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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Clinicopathological and prognostic significance of mTOR and phosphorylated mTOR expression in patients with esophageal squamous cell carcinoma: a systematic review and meta-analysis

Authors: Shuangjiang Li, Zhiqiang Wang, Jian Huang, Shan Cheng, Heng Du, Guowei Che, Yong Peng

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase responsible for regulating ribosomal biogenesis and protein synthesis. Dysregulation of mTOR contributes to tumorigenesis, angiogenesis, cellular growth and metastasis but its roles in esophageal squamous cell carcinoma (ESCC) are controversial. Therefore, the objective of this study is to evaluate the prognostic and clinicopathological significance of mTOR/p-mTOR expression in ESCC.

Methods

Literature retrieval was conducted by searching PubMed, EMBASE and the Web of Science for full-text papers that met our eligibility criteria. Odds ratio (OR) and hazard ratio (HR) with 95 % confidence interval (CI) served as the appropriate summarized statistics for assessments of clinicopathological and prognostic significance, respectively. Cochrane Q-test and I2-statistic were adopted to estimate the heterogeneity level between studies. Potential publication bias was detected by Begg’s test and Egger’s test.

Results

A total of 915 ESCC patients from nine original articles were included into this meta-analysis. The pooled analyses suggested that mTOR/p-mTOR expression was significantly correlated with the unfavorable outcomes of differentiation degree (OR: 2.63; 95 % CI: 1.71–4.05; P = 0.001), tumor invasion (OR: 1.48; 95 % CI: 1.02–2.13; P = 0.037), TNM stage (OR: 2.25; 95 % CI: 1.05–4.82; P = 0.037) and lymph node metastasis (OR: 1.82; 95 % CI: 1.06–3.11; P = 0.029), but had no significant relationship to the genders (OR: 0.81; 95 % CI: 0.50–1.32; P = 0.396). Moreover, mTOR/p-mTOR expression could independently predict the worse overall survival (HR: 2.04; 95 % CI: 1.58–2.62; P < 0.001), disease-free survival (HR: 2.39; 95 % CI: 1.64–3.49; P < 0.001) and cancer-specific survival (HR: 1.62; 95 % CI: 1.18–2.23; P = 0.003) of patients with ESCC. Such prognostic value of mTOR was not substantially altered by further subgroup analyses.

