Granulocyte macrophage colony‑stimulating factor as a predictor of the response of metastatic renal cell carcinoma 
to tyrosine kinase inhibitor therapy

Yamada,Daisuke; Matsushita,Hirokazu; Azuma,Takeshi; Nakagawa,Tohru; Nagata,Masayoshi; Yamada,Yukio; Suzuki,Motofumi; Fujimura,Tetsuya; Fukuhara,Hiroshi; Kume,Haruki; Homma,Yukio; Kakimi,Kazuhiro

doi:10.3892/mco.2014.360

November-December 2014 Volume 2 Issue 6

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

November-December 2014 Volume 2 Issue 6

Full Size Image

Article

Granulocyte macrophage colony‑stimulating factor as a predictor of the response of metastatic renal cell carcinoma to tyrosine kinase inhibitor therapy

Authors:
- Daisuke Yamada
- Hirokazu Matsushita
- Takeshi Azuma
- Tohru Nakagawa
- Masayoshi Nagata
- Yukio Yamada
- Motofumi Suzuki
- Tetsuya Fujimura
- Hiroshi Fukuhara
- Haruki Kume
- Yukio Homma
- Kazuhiro Kakimi
View Affiliations / Copyright

Affiliations: Department of Urology, Chibanishi General Hospital, Matsudo, Chiba 270‑2251, Japan, Department of Immunotherapeutics, University of Tokyo Hospital, Tokyo 113‑8655, Japan, Department of Urology, University of Tokyo Hospital, Tokyo 113‑8655, Japan, Department of Urology, National Center for Global Health and Medicine, Tokyo 162‑8655, Japan
Pages: 1023-1027
|
Published online on: July 29, 2014

https://doi.org/10.3892/mco.2014.360
Expand metrics +

Abstract

This prospective study was conducted to identify predictive markers for the response of metastatic renal cell carcinoma (RCC) to tyrosine kinase inhibitors (TKIs). Patients with histologically proven RCC with at least one measurable metastatic lesion were enrolled in this study. Blood samples were collected prior to treatment and the plasma levels of 27 cytokines were measured. Tumor response was assessed 8‑12 weeks after the initiation of TKI treatment. A total of 13 patients (11 men and 2 women) with a median age of 63 years received sunitinib (8 cases), sorafenib (1 case), or axitinib (4 cases). Partial response (PR) was achieved in 5 patients (38%), stable disease (SD) in 4 (30%) and progressive disease (PD) was noted in 4 (30%). The plasma granulocyte macrophage colony‑stimulating factor (GM‑CSF) level in PR cases was significantly higher compared to that in SD or PD cases (P=0.012). Therefore, GM‑CSF may be a predictive biomarker of the response of RCC to TKI treatment, suggesting that TKIs may exert clinical effects not only through suppression of the vascular endothelial growth factor, but also through immune system modulation.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar
2	Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 356:115–124. 2007. View Article : Google Scholar : PubMed/NCBI
3	Escudier B, Eisen T, Stadler WM, et al; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 356:125–134. 2007. View Article : Google Scholar : PubMed/NCBI
4	Shoji S, Nakano M, Sato H, Tang XY, Osamura YR, Terachi T, Uchida T and Takeya K: The current status of tailor-made medicine with molecular biomarkers for patients with clear cell renal cell carcinoma. Clin Exp Metastasis. 31:111–134. 2013. View Article : Google Scholar : PubMed/NCBI
5	Deprimo SE, Bello CL, Smeraglia J, Baum CM, Spinella D, Rini BI, Michaelson MD and Motzer RJ: Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med. 5:322007. View Article : Google Scholar : PubMed/NCBI
6	Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, Figlin RA, Baum MS and Motzer RJ: Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 103:763–773. 2011. View Article : Google Scholar
7	Clemons J, Gao D, Naam M, Breaker K, Garfield D and Flaig TW: Thyroid dysfunction in patients treated with sunitinib or sorafenib. Clin Genitourin Cancer. 10:225–231. 2012. View Article : Google Scholar : PubMed/NCBI
8	Wongkajornsilp A, Wamanuttajinda V, Kasetsinsombat K, Duangsa-ard S, Sa-ngiamsuntorn K, Hongeng S and Maneechotesuwan K: Sunitinib indirectly enhanced anti-tumor cytotoxicity of cytokine-induced killer cells and CD3⁺CD56⁺ subset through the co-culturing dendritic cells. PLoS One. 8:e789802013. View Article : Google Scholar : PubMed/NCBI
9	Gu Y, Zhao W, Meng F, Qu B, Zhu X, Sun Y, Shu Y and Xu Q: Sunitinib impairs the proliferation and function of human peripheral T cell and prevents T-cell-mediated immune response in mice. Clin Immunol. 135:55–62. 2010. View Article : Google Scholar : PubMed/NCBI
10	Adotevi O, Pere H, Ravel P, et al: A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother. 33:991–998. 2010. View Article : Google Scholar
11	Rini BI, Escudier B, Tomczak P, et al: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 378:1931–1939. 2011. View Article : Google Scholar : PubMed/NCBI
12	Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar
13	Lawicki S, Bedkowska GE, Gacuta-Szumarska E, Knapp P and Szmitkowski M: Pretreatment plasma levels and diagnostic utility of hematopoietic cytokines in cervical cancer or cervical intraepithelial neoplasia patients. Folia Histochem Cytobiol. 50:213–219. 2012. View Article : Google Scholar
14	Biancotto A, Wank A, Perl S, Cook W, Olnes MJ, Dagur PK, Fuchs JC, Langweiler M, Wang E and McCoy JP: Baseline levels and temporal stability of 27 multiplexed serum cytokine concentrations in healthy subjects. PLoS One. 8:e760912013. View Article : Google Scholar : PubMed/NCBI
15	Dolcetti L, Peranzoni E, Ugel S, et al: Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol. 40:22–35. 2010. View Article : Google Scholar : PubMed/NCBI
16	Serafini P, Mgebroff S, Noonan K and Borrello I: Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res. 68:5439–5449. 2008. View Article : Google Scholar : PubMed/NCBI
17	Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, Herber DL, Schneck J and Gabrilovich DI: Altered recognition of antigen is a mechanism of CD8⁺ T cell tolerance in cancer. Nat Med. 13:828–835. 2007. View Article : Google Scholar : PubMed/NCBI
18	Xin H, Zhang C, Herrmann A, Du Y, Figlin R and Yu H: Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res. 69:2506–2513. 2009. View Article : Google Scholar : PubMed/NCBI
19	Wang Y, Han G, Wang K, et al: Tumor-derived GM-CSF promotes inflammatory colon carcinogenesis via stimulating epithelial release of VEGF. Cancer Res. 74:716–726. 2014. View Article : Google Scholar : PubMed/NCBI
20	Tran HT, Liu Y, Zurita AJ, et al: Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 13:827–837. 2012. View Article : Google Scholar