Combined features based on MT1-MMP expression, CD11b + immunocytes density and LNR predict clinical outcomes of gastric cancer

Journal of Translational Medicine

Dai-Wen Pang²  Yan Li¹  Gui-Fang Yang³  Min Fang¹  Lin-Wei Wang¹  Chun-Wei Peng¹ 

[1] Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District Wuhan 430071, People’s Republic China;Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, and State Key Laboratory of Virology, Wuhan University, Wuhan, 430072, People’s Republic China;Department of Pathology, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District Wuhan, 430071, People’s Republic, China

关键词: Lymph node ratio;    Tumor microenvironment;    Prognosis;    Gastric cancer;   

Others  :  827360
DOI  :  10.1186/1479-5876-11-153

 received in 2013-01-29, accepted in 2013-06-13,  发布年份 2013

【 摘 要 】

Background

Given the complexity of tumor microenvironment, no single marker from cancer cells could adequately predict the clinical outcomes of gastric cancer (GC). The objective of this study was to evaluate the prognostic role of combined features including conventional pathology, proteinase and immune data in GC.

Methods

In addition to pathological studies, immunohistochemistry was used to assess membrane-type 1 matrix metalloproteinase (MT1-MMP) expression and CD11b + immunocytes density in three independent GC tissue microarrays containing 184 GC tissues. Separate and combined features were evaluated for their impact on overall survival (OS).

Results

We found that traditional factors including tumor size, histological grade, lymph node status, serosa invasion and TNM stage were associated with OS (P < 0.05 for all). Moreover, statistically significant differences in OS were found among lymph node ratio (LNR) subgroups (P < 0.001), MT1-MMP subgroups (P = 0.015), and CD11b + immunocytes density subgroups (P = 0.031). Most importantly, combined feature (MT1-MMP positive, low CD11b + immunocytes density and high LNR) was found by multivariate analysis to be an independent prognostic factors for OS after excluding other confounding factors (HR = 3.818 [95%CI: 2.223-6.557], P < 0.001). In addition, this combined feature had better performance in predicting clinical outcomes after surgery long before recurrence had occurred (Area under the curve: 0.689 [95%CI: 0.609-0.768], P < 0.001).

Conclusions

These findings indicate that better information on GC prognosis could be obtained from combined clinico-pathological factors, tumor cells and the tumor microenvironment.