Conclusions

Positive expression of mTOR and p-mTOR was significantly associated with the unfavorable conditions on the depth of tumor invasion, TNM stage, differentiation degree and lymph node metastasis. mTOR and p-mTOR could serve as a valuable predictor for the poor prognosis of ESCC. More high-quality worldwide studies performing a multivariate analysis based on larger sample size are urgently required for further verifying and modifying our findings in the future.
Appendix
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Literature
1.
Wu J, Chen QX. Prognostic and predictive significance of tumor length in patients with esophageal squamous cell carcinoma undergoing radical resection. BMC Cancer. 2016;16:394.CrossRefPubMedPubMedCentral
2.
Chen W, He Y, Zheng R, Zhang S, Zeng H, Zou X, et al. Esophageal cancer incidence and mortality in China, 2009. J Thorac Dis. 2013;5(1):19–26.PubMedPubMedCentral
3.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.CrossRefPubMed
4.
Mariette C, Balon JM, Piessen G, Fabre S, Van Seuningen I, Triboulet JP. Pattern of recurrence following complete resection of esophageal carcinoma and factors predictive of recurrent disease. Cancer. 2003;97(7):1616–23.CrossRefPubMed
5.
Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009;27(30):5062–7.CrossRefPubMed
6.
Kuwano H, Nakajima M, Miyazaki T, Kato H. Distinctive clinicopathological characteristics in esophageal squamous cell carcinoma. Ann Thorac Cardiovasc Surg. 2003;9(1):6–13.PubMed
7.
Okur A, Kantarci M, Akgun M, Alper F, Cayir K, Koc M, et al. Unbiased estimation of tumor regression rates during chemoradiotherapy for esophageal carcinoma using CT and stereology. Dis Esophagus. 2005;18(2):114–9.CrossRefPubMed
8.
Smit JK, Pultrum BB, van Dullemen HM, Van Dam GM, Groen H, Plukker JT. Prognostic factors and patterns of recurrence in esophageal cancer assert arguments for extended two-field transthoracic esophagectomy. Am J Surg. 2010;200(4):446–53.CrossRefPubMed
9.
Doki Y, Ishikawa O, Takachi K, Miyashiro I, Sasaki Y, Ohigashi H, et al. Association of the primary tumor location with the site of tumor recurrence after curative resection of thoracic esophageal carcinoma. World J Surg. 2005;29(6):700–7.CrossRefPubMed
10.
Nakagawa S, Kanda T, Kosugi S, Ohashi M, Suzuki T, Hatakeyama K. Recurrence pattern of squamous cell carcinoma of the thoracic esophagus after extended radical esophagectomy with three-field lymphadenectomy. J Am Coll Surg. 2004;198(2):205–11.CrossRefPubMed
11.
12.
Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6(9):729–34.CrossRefPubMed
13.
Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006;441(7092):424–30.CrossRefPubMed
14.
Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N. mTOR, translation initiation and cancer. Oncogene. 2006;25(48):6416–22.CrossRefPubMed
15.
Witzens-Harig M, Memmer ML, Dreyling M, Hess G. A phase I/II trial to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor Temsirolimus added to standard therapy of Rituximab and DHAP for the treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma - the STORM trial. BMC Cancer. 2013;13:308.CrossRefPubMedPubMedCentral
16.
Heits N, Heinze T, Bernsmeier A, Kerber J, Hauser C, Becker T, et al. Influence of mTOR-inhibitors and mycophenolic acid on human cholangiocellular carcinoma and cancer associated fibroblasts. BMC Cancer. 2016;16:322.CrossRefPubMedPubMedCentral
17.
Nishikawa T, Takaoka M, Ohara T, Tomono Y, Hao H, Bao X, et al. Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice. Cancer Biol Ther. 2013;14(3):230–6.CrossRefPubMedPubMedCentral
18.
Li L, Liu D, Qiu ZX, Zhao S, Zhang L, Li WM. The prognostic role of mTOR and p-mTOR for survival in non-small cell lung cancer: a systematic review and meta-analysis. PLoS One. 2015;10(2):e0116771.CrossRefPubMedPubMedCentral
19.
Yu G, Wang J, Chen Y, Wang X, Pan J, Li G, et al. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer. Clin Cancer Res. 2009;15(5):1821–9.CrossRefPubMed
20.
Xiao L, Wang YC, Li WS, Du Y. The role of mTOR and phospho-p70S6K in pathogenesis and progression of gastric carcinomas: an immunohistochemical study on tissue microarray. J Exp Clin Cancer Res. 2009;28:152.CrossRefPubMedPubMedCentral
21.
Azim HA, Kassem L, Treilleux I, Wang Q, El Enein MA, Anis SE, et al. Analysis of PI3K/mTOR Pathway Biomarkers and Their Prognostic Value in Women with Hormone Receptor-Positive, HER2-Negative Early Breast Cancer. Transl Oncol. 2016;9(2):114–23.CrossRefPubMedPubMedCentral
22.
Wu S, Sun C, Tian D, Li Y, Gao X, He S, et al. Expression and clinical significances of Beclin1, LC3 and mTOR in colorectal cancer. Int J Clin Exp Pathol. 2015;8(4):3882–91.PubMedPubMedCentral
23.
Lu Q, Wang J, Yu G, Guo T, Hu C, Ren P. Expression and clinical significance of mammalian target of rapamycin/P70 ribosomal protein S6 kinase signaling pathway in human colorectal carcinoma tissue. Oncol Lett. 2015;10(1):277–82.PubMedPubMedCentral
24.
Li S, Kong Y, Si L, Chi Z, Cui C, Sheng X, et al. Phosphorylation of mTOR and S6RP predicts the efficacy of everolimus in patients with metastatic renal cell carcinoma. BMC Cancer. 2014;14:376.CrossRefPubMedPubMedCentral
25.
Li S, Lai Y, Fan J, Shen C, Che G. Clinicopathological and prognostic significance of Nestin expression in patients with non-small cell lung cancer: a systematic review and meta-analysis. Clin Exp Med. 2016 Apr 21. [Epub ahead of print]
26.
Wang L, Yu X, Li J, Zhang Z, Hou J, Li F. Prognostic significance of p53 expression in patients with esophageal cancer: a meta-analysis. BMC Cancer. 2016;16:373.CrossRefPubMedPubMedCentral
27.
