Abstract
Osteosarcoma (OS) is the most common malignant bone tumor in patients under 20 years old. Studies have shown that cytokines play important roles in regulating immune responses in OS. In the current study, we investigated the effect of cytokines on OS by assessing serum cytokine profiles. Serum levels of 11 cytokines were measured by multiplex protein arrays in 58 patients with OS and 72 healthy controls. Results showed that serum levels of interleukin 1 receptor antagonist (IL-1Ra), IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α) were significantly increased in patients than in controls (2.5-fold, 2.4-fold, 2.7-fold, and 2.1-fold, respectively). When comparing the expression of cytokines in OS patients with different clinical parameters, cases with osteoblastic subtype revealed increased level of IL-6 than patients with other subtypes (p < 0.05); cases with metastasis demonstrated significantly higher level of TNF-α than those without metastasis (p < 0.05), whereas OS patients whose tumor size were bigger than 8 cm presented elevated levels of IL-8 and TNF-α than those with small tumor size (p < 0.05 and p < 0.05, respectively). These data indicated that IL-1Ra, IL-6, IL-8, and TNF-α were associated with increased risk of OS, in which IL-8 and TNF-α may be further correlated with the progression of this disease.
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Schwab JH, Springfield DS, Raskin KA, Mankin HJ, Hornicek FJ. What’s new in primary bone tumors. J Bone Joint Surg Am. 2012;94:1913–9.
Szuhai K, Cleton-Jansen AM, Hogendoorn PC, Bovée JV. Molecular pathology and its diagnostic use in bone tumors. Cancer Genet. 2012;205:193–204.
Arndt CA, Rose PS, Folpe AL, Laack NN. Common musculoskeletal tumors of childhood and adolescence. Mayo Clin Proc. 2012;87:475–87.
Goldszmid RS, Trinchieri G. The price of immunity. Nat Immunol. 2012;13:932–8.
Turtle CJ, Hudecek M, Jensen MC, Riddell SR. Engineered T cells for anti-cancer therapy. Curr Opin Immunol. 2012;24:633–97.
Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest. 2012;122:3476–89.
Oliphant CJ, Barlow JL, McKenzie AN. Insights into the initiation of type 2 immune responses. Immunology. 2011;134:378–85.
Haddad H, Rini BI. Current treatment considerations in metastatic renal cell carcinoma. Curr Treat Options Oncol. 2012;13:212–29.
Keyel PA, Tkacheva OA, Larregina AT, Salter RD. Coordinate stimulation of macrophages by microparticles and TLR ligands induces foam cell formation. J Immunol. 2012;189:4621–9.
Naugler WE, Karin M. The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med. 2008;14:109–19.
Jourdan M, Reme T, Goldschmidt H, Fiol G, Pantesco V, De Vos J, et al. Gene expression of anti- and pro-apoptotic proteins in malignant and normal plasma cells. Br J Haematol. 2009;145:45–58.
Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008;14:6735–41.
Zhou C, Shen Q, Xue J, Ji C, Chen J. Overexpression of TTRAP inhibits cell growth and induces apoptosis in osteosarcoma cells. BMB Rep. 2013;46:113–8.
Inoue T, Hagiyama M, Enoki E, Sakurai MA, Tan A, Wakayama T, et al. Cell adhesion molecule 1 is a new osteoblastic cell adhesion molecule and a diagnostic marker for osteosarcoma. Life Sci. 2013;92:91–9.
Shatz M, Menendez D, Resnick MA. The human TLR innate immune gene family is differentially influenced by DNA stress and p53 status in cancer cells. Cancer Res. 2012;72:3948–57.
Baumhoer D, Smida J, Zillmer S, Rosemann M, Atkinson MJ, Nelson PJ, et al. Strong expression of CXCL12 is associated with a favorable outcome in osteosarcoma. Mod Pathol. 2012;25:522–8.
Granowits E, Clark B, Mancilla J, Dinarello C. Interleukin-1 receptor antagonist competitively inhibits the binding of interleukin-1 to the type II interleukin-1 receptor. J Biol Chem. 1991;266:14147–50.
McIntyre KW, Stepan GJ, Kolinsky KD, Benjamin WR, Plocinski JM, Kaffka KL, et al. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med. 1991;173:931–9.
Dinarello CA. Reduction of inflammation by decreasing production of interleukin-1 or by specific receptor antagonism. Int J Tissue React. 1992;14:65–75.
Arend WP, Malyak M, Guthridge CJ, Gabay C. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol. 1998;16:27–55.
Hönicke AS, Ender SA, Radons J. Combined administration of EGCG and IL-1 receptor antagonist efficiently downregulates IL-1-induced tumorigenic factors in U-2 OS human osteosarcoma cells. Int J Oncol. 2012;41:753–8.
Eustace D, Han X, Gooding R, Rowbottom A, Riches P, Heyderman E. Interleukin-6 (IL-6) functions as an autocrine growth factor in cervical carcinomas in vitro. Gynecol Oncol. 1993;50:15–9.
Lu C, Kerbel RS. Interleukin-6 undergoes transition from paracrine growth inhibitor to autocrine stimulator during human melanoma progression. J Cell Biol. 1993;120:1281–8.
Culig Z, Steiner H, Bartsch G, Hobisch A. Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem. 2005;95:497–505.
Berek JS, Chung C, Kaldi K, Watson JM, Knox RM, Martinez-Maza O. Serum interleukin-6 levels correlate with disease status in patients with epithelial ovarian cancer. Am J Obstet Gynecol. 1991;164:1038–42.
Tang CH, Chen CF, Chen WM, Fong YC. IL-6 increases MMP-13 expression and motility in human chondrosarcoma cells. J Biol Chem. 2011;286:11056–66.
Lo CW, Chen MW, Hsiao M, Wang S, Chen CA, Hsiao SM, et al. IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer. Cancer Res. 2011;71:424–34.
Tzeng HE, Tsai CH, Chang ZL, Su CM, Wang SW, Hwang WL, et al. Interleukin-6 induces vascular endothelial growth factor expression and promotes angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma. Biochem Pharmacol. 2013;85:531–40.
Carbone M, Ly BH, Dodson RF, Pagano I, Morris PT, Dogan UA, et al. Malignant mesothelioma: facts, myths, and hypotheses. J Cell Physiol. 2012;227:44–58.
Cordero JB, Macagno JP, Stefanatos RK, Strathdee KE, Cagan RL, Vidal M. Oncogenic ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev Cell. 2010;18:999–1011.
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Hong Xiao and Ling Chen contributed equally to this work.
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Xiao, H., Chen, L., Luo, G. et al. Effect of the cytokine levels in serum on osteosarcoma. Tumor Biol. 35, 1023–1028 (2014). https://doi.org/10.1007/s13277-013-1136-x
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DOI: https://doi.org/10.1007/s13277-013-1136-x