[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

An Erratum to this article was published on 24 April 2013

Abstract

Hormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. A better understanding of the molecular mechanisms involved in HR should lead to more rational approaches to therapy. The role of IL-6/STAT3 signaling in the transition of HR with aggressive tumor behavior and its possible link with myeloid-derived suppressor cells (MDSCs) were identified. In the present study, murine prostate cancer cell line (TRAMP-C1) and a hormone-resistant cell sub-line (TRAMP-HR) were used. Changes in tumor growth, invasion ability, and the responsible pathway were investigated in vitro and in vivo. We also examined the role of IL-6 in HR tumor progression and the recruitment of MDSCs. As seen in both in vitro and in vivo experiments, HR had aggressive tumor growth compared to TRAMP-C1. From mRNA and protein analysis, a higher expression of IL-6 associated with a more activated STAT3 was noted in HR tumor. When IL-6 signaling in prostate cancer was blocked, aggressive tumor behavior could be overcome. The underlying changes included decreased cell proliferation, less epithelial–mesenchymal transition, and decreased STAT3 activation. In addition to tumor progression, circulating IL-6 levels were significantly correlated with MDSC recruitment in vivo. Inhibition of IL-6 abrogated the recruitment of MDSCs in tumor- bearing mice, associated with slower tumor growth and attenuated angiogenesis. In conclusion, altered IL-6/STAT3 signaling is crucial in HR transition, aggressive behavior, and MDSC recruitment. These findings provide evidence for therapeutically targeting IL-6 signaling in prostate cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

HR:

Hormone-resistant

HS:

Hormone-sensitive

MDSCs:

Myeloid-derived suppressor cells

AR:

Androgen receptor

EMT:

Epithelial–mesenchymal transition

VEGF:

Vascular endothelial growth factor

WBI:

Whole-body irradiation

LI:

Local irradiation

RT:

Irradiation

References

  1. Craft N, Chhor C, Tran C, Belldegrun A, DeKernion J, Witte ON, Said J, Reiter RE, Sawyers CL (1999) Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process. Cancer Res 59:5030–5036

    CAS  PubMed  Google Scholar 

  2. Wu CT, Chen WC, Liao SK, Hsu CL, Lee KD, Chen MF (2007) The radiation response of hormone-resistant prostate cancer induced by long-term hormone therapy. Endocr Relat Cancer 14:633–643

    Article  CAS  PubMed  Google Scholar 

  3. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10:33–39

    Article  PubMed  Google Scholar 

  4. Edwards J, Bartlett JM (2005) The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 1: Modifications to the androgen receptor. BJU Int 95:1320–1326

    Article  CAS  PubMed  Google Scholar 

  5. Kinkade CW, Castillo-Martin M, Puzio-Kuter A, Yan J, Foster TH, Gao H, Sun Y, Ouyang X, Gerald WL, Cordon-Cardo C et al (2008) Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 118:3051–3064

    CAS  PubMed  Google Scholar 

  6. Chen MF, Chen WC, Chang YJ, Wu CF, Wu CT (2010) Role of DNA methyltransferase 1 in hormone-resistant prostate cancer. J Mol Med (Berl) 88:953–962

    Article  CAS  Google Scholar 

  7. Kishimoto T (2005) Interleukin-6: from basic science to medicine—40 years in immunology. Annu Rev Immunol 23:1–21

    Article  CAS  PubMed  Google Scholar 

  8. Schafer ZT, Brugge JS (2007) IL-6 involvement in epithelial cancers. J Clin Invest 117:3660–3663

    Article  CAS  PubMed  Google Scholar 

  9. Culig Z, Steiner H, Bartsch G, Hobisch A (2005) Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem 95:497–505

    Article  CAS  PubMed  Google Scholar 

  10. Chen CC, Chen WC, Lu CH, Wang WH, Lin PY, Lee KD, Chen MF (2010) Significance of interleukin-6 signaling in the resistance of pharyngeal cancer to irradiation and the epidermal growth factor receptor inhibitor. Int J Radiat Oncol Biol Phys 76:1214–1224

    Article  CAS  PubMed  Google Scholar 

  11. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  CAS  PubMed  Google Scholar 

  12. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545

    Article  CAS  PubMed  Google Scholar 

  13. Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (2006) Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol 176:284–290

    CAS  PubMed  Google Scholar 

  14. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM (2005) Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11:6713–6721

    Article  CAS  PubMed  Google Scholar 

  15. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174

    Article  CAS  PubMed  Google Scholar 

  16. Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI (2004) Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 172:989–999

    CAS  PubMed  Google Scholar 

  17. Malinowska K, Neuwirt H, Cavarretta IT, Bektic J, Steiner H, Dietrich H, Moser PL, Fuchs D, Hobisch A, Culig Z (2009) Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer 16:155–169

