induced TWIST1 expression and prostate cancer invasion. Cancer Lett. 2013;336:167–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Shariat SF, Kattan MW, Traxel E, et al. Association of pre-and postoperative plasma levels of transforming growth factor beta(1) and interleukin 6 and its soluble receptor with prostate cancer progression. Clin Cancer Res. 2004;10:1992–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Ivanovic V, Melman A, Davis-Joseph B, et al. Elevated plasma levels of TGF beta 1 in patients with invasive prostate cancer. Nat Med. 1995;1:282–4.PubMedCrossRefGoogle Scholar
  13. 13.
    Oleinika K, Nibbs RJ, Graham GJ, et al. Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol. 2013;171:36–45.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Tran DQ. TGF-beta: the sword, the wand, and the shield of FOXP3(+) regulatory T cells. J Mol Cell Biol. 2012;4:29–37.PubMedCrossRefGoogle Scholar
  15. 15.
    Wu CT, Chen MF, Chen WC, et al. The role of IL-6 in the radiation response of prostate cancer. Radiat Oncol. 2013;8:159.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009;19:128–39.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Yao Z, Fenoglio S, Gao DC, et al. TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc Natl Acad Sci USA. 2010;107:15535–40.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Chen MF, Wang WH, Lin PY, et al. Significance of the TGF-beta1/IL-6 axis in oral cancer. Clin Sci (Lond). 2012;122:459–72.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Wu CT, Hsieh CC, Lin CC, et al. Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells. J Mol Med (Berl). 2012;90:1343–55.PubMedCrossRefGoogle Scholar
  20. 20.
    Wu CT, Chen WC, Liao SK, et al. The radiation response of hormone-resistant prostate cancer induced by long-term hormone therapy. Endocr Relat Cancer. 2007;14:633–43.PubMedCrossRefGoogle Scholar
  21. 21.
    Hurwitz AA, Foster BA, Allison JP, et al. The TRAMP mouse as a model for prostate cancer. Curr Protoc Immunol. 2001;Chapter 20:Unit 20.5.Google Scholar
  22. 22.
    Miller AM, Lundberg K, Ozenci V, et al. CD4 + CD25 high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol. 2006;177:7398–405.PubMedCrossRefGoogle Scholar
  23. 23.
    Flammiger A, Weisbach L, Huland H, et al. High tissue density of FOXP3 + T cells is associated with clinical outcome in prostate cancer. Eur J Cancer. 2013;49:1273–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Cretney E, Kallies A, Nutt SL. Differentiation and function of Foxp3(+) effector regulatory T cells. Trends Immunol. 2013;34:74–80.PubMedCrossRefGoogle Scholar
  25. 25.
    Li MO, Flavell RA. TGF-beta, T-cell tolerance and immunotherapy of autoimmune diseases and cancer. Expert Rev Clin Immunol. 2006;2:257–65.PubMedCrossRefGoogle Scholar
  26. 26.
    Fuxe J, Karlsson MC. TGF-beta-induced epithelial–mesenchymal transition: a link between cancer and inflammation. Semin Cancer Biol. 2012;22:455–61.PubMedCrossRefGoogle Scholar
  27. 27.
    Thompson TC, Truong LD, Timme TL, et al. Transforming growth factor beta 1 as a biomarker for prostate cancer. J Cell Biochem Suppl. 1992;16H:54–61.PubMedCrossRefGoogle Scholar
  28. 28.
    Adler HL, McCurdy MA, Kattan MW, et al. Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J Urol. 1999;161:182–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Smith AL, Robin TP, Ford HL. Molecular pathways: targeting the TGF-beta pathway for cancer therapy. Clin Cancer Res. 2012;18:4514–21.PubMedCrossRefGoogle Scholar
  30. 30.
    Thiery JP, Acloque H, Huang RY, et al. Epithelial–mesenchymal transitions in development and disease. Cell. 2009;139:871–90.PubMedCrossRefGoogle Scholar
  31. 31.
    Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRefGoogle Scholar
  32. 32.
    Shiota M, Zardan A, Takeuchi A, et al. Clusterin mediates TGF-beta-induced epithelial–mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer Res. 2012;72:5261–72.PubMedCrossRefGoogle Scholar
  33. 33.
    Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927–39.PubMedCrossRefGoogle Scholar
  34. 34.
    Sharma S, Sharma MC, Sarkar C. Morphology of angiogenesis in human cancer: a conceptual overview, histoprognostic perspective and significance of neoangiogenesis. Histopathology. 2005;46:481–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Whiteside TL. What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol. 2012;22:327–34.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4 + CD25-naive T cells to CD4 + CD25 + regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198:1875–86.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Chiaverotti T, Couto SS, Donjacour A, et al. Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. Am J Pathol. 2008;172:236–46.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2015

Authors and Affiliations

  • Chun-Te Wu
    • 1
    • 2
  • Ying-Hsu Chang
    • 2
    • 3
  • Wei-Yu Lin
    • 2
    • 4
  • Wen-Cheng Chen
    • 2
    • 5
  • Miao-Fen Chen
    • 2
    • 5
  1. 1.Department of UrologyChang Gung Memorial Hospital at KeelungKeelungTaiwan
  2. 2.College of MedicineChang Gung UniversityTaoyuanTaiwan
  3. 3.Department of UrologyChang Gung Memorial Hospital at LinkoLinkoTaiwan
  4. 4.Department of UrologyChang Gung Memorial Hospital at ChiayiChiayiTaiwan
  5. 5.Department of Radiation OncologyChang Gung Memorial Hospital at ChiayiChiayiTaiwan

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