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Cancer Stemness, Immune Cells, and Epithelial–Mesenchymal Transition Cooperatively Predict Prognosis in Colorectal Carcinoma

  • Fangying Xu
    Correspondence
    Addresses for correspondence: Fangying Xu or Maode Lai, Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058 China. Fax: +86-571-88208197
    Affiliations
    Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
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  • Si Li
    Affiliations
    Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
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  • Jing Zhang
    Affiliations
    Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
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  • Lili Wang
    Affiliations
    Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
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  • Xuesong Wu
    Affiliations
    Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
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  • Jing Wang
    Affiliations
    Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
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  • Qiong Huang
    Affiliations
    Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
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  • Maode Lai
    Correspondence
    Addresses for correspondence: Fangying Xu or Maode Lai, Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058 China. Fax: +86-571-88208197
    Affiliations
    Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
    Search for articles by this author

      Abstract

      Background

      Tumor tissues consist of heterogeneous cancer cells and stroma cells, including cancer stem cells and immune cells. Epithelial–mesenchymal transition (EMT) programs closely associate with acquisition of stemness. We investigated for the first time the clinical significance of combining cancer stem cells, immune cells, and EMT traits.

      Materials and Methods

      In 419 colorectal carcinomas, stem-cell markers (Nanog, Lgr5, CD44v6, ALDH1A1), EMT markers (E-cadherin, Snail), and immune-cell markers (CD3+, CD4+ or CD8+ T lymphocytes, CD20+ B lymphocytes, CD68+ macrophages) were detected in tumor center (TC) and tumor invasive front by an immunohistochemical method. Unsupervised hierarchical clustering analysis was performed to group the data according to correlation analyses. Survival analysis and chi-square test were performed to explore the significance of this clustering.

      Results

      There were correlations among the expression of Nanog, Lgr5, CD44v6, and immune cell counts (P < .05). Nanog, Lgr5, CD44v6, and ALDH1A1 positively related to E-cadherin or Snail (P < .05). A cluster (termed cluster SIE) based on cancer stemness markers (Nanog, Lgr5, CD44v6, ALDH1A1 in TC), EMT markers (E-cadherin, Snail in TC), and immune-cell markers (CD4+ and CD8+ T-lymphocyte counts in TC, and CD68+ macrophages in tumor invasive front) could significantly predict 5-year survival (P = .040). Multivariate Cox proportional hazard model showed that only tumor, node, metastasis classification system stage and cluster SIE were independent prognostic predictors (hazard ratio = 1.920; 95% confidence interval, 1.082-3.407; P = .026).

      Conclusion

      Cancer stemness, immune state, and EMT programs should be considered as a whole. Cluster SIE was an independent predictor for 5-year survival of patients with colorectal cancer.

