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Targeted Oncology

, Volume 13, Issue 3, pp 371–378 | Cite as

Association of Expression Levels or Activation Status of STAT3 with Treatment Outcomes of Sunitinib in Patients with Renal Cell Carcinoma

  • Kazuhiro Yamamoto
  • Takuto Hara
  • Tsutomu Nakagawa
  • Midori Hirai
  • Hideaki Miyake
  • Masato Fujisawa
  • Ikuko Yano
Original Research Article

Abstract

Background

The expression level of signal transducer and activator of transcription 3 (STAT3) in tumor cells is reported to associate with response to therapy and with survival time in various types of cancer.

Objective

This retrospective study aimed to elucidate the association of STAT3 expression in tumor cells with the therapeutic outcomes of sunitinib in patients with renal cell carcinoma (RCC).

Patients and Methods

Patients with metastatic RCC who received sunitinib therapy were enrolled in this study. All patients underwent nephrectomy for RCC, and nephrectomy specimens were stained for STAT3 and phosphorylated STAT3 (p-STAT3) by immunohistochemistry.

Results

We assessed 51 patients receiving sunitinib as a first-line therapy. STAT3 expression levels did not influence progression-free survival (PFS) and overall survival (OS); however, patients with p-STAT3-positive tumors exhibited significantly worse PFS compared with those with p-STAT3-negative tumors (log-rank test, P = 0.034). OS tended to be prolonged in patients with p-STAT3-negative tumors. Objective response rate or disease control rate based on the best overall response did not show a significant association with STAT3 or p-STAT3 expression. Univariate Cox proportional hazard regression analyses for clinical predictors revealed that p-STAT3 positivity significantly correlated with shorter PFS (hazard ratio [HR], 2.22, P = 0.041), whereas p-STAT3 expression was not related to the OS.

Conclusions

Activated STAT3 in tumor tissues shows a significant association with poor prognosis in patients with RCC who received sunitinib as a first-line therapy, and positive p-STAT3 expression could be a potential biomarker for refractoriness to sunitinib therapy.

Notes

Acknowledgements

The authors would like to thank Enago (www.enago.jp) for the English language review.

Compliance with Ethical Standards

Funding

This work was supported in part by a research grant from Kurozumi Medical Foundation.

Conflict of Interest

H. Miyake and M. Fujisawa have received lecture fees from Pfizer. K. Yamamoto, T. Hara, T. Nakagawa, M. Hirai, and I. Yano declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

