Abstract
There are currently no accurate predictive markers of metachronous liver metastasis from colorectal cancer. Recent studies demonstrated that the expression patterns of sphingosine-1-phosphate receptor 1 (S1PR1) are altered in several tumors, but in colorectal cancer, the patterns remain unknown. Our study was designed to evaluate the expression and prognostic significance of S1PR1 protein in patients with colorectal cancer. The expression of S1PR1 was detected using the tissue microarray technique and immunohistochemical method and compared with clinicopathological parameters in 153 colorectal cancer patients. The prognostic value of S1PR1 expression was evaluated by Kaplan-Meier and Cox regression analysis. A molecular prognostic stratification scheme incorporating S1PR1 expression was determined by using receiver operating characteristic (ROC) analysis. S1PR1 was significantly highly expressed in 70.6 % (108/153) of the colorectal cancer lesions compared to their high expressions in only 5.9 % (9/153) of the adjacent non-cancerous tissues. Upregulated expression of S1PR1 was significantly associated with depth invasion and metachronous liver metastasis. Increased S1PR1 expression in colorectal cancer was positively correlated with poor overall survival. Multivariate survival analysis suggested that S1PR1 expression was an independent prognostic indicator for the disease. Applying the prognostic value of S1PR1 density to TNM stage system showed a better prognostic value in patients with colorectal cancer. Aberrant S1PR1 expression in colorectal cancer was associated with metachronous liver metastasis and worse survival outcome, and also, it was an independent prognostic factor. According to our analysis, combined TNM stage and intratumoral expression of S1PR1 demonstrated a better prognostic value than any of these two parameters alone. Conclusively, we suggest that detection and analysis of S1PR1 expression in colorectal cancer tissue might be used for predicting prognosis of colorectal cancer.
References
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.
Kobayashi H, Mochizuki H, Sugihara K, Morita T, Kotake K, Teramoto T, et al. Characteristics of recurrence and surveillance tools after curative resection for colorectal cancer: a multicenter study. Surgery. 2007;141:67–75.
Nagtegaal ID, Quirke P, Schmoll HJ. Has the new TNM classification for colorectal cancer improved care? Nat Rev Clin Oncol. 2012;9:119–23.
Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature. 2013;501:328–37.
Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell. 2012;21:283–96.
Spiegel S, Milstien S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol. 2011;11:403–15.
Arnon TI, Xu Y, Lo C, Pham T, An J, Coughlin S, et al. GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood. Science. 2011;333:1898–903.
Pyne NJ, Pyne S. Sphingosine 1-phosphate and cancer. Nat Rev Cancer. 2010;10:489–503.
Maceyka M, Harikumar KB, Milstien S, Spiegel S. Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol. 2012;22:50–60.
Kunkel GT, Maceyka M, Milstien S, Spiegel S. Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov. 2013;12:688–702.
Arnon TI, Horton RM, Grigorova IL, Cyster JG. Visualization of splenic marginal zone b-cell shuttling and follicular b-cell egress. Nature. 2013;493:684–8.
Chae SS, Paik JH, Furneaux H, Hla T. Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference. J Clin Invest. 2004;114:1082–9.
Visentin B, Vekich JA, Sibbald BJ, Cavalli AL, Moreno KM, Matteo RG, et al. Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell. 2006;9:225–38.
Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002;296:346–9.
Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on s1p receptor 1. Nature. 2004;427:355–60.
Lee H, Deng J, Kujawski M, Yang C, Liu Y, Herrmann A, et al. STAT3-induced s1pr1 expression is crucial for persistent STAT3 activation in tumors. Nat Med. 2010;16:1421–8.
Morikawa T, Baba Y, Yamauchi M, Kuchiba A, Nosho K, Shima K, et al. STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17:1452–62.
Sobin LH, Gospodarowicz MK, Wittekind C, International Union against Cancer. TNM classification of malignant tumours. 7th ed. Chichester, West Sussex, UK; Hoboken, NJ: Wiley-Blackwell; 2009.
Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26:2707–16.
Weichert W, Roske A, Niesporek S, Noske A, Buckendahl AC, Dietel M, et al. Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: Specific role of class i histone deacetylases in vitro and in vivo. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14:1669–77.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Statistics Subcommittee of the NCIEWGoCD: reporting recommendations for tumor marker prognostic studies. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23:9067–72.
Pritchard CC, Grady WM. Colorectal cancer molecular biology moves into clinical practice. Gut. 2011;60:116–29.
Yuan LW, Liu DC, Yang ZL. Correlation of S1P1 and ERp29 expression to progression, metastasis, and poor prognosis of gallbladder adenocarcinoma. Hepato Biliary Pancreat Dis Int HBPD INT. 2013;12:189–95.
Liu Y, Deng J, Wang L, Lee H, Armstrong B, Scuto A, et al. S1pr1 is an effective target to block STAT3 signaling in activated B cell-like diffuse large B-cell lymphoma. Blood. 2012;120:1458–65.
Nguyen AV, Wu YY, Liu Q, Wang D, Nguyen S, Loh R, et al. STAT3 in epithelial cells regulates inflammation and tumor progression to malignant state in colon. Neoplasia. 2013;15:998–1008.
Liang J, Nagahashi M, Kim EY, Harikumar KB, Yamada A, Huang WC, et al. Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell. 2013;23:107–20.
Deng J, Liu Y, Lee H, Herrmann A, Zhang W, Zhang C, et al. S1pr1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer Cell. 2012;21:642–54.
Priceman SJ, Shen S, Wang L, Deng J, Yue C, Kujawski M, et al. S1pr1 is crucial for accumulation of regulatory T cells in tumors via STAT3. Cell Rep. 2014;6:992–9.
Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12:253–68.
Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, et al. Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol. 2010;22:238–44.
Dolcetti L, Peranzoni E, Ugel S, Marigo I. Fernandez Gomez A, Mesa C, Geilich M, Winkels G, Traggiai E, Casati A, Grassi F, Bronte V: Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol. 2010;40:22–35.
Yu H, Pardoll D, Jove R. Stats in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9:798–809.
Kujawski M, Kortylewski M, Lee H, Herrmann A, Kay H, Yu H. STAT3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest. 2008;118:3367–77.
Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R. Immature immunosuppressive CD14 + HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res. 2010;70:4335–45.
Zhao L, Lim SY, Gordon-Weeks AN, Tapmeier TT, Im JH, Cao Y, et al. Recruitment of a myeloid cell subset (CD11B/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis. Hepatology. 2013;57:829–39.
Tye H, Kennedy CL, Najdovska M, McLeod L, McCormack W, Hughes N, et al. STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell. 2012;22:466–78.
Zhang L, Yang Z, Ma A, Qu Y, Xia S, Xu D, et al. Growth arrest and DNA damage 45G down-regulation contributes to Janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma. Hepatology. 2014;59:178–89.
Lappano R, Maggiolini M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov. 2011;10:47–60.
Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9:883–97.
Acknowledgments
This study was supported by the National Natural Science Foundation of China (81101566, 81272390, 81372315), the Shanghai Science and Technology Committee Project (13JC1401601, 134119a4800), the Shanghai Science and Technology Committee Talent Program (12XD1401900), and the Outstanding Academic Leaders Project of the Health System in Shanghai (XBR2011031).
Conflicts of interest
None
Author information
Authors and Affiliations
Corresponding author
Additional information
Qi Lin, Ye Wei, and Yunshi Zhong contributed equally to this work.
Rights and permissions
About this article
Cite this article
Lin, Q., Wei, Y., Zhong, Y. et al. Aberrant expression of sphingosine-1-phosphate receptor 1 correlates with metachronous liver metastasis and poor prognosis in colorectal cancer. Tumor Biol. 35, 9743–9750 (2014). https://doi.org/10.1007/s13277-014-2267-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-014-2267-4