【 授权许可】

   
2013 Peng et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global Cancer Statistics. Ca-A Cancer J Clin 2011, 61:69-90.
• [2]Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, Bruneval P, Trajanoski Z, Fridman WH, Pages F, Galon J: Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 2011, 29:610-618.
• [3]Warneke VS, Behrens HM, Hartmann JT, Held H, Becker T, Schwarz NT, Rocken C: Cohort Study Based on the Seventh Edition of the TNM Classification for Gastric Cancer: Proposal of a New Staging System. J Clin Oncol 2011, 29:2364-2371.
• [4]Wong H, Yau T: Targeted Therapy in the Management of Advanced Gastric Cancer: Are We Making Progress in the Era of Personalized Medicine? Oncologist 2012, 17:346-358.
• [5]Hemingway H: Ten steps towards improving prognosis research. Brit Med J 2009, 339:b4184.
• [6]Maduekwe UN, Lauwers GY, Fernandez-Del-Castillo C, Berger DL, Ferguson CM, Rattner DW, Yoon SS: New metastatic lymph node ratio system reduces stage migration in patients undergoing D1 lymphadenectomy for gastric adenocarcinoma. Ann Surg Oncol 2010, 17:1267-1277.
• [7]Xu DZ, Geng QR, Long ZJ, Zhan YQ, Li W, Zhou ZW, Chen YB, Sun XW, Chen G, Liu Q: Positive lymph node ratio is an independent prognostic factor in gastric cancer after d2 resection regardless of the examined number of lymph nodes. Ann Surg Oncol 2009, 16:319-326.
• [8]Wang W, Xu DZ, Li YF, Guan YX, Sun XW, Chen YB, Kesari R, Huang CY, Li W, Zhan YQ, Zhou ZW: Tumor-ratio-metastasis staging system as an alternative to the 7th edition UICC TNM system in gastric cancer after D2 resection–results of a single-institution study of 1343 Chinese patients. Ann Oncol 2011, 22:2049-2056.
• [9]Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011, 144:646-674.
• [10]Joyce JA, Pollard JW: Microenvironmental regulation of metastasis. Nat Rev Cancer 2009, 9:239-252.
• [11]Poincloux R, Lizarraga F, Chavrier P: Matrix invasion by tumour cells: a focus on MT1-MMP trafficking to invadopodia. J Cell Sci 2009, 122:3015-3024.
• [12]Belov L, Zhou J, Christopherson RI: Cell Surface Markers in Colorectal Cancer Prognosis. Int J Mol Sci 2011, 12:78-113.
• [13]Ota I, Li XY, Hu YX, Weiss SJ: Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. PROC NAT ACAD SCI USA 2009, 106:20318-20323.
• [14]Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, et al.: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006, 313:1960-1964.
• [15]Stepanova K, Sinkora M: The expression of CD25, CD11b, SWC1, SWC7, MHC-II, and family of CD45 molecules can be used to characterize different stages of gamma delta T lymphocytes in pigs. Develop Comp Immunol 2012, 36:728-740.
• [16]Lundahl J, Jacobson SH, Paulsson JM: IL-8 from Local Subcutaneous Wounds Regulates CD11b Activation. Scand J Immunol 2012, 75:419-425.
• [17]Blankenstein T, Coulie PG, Gilboa E, Jaffee EM: The determinants of tumour immunogenicity. Nat Rev Cancer 2012, 12:307-313.
• [18]Wittekind C, Meyer H-J: TNM Classification of Malignant Tumours (ed 7). Germany: Wiley; 2010.
• [19]Peng CW, Liu XL, Liu X, Li Y: Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion: laboratory evidence and clinical significance. J Transl Med 2010, 8:101. BioMed Central Full Text
• [20]Marchet A, Mocellin S, Ambrosi A, Morgagni P, Garcea D, Marrelli D, Roviello F, De Manzoni G, Minicozzi A, Natalini G, et al.: The ratio between metastatic and examined lymph nodes (N ratio) is an independent prognostic factor in gastric cancer regardless of the type of lymphadenectomy: results from an Italian multicentric study in 1853 patients. Ann Surg 2007, 245:543-552.
• [21]Peng CW, Tian Q, Yang GF, Fang M, Zhang ZL, Peng J, Pang DW, Li Y: Quantum-dots based simultaneous detection of multiple biomarkers of tumor stromal features to predcit clinical outcomes in gastric cancer. Biomaterials 2012, 33:5742-5752.
• [22]Peng C-W, Liu X-L, Chen C, Liu X, Yang X-Q, Pang D-W, Zhu X-B, Li Y: Patterns of cancer invasion revealed by QDs-based quantitative multiplexed imaging of tumor microenvironment. Biomaterials 2011, 32:2907-2917.
• [23]Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G: Prognostic and Predictive Impact of Intra- and Peritumoral Immune Infiltrates. Cancer Res 2011, 71:5601-5605.
• [24]Leung WK, Wu MS, Kakugawa Y, Kim JJ, Yeoh KG, Goh KL, Wu KC, Wu DC, Sollano J, Kachintorn U, et al.: Screening for gastric cancer in Asia: current evidence and practice. Lancet Oncol 2008, 9:279-287.
• [25]Zhang M, Zhu GY, Gao HY, Zhao SP, Xue YW: Expression of Tissue Levels of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Gastric Adenocarcinoma. J Surg Oncol 2011, 103:243-247.
• [26]Perentes JY, Kirkpatrick ND, Nagano S, Smith EY, Shaver CM, Sgroi D, Garkavtsev I, Munn LL, Jain RK, Boucher Y: Cancer Cell-Associated MT1-MMP Promotes Blood Vessel Invasion and Distant Metastasis in Triple-Negative Mammary Tumors. Cancer Res 2011, 71:4527-4538.
• [27]Sconocchia G, Zlobec I, Lugli A, Calabrese D, Iezzi G, Karamitopoulou E, Patsouris ES, Peros G, Horcic M, Tornillo L, et al.: Tumor infiltration by Fc gamma RIII (CD16) + myeloid cells is associated with improved survival in patients with colorectal carcinoma. Int J Cancer 2011, 128:2663-2672.
• [28]Ladoire S, Mignot G, Dabakuyo S, Arnould L, Apetoh L, Rebe C, Coudert B, Martin F, Bizollon MH, Vanoli A, et al.: In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol 2011, 224:389-400.
• [29]Rausei S, Dionigi G, Boni L, Rovera F, Dionigi R: How does the 7th TNM edition fit in gastric cancer management? Ann Surg Oncol 2011, 18:1219-1221.
• [30]Songun I, Putter H, Kranenbarg EMK, Sasako M, Van de Velde CJH: Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 2010, 11:439-449.
• [31]Association JGC: Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011, 14:101-112.
• [32]Jung H, Lee HH, Song KY, Jeon HM, Park CH: Validation of the seventh edition of the american joint committee on cancer TNM staging system for gastric cancer. Cancer 2011, 117:2371-2378.
• [33]Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, et al.: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010, 376:687-697.
• [34]Kanazawa A, Oshima T, Yoshihara K, Tamura S, Yamada T, Inagaki D, Sato T, Yamamoto N, Shiozawa M, Morinaga S, et al.: Relation of MT1-MMP Gene Expression to Outcomes in Colorectal Cancer. J Surg Oncol 2010, 102:571-575.
• [35]Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, Ellis IO, Green AR: Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 2011, 29:1949-1955.
• [36]Broussard EK, Disis ML: TNM staging in colorectal cancer: T is for T cell and M is for memory. J Clin Oncol 2011, 29:601-603.
• [37]Mahmoud SMA, Paish EC, Powe DG, Macmillan RD, Lee AHS, Ellis IO, Green AR: An evaluation of the clinical significance of FOXP3(+) infiltrating cells in human breast cancer. Breast Cancer Res Treat 2011, 127:99-108.
• [38]Oldenhuis C, Oosting SF, Gietema JA, De Vries EGE: Prognostic versus predictive value of biomarkers in oncology. Eur J Cancer 2008, 44:946-953.
• [39]Hewitt SM: Tissue Microarrays as a Tool in the Discovery and Validation of Predictive Biomarkers. Molecular Profiling: Methods and Protocols 2012, 823:201-214.
• [40]Solis LM, Behrens C, Raso MG, Lin HY, Kadara H, Yuan P, Galindo H, Tang X, Lee JJ, Kalhor N, et al.: Histologic patterns and molecular characteristics of lung adenocarcinoma associated with clinical outcome. Cancer 2012, 118:2889-2899.
• [41]Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P, et al.: In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009, 27:5944-5951.
• [42]Simon RM, Paik S, Hayes DF: Use of Archived Specimens in Evaluation of Prognostic and Predictive Biomarkers. J Natl Cancer Inst 2009, 101:1446-1452.