Li S, Fan J, Liu J, Zhou J, Ren Y, Shen C, et al. Neoadjuvant therapy and risk of bronchopleural fistula after lung cancer surgery: a systematic meta-analysis of 14 912 patients. Jpn J Clin Oncol. 2016;46(6):534–46.CrossRefPubMed
28.
Jiang Y, Li W, He X, Zhang H, Jiang F, Chen Z. Lgr5 expression is a valuable prognostic factor for colorectal cancer: evidence from a meta-analysis. BMC Cancer. 2015;15:948.CrossRefPubMedPubMedCentral
29.
Li SJ, Fan J, Zhou J, Ren YT, Shen C, Che GW. Diabetes Mellitus and Risk of Bronchopleural Fistula After Pulmonary Resections: A Meta-Analysis. Ann Thorac Surg. 2016;102(1):328–39.CrossRefPubMed
30.
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.CrossRefPubMedPubMedCentral
31.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.CrossRefPubMed
32.
Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.​handbook.​cochrane.​org.
33.
Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17(24):2815–34.CrossRefPubMed
34.
Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.CrossRefPubMedPubMedCentral
35.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.CrossRefPubMed
36.
37.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.CrossRefPubMed
38.
Boone J, Ten Kate FJ, Offerhaus GJ, van Diest PJ, Rinkes IH, van Hillegersberg R. mTOR in squamous cell carcinoma of the oesophagus: a potential target for molecular therapy? J Clin Pathol. 2008;61(8):909–13.CrossRefPubMed
39.
Chen HZ, Li C, Li SL, Chen KS, Yang JP. Clinical pathological significance of mTOR and Cyclin D1 protein expression in esophageal squamous cell carcinoma. World Chin J Digestol. 2010;18(24):2533–7 (in Chinese).CrossRef
40.
Chuang WY, Chang YS, Chao YK, Yeh CJ, Ueng SH, Chang CY, et al. Phosphorylated mTOR expression correlates with podoplanin expression and high tumor grade in esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2015;8(10):12757–65.PubMedPubMedCentral
41.
Hirashima K, Baba Y, Watanabe M, Karashima R, Sato N, Imamura Y, et al. Phosphorylated mTOR expression is associated with poor prognosis for patients with esophageal squamous cell carcinoma. Ann Surg Oncol. 2010;17(9):2486–93.CrossRefPubMed
42.
Hou G, Yang S, Zhou Y, Wang C, Zhao W, Lu Z. Targeted inhibition of mTOR signaling improves sensitivity of esophageal squamous cell carcinoma cells to cisplatin. J Immunol Res. 2014;2014:845763.CrossRefPubMedPubMedCentral
43.
Kim SH, Chau GC, Jang YH, Lee SI, Pyo S, Um SH. Clinicopathologic significance and function of mammalian target of rapamycin activation in esophageal squamous cell carcinoma. Hum Pathol. 2013;44(2):226–36.CrossRefPubMed
44.
Li SH, Huang EY, Lu HI, Huang WT, Yen CC, Huang WC, et al. Phosphorylated mammalian target of rapamycin expression is associated with the response to chemoradiotherapy in patients with esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 2012;144(6):1352–9. 1359.e1.CrossRefPubMed
45.
Li SH, Chen CH, Lu HI, Huang WT, Tien WY, Lan YC, et al. Phosphorylated p70S6K expression is an independent prognosticator for patients with esophageal squamous cell carcinoma. Surgery. 2015;157(3):570–80.CrossRefPubMed
46.
Lu J, Pan Y, Xia X, Gu Y, Lei Y. Prognostic Significance of mTOR and PTEN in Patients with Esophageal Squamous Cell Carcinoma. Biomed Res Int. 2015;2015:417210.PubMedPubMedCentral
47.
Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science. 1991;253(5022):905–9.CrossRefPubMed
48.
Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol. 2005;16(4):525–37.CrossRefPubMed
49.
Keith CT, Schreiber SL. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science. 1995;270(5233):50–1.CrossRefPubMed
50.
51.
Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006;22(2):159–68.CrossRefPubMed
52.
53.
Adjei AA, Hidalgo M. Intracellular signal transduction pathway proteins as targets for cancer therapy. J Clin Oncol. 2005;23(23):5386–403.CrossRefPubMed
54.
Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115(5):577–90.CrossRefPubMed
55.
Rutter GA, Da Silva XG, Leclerc I. Roles of 5'-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem J. 2003;375(Pt 1):1–16.CrossRefPubMedPubMedCentral
56.
Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J. Amino acid sufficiency and mTOR regulate p70S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem. 1998;273(23):14484–94.CrossRefPubMed
57.
58.
Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5(8):671–88.CrossRefPubMed
59.
Sato T, Nakashima A, Guo L, Coffman K, Tamanoi F. Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer. Oncogene. 2010;29(18):2746–52.CrossRefPubMedPubMedCentral
60.
Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2005;37(1):19–24.CrossRefPubMed
61.
Rice TW, Rusch VW, Ishwaran H, Blackstone EH. Cancer of the esophagus and esophagogastric junction: data-driven staging for the seventh edition of the American Joint Committee on Cancer/International Union Against Cancer Cancer Staging Manuals. Cancer. 2010;116(16):3763–73.CrossRefPubMed
62.
Zhang J, Jiang Y, Wu C, Cai S, Wang R, Zhen Y, et al. Comparison of clinicopathologic features and survival between eastern and western population with esophageal squamous cell carcinoma. J Thorac Dis. 2015;7(10):1780–6.PubMedPubMedCentral
63.
Wang LD, Zhou FY, Li XM, Sun LD, Song X, Jin Y, et al. Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat Genet. 2010;42(9):759–63.CrossRefPubMed
Metadata
Title
Clinicopathological and prognostic significance of mTOR and phosphorylated mTOR expression in patients with esophageal squamous cell carcinoma: a systematic review and meta-analysis
Authors
Shuangjiang Li
Zhiqiang Wang
Jian Huang
Shan Cheng
Heng Du
Guowei Che
Yong Peng
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2940-7

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