Abstract
The mTOR/p70S6K signal transduction pathway plays a key role in the regulation of cancer cells’ survival and proliferation. However, its roles in osteosarcoma, which is one of the most rapidly growing sarcomas, remain unknown. This study investigated for the first time the correlation between the mTOR/p70S6K signal transduction pathway in human osteosarcoma and patients’ prognosis. The expression patterns of mTOR and p70S6K in paraffin-embedded specimens gathered from 65 patients with primary osteosarcoma were detected by the method of immunohistochemistry using antibodies against mTOR and p70S6K. Kaplan–Meier survival and Cox regression analyses were performed to evaluate the prognosis of patients. Immunostaining revealed that the mTOR/p70S6K signal transduction pathway is activated in human osteosarcoma. Additionally, positive expression of mTOR and p70S6K proteins was significantly correlated with surgical stage, metastasis pattern and percentage of dead cells of osteosarcoma. Moreover, in univariate analysis, surgical stage, metastasis pattern and percentage of dead cells, mTOR and p70S6K expression showed significant influence on overall survival (OS) and disease-free survival (DFS). In multivariate analysis, surgical stage (IIA vs. IIB/III), metastasis pattern (without vs. with), percentage of dead cells (≥90 vs. <90%), mTOR expression pattern (negative vs. positive) and p70S6K expression pattern (negative vs. positive) were significant for DFS and OS. Our results demonstrate the correlation of mTOR and p70S6K expression patterns with the oncological progression of osteosarcoma patients, suggesting the prognostic significance of the mTOR/p70S6K signal transduction pathway in osteosarcoma patients, which may lay a foundation for making further investigations on the mTOR/p70S6K signal transduction pathway as a potential target for osteosarcoma therapy.
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Abbreviations
- mTOR:
-
Mammalian target of rapamycin
- p70S6K:
-
p70 S6 kinase
References
Longhi A, Errani C, De Paolis M. Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treat Rev. 2006;32:423–36.
Chou AJ, Gorlick R. Chemotherapy resistance in osteosarcoma: current challenges and future directions. Expert Rev Anticancer Ther. 2006;6:1075–85.
Ek ETH, Ojaimi J, Kitagawa Y, Choong PFM. Outcome of patients with osteosarcoma over 40 years of age: is angiogenesis a marker of survival? Int Semin Surg Oncol. 2006;3:7–18.
Huang J, Zhu B, Lu L, Lian Z, Wang Y, Yang X, et al. The expression of novel gene URG4 in osteosarcoma: correlation with patients’ prognosis. Pathology. 2009;41:149–54.
Zhou Q, Zhu Y, Deng Z, Long H, Zhang S, Chen X. VEGF and EMMPRIN expression correlates with survival of patients with osteosarcoma. Surg Oncol. 2009. doi:10.1016/j.suronc.2009.09.002.
Osaka E, Suzuki T, Osaka S, Yoshida Y, Sugita H, Asami S, et al. Survivin as a prognostic factor for osteosarcoma patient. Acta Histochem Cytochem. 2006;39:95–100.
Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2005;37:19–24.
Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med. 2005;11:353–61.
Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol. 2005;17:158–66.
Law BK. Rapamycin: an anti-cancer immunosuppressant? Crit Rev Oncol Hematol. 2005;56:47–60.
Couch FJ, et al. Localization of PS6 K to chromosomal region 17q23 and determination of its amplification in breast cancer. Cancer Res. 1999;59:1408–11.
Liu L, et al. Rapamycin inhibits cell motility by suppression of mTOR mediated S6K1 and 4EBP1 pathways. Oncogene. 2006;25:7029–40.
Bärlund M, et al. Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis. J Natl Cancer Inst. 2000;92:1252–9.
Heinonen H, Nieminen A, Saarela M, Kallioniemi A, Klefström J, Hautaniemi S, et al. Deciphering downstream gene targets of PI3K/mTOR/p70S6K pathway in breast cancer. BMC Genomics. 2008;9:348–59.
Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res. 1980;153:106–20.
Salzer-Kuntschik M, Delling G, Beron G, Sigmund R. Morphological grades of regression in osteosarcoma after polychemotherapy-study COSS 80. J Cancer Res Clin Oncol. 1983;106(Suppl):21–4.
Pantuck AJ, Seligson DB, Klatte T. Prognostic relevance of the mTOR pathway in renal cell carcinoma. Cancer. 2007;109:2257–67.
Kreuter M, Bieker R, Bielack SS. Prognostic relevance of increased angiogenesis in osteosarcoma. Clin Cancer Res. 2004;10:8531–7.
Kaya M, Wada T, Kawaguchi S. Increased pretherapeutic serum vascular endothelial growth factor in patients with early clinical relapse of osteosarcoma. Br J Cancer. 2002;86:864–9.
Workman P. Inhibiting the phosphoinositide 3-kinase pathway for cancer treatment. Biochem Soc Trans. 2004;32:393–6.
Granville CA, Memmot RM, Gills JJ, Dennis PA. Handicapping the race to develop inhibitors of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway. Clin Cancer Res. 2006;12:679–89.
Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science. 2001;294:1942–5.
Mungamuri SK, Yang XH, Thor AD, Somasundaram K. Survival signaling by notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res. 2006;66:4715–24.
Majumder PK, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med. 2004;10:594–601.
Morgensztern D, McLeod HL. Mcleod. PI3 K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drugs. 2005;16:797–803.
Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ. p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci USA. 2001;98:9666–70.
Beevers CS, Li F, Liu L, Huang S. Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells. Int J Cancer. 2006;119:757–64.
Hou G, Xue L, Lu Z, Fan T, Tian F, Xue Y. An activated mTOR/p70S6K signaling pathway in esophageal squamous cell carcinoma cell lines and inhibition of the pathway by rapamycin and siRNA against mTOR. Cancer Lett. 2007;253:236–48.
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This study was supported by Hunan Provincial Natural Science Foundation.
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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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Zhou, Q., Deng, Z., Zhu, Y. et al. mTOR/p70S6K Signal transduction pathway contributes to osteosarcoma progression and patients’ prognosis. Med Oncol 27, 1239–1245 (2010). https://doi.org/10.1007/s12032-009-9365-y
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DOI: https://doi.org/10.1007/s12032-009-9365-y