      Keywords

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      References

        • Tlsty T.D.
        • Coussens L.M.
        Tumor stroma and regulation of cancer development.
        Annu Rev Pathol. 2006; 1: 119-150
        • Clarke M.F.
        • Dick J.E.
        • Dirks P.B.
        • et al.
        Cancer stem cells—perspectives on current status and future directions: AACR workshop on cancer stem cells.
        Cancer Res. 2006; 66: 9339-9344
        • Nguyen L.V.
        • Vanner R.
        • Dirks P.
        • Eaves C.J.
        Cancer stem cells: an evolving concept.
        Nat Rev Cancer. 2012; 12: 133-143
        • Korkaya H.
        • Liu S.
        • Wicha M.S.
        Breast cancer stem cells, cytokine networks, and the tumor microenvironment.
        J Clin Invest. 2011; 121: 3804-3809
        • Bruttel V.S.
        • Wischhusen J.
        Cancer stem cell immunology: key to understanding tumorigenesis and tumor immune escape?.
        Front Immunol. 2014; 5: 360
        • Kise K.
        • Kinugasa-Katayama Y.
        • Takakura N.
        Tumor microenvironment for cancer stem cells.
        Adv Drug Deliv Rev. 2016; 99: 197-205
        • Kalluri R.
        • Weinberg R.A.
        The basics of epithelial–mesenchymal transition.
        J Clin Invest. 2009; 119: 1420-1428
        • Scheel C.
        • Weinberg R.A.
        Cancer stem cells and epithelial–mesenchymal transition: concepts and molecular links.
        Semin Cancer Biol. 2012; 22: 396-403
        • Park J.H.
        • McMillan D.C.
        • Powell A.G.
        • et al.
        Evaluation of a tumor microenvironment-based prognostic score in primary operable colorectal cancer.
        Clin Cancer Res. 2015; 21: 882-888
        • Saito S.
        • Okabe H.
        • Watanabe M.
        • et al.
        CD44v6 expression is related to mesenchymal phenotype and poor prognosis in patients with colorectal cancer.
        Oncol Rep. 2013; 29: 1570-1578
        • Kahlert C.
        • Gaitzsch E.
        • Steinert G.
        • et al.
        Expression analysis of aldehyde dehydrogenase 1A1 (ALDH1A1) in colon and rectal cancer in association with prognosis and response to chemotherapy.
        Ann Surg Oncol. 2012; 19: 4193-4201
        • Meng H.M.
        • Zheng P.
        • Wang X.Y.
        • et al.
        Over-expression of Nanog predicts tumor progression and poor prognosis in colorectal cancer.
        Cancer Biol Ther. 2010; 9: 295-302
        • He S.
        • Zhou H.
        • Zhu X.
        • et al.
        Expression of Lgr5, a marker of intestinal stem cells, in colorectal cancer and its clinicopathological significance.
        Biomed Pharmacother. 2014; 68: 507-513
        • Kreso A.
        • Dick J.E.
        Evolution of the cancer stem cell model.
        Cell Stem Cell. 2014; 14: 275-291
        • Plaks V.
        • Kong N.W.
        • Werb Z.
        The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells?.
        Cell Stem Cell. 2015; 16: 225-238
        • Oskarsson T.
        • Batlle E.
        • Massague J.
        Metastatic stem cells: sources, niches, and vital pathways.
        Cell Stem Cell. 2014; 14: 306-321
        • Amsterdam A.
        • Raanan C.
        • Schreiber L.
        • Polin N.
        • Givol D.
        LGR5 and Nanog identify stem cell signature of pancreas beta cells which initiate pancreatic cancer.
        Biochem Biophys Res Commun. 2013; 433: 157-162
        • Luo Y.
        • Dallaglio K.
        • Chen Y.
        • et al.
        ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets.
        Stem Cells. 2012; 30: 2100-2113
        • Todaro M.
        • Gaggianesi M.
        • Catalano V.
        • et al.
        CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis.
        Cell Stem Cell. 2014; 14: 342-356
        • Lugli A.
        • Iezzi G.
        • Hostettler I.
        • et al.
        Prognostic impact of the expression of putative cancer stem cell markers CD133, CD166, CD44s, EpCAM, and ALDH1 in colorectal cancer.
        Br J Cancer. 2010; 103: 382-390
        • Dalerba P.
        • Dylla S.J.
        • Park I.K.
        • et al.
        Phenotypic characterization of human colorectal cancer stem cells.
        Proc Natl Acad Sci U S A. 2007; 104: 10158-10163
        • Yao C.
        • Su L.
        • Shan J.
        • et al.
        IGF/STAT3/NANOG/Slug signaling axis simultaneously controls epithelial–mesenchymal transition and stemness maintenance in colorectal cancer.
        Stem Cells. 2016; 34: 820-831
        • Yang L.
        • Tang H.
        • Kong Y.
        • et al.
        LGR5 promotes breast cancer progression and maintains stem-like cells through activation of Wnt/beta-catenin signaling.
        Stem Cells. 2015; 33: 2913-2924
        • Cojoc M.
        • Peitzsch C.
        • Kurth I.
        • et al.
        Aldehyde dehydrogenase is regulated by beta-catenin/TCF and promotes radioresistance in prostate cancer progenitor cells.
        Cancer Res. 2015; 75: 1482-1494
        • Huynh P.T.
        • Beswick E.J.
        • Coronado Y.A.
        • et al.
        CD90(+) stromal cells are the major source of IL-6, which supports cancer stem-like cells and inflammation in colorectal cancer.
        Int J Cancer. 2016; 138: 1971-1981
        • Wei J.
        • Barr J.
        • Kong L.Y.
        • et al.
        Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway.
        Mol Cancer Ther. 2010; 9: 67-78
        • Wu A.
        • Wei J.
        • Kong L.Y.
        • et al.
        Glioma cancer stem cells induce immunosuppressive macrophages/microglia.
        Neurooncology. 2010; 12: 1113-1125
        • Zhou W.
        • Ke S.Q.
        • Huang Z.
        • et al.
        Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth.
        Nat Cell Biol. 2015; 17: 170-182
        • Sarkar S.
        • Doring A.
        • Zemp F.J.
        • et al.
        Therapeutic activation of macrophages and microglia to suppress brain tumor–initiating cells.
        Ann Neurosci. 2013; 20: 154
        • Kryczek I.
        • Lin Y.
        • Nagarsheth N.
        • et al.
        IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L.
        Immunity. 2014; 40: 772-784
        • Huang W.C.
        • Chan M.L.
        • Chen M.J.
        • Tsai T.H.
        • Chen Y.J.
        Modulation of macrophage polarization and lung cancer cell stemness by MUC1 and development of a related small-molecule inhibitor pterostilbene.
        Oncotarget. 2016; 7: 39363-39375
        • Algars A.
        • Irjala H.
        • Vaittinen S.
        • et al.
        Type and location of tumor-infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients.
        Int J Cancer. 2012; 131: 864-873
        • Yu P.
        • Fu Y.X.
        Tumor-infiltrating T lymphocytes: friends or foes?.
        Lab Invest. 2006; 86: 231-245
        • Mani S.A.
        • Guo W.
        • Liao M.J.
        • et al.
        The epithelial–mesenchymal transition generates cells with properties of stem cells.
        Cell. 2008; 133: 704-715
        • Padua D.
        • Massague J.
        Roles of TGFbeta in metastasis.
        Cell Res. 2009; 19: 89-102
        • Moustakas A.
        • Heldin C.H.
        Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression.
        Cancer Sci. 2007; 98: 1512-1520
        • Bellomo C.
        • Caja L.
        • Moustakas A.
        Transforming growth factor β as regulator of cancer stemness and metastasis.
        Br J Cancer. 2016; 115: 761-769
        • Yang M.H.
        • Chen C.L.
        • Chau G.Y.
        • et al.
        Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma.
        Hepatology. 2009; 50: 1464-1474
        • Guinney J.
        • Dienstmann R.
        • Wang X.
        • et al.
        The consensus molecular subtypes of colorectal cancer.
        Nat Med. 2015; 21: 1350-1356
        • Ziskin J.L.
        • Dunlap D.
        • Yaylaoglu M.
        • et al.
        In situ validation of an intestinal stem cell signature in colorectal cancer.
        Gut. 2013; 62: 1012-1023
        • Sun X.
        • Jackson L.
        • Dey S.K.
        • Daikoku T.
        In pursuit of leucine-rich repeat-containing G protein–coupled receptor-5 regulation and function in the uterus.
        Endocrinology. 2009; 150: 5065-5073