References

  1. 1.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.  https://doi.org/10.1056/NEJMoa065044.CrossRefPubMedGoogle Scholar
  2. 2.
    Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1280–9.  https://doi.org/10.1200/jco.2008.19.3342.CrossRefPubMedGoogle Scholar
  3. 3.
    Motzer RJ, Jonasch E, Agarwal N, Bhayani S, Bro WP, Chang SS, et al. Kidney Cancer, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2017;15:804–34.  https://doi.org/10.6004/jnccn.2017.0100.CrossRefGoogle Scholar
  4. 4.
    Darnell JE Jr. STATs and gene regulation. Science. 1997;277:1630–5.  https://doi.org/10.1126/science.277.5332.1630.CrossRefPubMedGoogle Scholar
  5. 5.
    Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98:295–303.CrossRefPubMedGoogle Scholar
  6. 6.
    Wendt MK, Balanis N, Carlin CR, Schiemann WP. STAT3 and epithelial-mesenchymal transitions in carcinomas. JAKSTAT. 2014;3:e28975.  https://doi.org/10.4161/jkst.28975.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Yu H, Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer. 2004;4:97–105.  https://doi.org/10.1038/nrc1275.CrossRefPubMedGoogle Scholar
  8. 8.
    Anglesio MS, George J, Kulbe H, Friedlander M, Rischin D, Lemech C, et al. IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clin Cancer Res. 2011;17:2538–48.  https://doi.org/10.1158/1078-0432.ccr-10-3314.CrossRefPubMedGoogle Scholar
  9. 9.
    Bai L, Yang JC, Ok JH, Mack PC, Kung HJ, Evans CP. Simultaneous targeting of Src kinase and receptor tyrosine kinase results in synergistic inhibition of renal cell carcinoma proliferation and migration. Int J Cancer. 2012;130:2693–702.  https://doi.org/10.1002/ijc.26303.CrossRefPubMedGoogle Scholar
  10. 10.
    Xin H, Zhang C, Herrmann A, Du Y, Figlin R, Yu H. Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res. 2009;69:2506–13.  https://doi.org/10.1158/0008-5472.can-08-4323.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yang F, Jove V, Xin H, Hedvat M, Van Meter TE, Yu H. Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by inhibiting STAT3 and AKT signaling pathways. Mol Cancer Res. 2010;8:35–45.  https://doi.org/10.1158/1541-7786.mcr-09-0220.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zhang Y, Wang Q. Sunitinib reverse multidrug resistance in gastric cancer cells by modulating Stat3 and inhibiting P-gp function. Cell Biochem Biophys. 2013;67:575–81.  https://doi.org/10.1007/s12013-013-9544-5.CrossRefPubMedGoogle Scholar
  13. 13.
    Eto M, Kamba T, Miyake H, Fujisawa M, Kamai T, Uemura H, et al. STAT3 polymorphism can predict the response to interferon-alpha therapy in patients with metastatic renal cell carcinoma. Eur Urol. 2013;63:745–52.  https://doi.org/10.1016/j.eururo.2012.09.052.CrossRefPubMedGoogle Scholar
  14. 14.
    Ito N, Eto M, Nakamura E, Takahashi A, Tsukamoto T, Toma H, et al. STAT3 polymorphism predicts interferon-alfa response in patients with metastatic renal cell carcinoma. J Clin Oncol. 2007;25:2785–91.  https://doi.org/10.1200/jco.2006.09.8897.CrossRefPubMedGoogle Scholar
  15. 15.
    Yamamoto K, Ioroi T, Kanaya K, Shinomiya K, Komoto S, Hirata S, et al. STAT3 polymorphism rs4796793 may be a predictive factor of tumor response to multiple tyrosine kinase inhibitors in metastatic renal cell carcinoma in Japanese population. Med Oncol. 2016;33:24.  https://doi.org/10.1007/s12032-016-0733-0.CrossRefPubMedGoogle Scholar
  16. 16.
    Panse G, Leung CH, Ingram DR, Wani K, Torres KE, Lin H, et al. The role of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in peripheral nerve sheath tumours. Histopathology. 2017;70:946–53.  https://doi.org/10.1111/his.13154.CrossRefPubMedGoogle Scholar
  17. 17.
    Qin J, Yang B, Xu BQ, Smithc A, Xu L, Yuan JL, et al. Concurrent CD44s and STAT3 expression in human clear cell renal cellular carcinoma and its impact on survival. Int J Clin Exp Pathol. 2014;7:3235–44.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17:2530–40.  https://doi.org/10.1200/jco.1999.17.8.2530.CrossRefPubMedGoogle Scholar
  19. 19.
    Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289–96.CrossRefPubMedGoogle Scholar
  20. 20.
    Horiguchi A, Oya M, Shimada T, Uchida A, Marumo K, Murai M. Activation of signal transducer and activator of transcription 3 in renal cell carcinoma: a study of incidence and its association with pathological features and clinical outcome. J Urol. 2002;168:762–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Tam L, McGlynn LM, Traynor P, Mukherjee R, Bartlett JM, Edwards J. Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer. Br J Cancer. 2007;97:378–83.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kaminska K, Czarnecka AM, Escudier B, Lian F, Szczylik C. Interleukin-6 as an emerging regulator of renal cell cancer. Urol Oncol. 2015;33:476–85.  https://doi.org/10.1016/j.urolonc.2015.07.010.CrossRefPubMedGoogle Scholar
  23. 23.
    Hrab M, Olek-Hrab K, Antczak A, Kwias Z, Milecki T. Interleukin-6 (IL-6) and C-reactive protein (CRP) concentration prior to total nephrectomy are prognostic factors in localized renal cell carcinoma (RCC). Rep Pract Oncol Radiother. 2013;18:304–9.  https://doi.org/10.1016/j.rpor.2013.06.002.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Zhu Y, Liu H, Xu L, An H, Liu W, Liu Y, et al. p21-activated kinase 1 determines stem-like phenotype and sunitinib resistance via NF-kappaB/IL-6 activation in renal cell carcinoma. Cell Death Dis. 2015;6:e1637.  https://doi.org/10.1038/cddis.2015.2.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Piva F, Giulietti M, Santoni M, Occhipinti G, Scarpelli M, Lopez-Beltran A, et al. Epithelial to mesenchymal transition in renal cell carcinoma: implications for Cancer therapy. Mol Diagn Ther. 2016;20:111–7.  https://doi.org/10.1007/s40291-016-0192-5.CrossRefPubMedGoogle Scholar
  26. 26.
    Mizumoto A, Yamamoto K, Nakayama Y, Takara K, Nakagawa T, Hirano T, et al. Induction of epithelial-mesenchymal transition via activation of epidermal growth factor receptor contributes to Sunitinib resistance in human renal cell carcinoma cell lines. J Pharmacol Exp Ther. 2015;355:152–8.  https://doi.org/10.1124/jpet.115.226639.CrossRefPubMedGoogle Scholar
  27. 27.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584–90.  https://doi.org/10.1200/jco.2008.20.1293.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Uemura H, Shinohara N, Yuasa T, Tomita Y, Fujimoto H, Niwakawa M, et al. A phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma: insights into the treatment, efficacy and safety. Jpn J Clin Oncol. 2010;40:194–202.  https://doi.org/10.1093/jjco/hyp146.CrossRefPubMedGoogle Scholar
  29. 29.
    Tomita Y, Shinohara N, Yuasa T, Fujimoto H, Niwakawa M, Mugiya S, et al. Overall survival and updated results from a phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma. Jpn J Clin Oncol. 2010;40:1166–72.  https://doi.org/10.1093/jjco/hyq146.CrossRefPubMedGoogle Scholar
  30. 30.
    Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27:5794–9.  https://doi.org/10.1200/jco.2008.21.4809.CrossRefPubMedGoogle Scholar
  31. 31.
    Bamias A, Karadimou A, Lampaki S, Lainakis G, Malettou L, Timotheadou E, et al. Prognostic stratification of patients with advanced renal cell carcinoma treated with sunitinib: comparison with the memorial Sloan-Kettering prognostic factors model. BMC Cancer. 2010;10:45.  https://doi.org/10.1186/1471-2407-10-45.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, et al. Adjuvant Sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2017;  https://doi.org/10.1016/j.eururo.2017.09.008.
  33. 33.
    Park YH, Ku JH, Kwak C, Kim HH. Post-treatment neutrophil-to-lymphocyte ratio in predicting prognosis in patients with metastatic clear cell renal cell carcinoma receiving sunitinib as first line therapy. Springerplus. 2014;3:243.  https://doi.org/10.1186/2193-1801-3-243.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PharmacyKobe University HospitalKobeJapan
  2. 2.Division of UrologyKobe University Graduate School of MedicineKobeJapan
  3. 3.Division of Pharmaceutics, Department of Internal RelatedKobe University Graduate School of MedicineKobeJapan
  4. 4.Department of UrologyHamamatsu University School of MedicineShizuokaJapan

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