    Article  CAS  PubMed  Google Scholar 

  18. Kozin SV, Kamoun WS, Huang Y, Dawson MR, Jain RK, Duda DG (2010) Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res 70:5679–5685

    Article  CAS  PubMed  Google Scholar 

  19. Seung LP, Weichselbaum RR, Toledano A, Schreiber K, Schreiber H (1996) Radiation can inhibit tumor growth indirectly while depleting circulating leukocytes. Radiat Res 146:612–618

    Article  CAS  PubMed  Google Scholar 

  20. Levy DE, Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662

    Article  CAS  PubMed  Google Scholar 

  21. Rose-John S, Waetzig GH, Scheller J, Grotzinger J, Seegert D (2007) The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opin Ther Targets 11:613–624

    Article  CAS  PubMed  Google Scholar 

  22. Culig Z, Puhr M (2011) Interleukin-6: a multifunctional targetable cytokine in human prostate cancer. Mol Cell Endocrinol. doi:10.1016/j.mce.2011.05.033

  23. Wallner L, Dai J, Escara-Wilke J, Zhang J, Yao Z, Lu Y, Trikha M, Nemeth JA, Zaki MH, Keller ET (2006) Inhibition of interleukin-6 with CNTO328, an anti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent prostate cancer to an androgen-independent phenotype in orchiectomized mice. Cancer Res 66:3087–3095

    Article  CAS  PubMed  Google Scholar 

  24. Karkera J, Steiner H, Li W, Skradski V, Moser PL, Riethdorf S, Reddy M, Puchalski T, Safer K, Prabhakar U et al (2011) The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. Prostate 71:1455–1465

    Article  CAS  PubMed  Google Scholar 

  25. Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454

    Article  CAS  PubMed  Google Scholar 

  26. Fizazi K, De Bono JS, Flechon A, Heidenreich A, Voog E, Davis NB, Qi M, Bandekar R, Vermeulen JT, Cornfeld M et al (2012) Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur J Cancer 48:85–93

    Article  CAS  PubMed  Google Scholar 

  27. Shariat SF, Kattan MW, Traxel E, Andrews B, Zhu K, Wheeler TM, Slawin KM (2004) 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 10:1992–1999

    Article  CAS  PubMed  Google Scholar 

  28. George DJ, Halabi S, Shepard TF, Sanford B, Vogelzang NJ, Small EJ, Kantoff PW (2005) The prognostic significance of plasma interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from Cancer and Leukemia Group B 9480. Clin Cancer Res 11:1815–1820

    Article  CAS  PubMed  Google Scholar 

  29. Kao J, Ko EC, Eisenstein S, Sikora AG, Fu S, Chen SH (2011) Targeting immune suppressing myeloid-derived suppressor cells in oncology. Crit Rev Oncol Hematol 77:12–19

    Article  PubMed  Google Scholar 

  30. Kusmartsev S, Gabrilovich DI (2002) Immature myeloid cells and cancer-associated immune suppression. Cancer Immunol Immunother 51:293–298

    Article  CAS  PubMed  Google Scholar 

  31. Menetrier-Caux C, Montmain G, Dieu MC, Bain C, Favrot MC, Caux C, Blay JY (1998) Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood 92:4778–4791

    CAS  PubMed  Google Scholar 

  32. Ahn GO, Tseng D, Liao CH, Dorie MJ, Czechowicz A, Brown JM (2010) Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc Natl Acad Sci USA 107:8363–8368

    Article  CAS  PubMed  Google Scholar 

  33. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian LM, Carbone DP, Lin PC (2004) Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6:409–421

    Article  CAS  PubMed  Google Scholar 

  34. Sharma S, Sharma MC, Sarkar C (2005) Morphology of angiogenesis in human cancer: a conceptual overview, histoprognostic perspective and significance of neoangiogenesis. Histopathology 46:481–489

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by grants from the National Science Council (grants 97-2314-B-182A-079-MY3) and CMRPG 290041.

Competing interests

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

Author information

Authors and Affiliations

  1. Department of Urology, Chang Gung Memorial Hospital, Keelung, Taiwan

    Chun-Te Wu & Cheng-Chia Lin

  2. College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Chun-Te Wu, Ching-Chuan Hsieh, Wen-Cheng Chen, Ji-Hong Hong & Miao-Fen Chen

  3. Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan

    Ching-Chuan Hsieh

  4. Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan

    Wen-Cheng Chen & Miao-Fen Chen

  5. Department of Radiation Oncology, Chung Gung Memorial Hospital, Linkou, Taiwan

    Ji-Hong Hong

Authors
  1. Chun-Te Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ching-Chuan Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cheng-Chia Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-Cheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ji-Hong Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Miao-Fen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Miao-Fen Chen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 1531 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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 90, 1343–1355 (2012). https://doi.org/10.1007/s00109-012-0916-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-012-0916-x

Keywords

Search

Navigation