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Colonic carcinogenesis along different genetic routes: glycophenotyping of tumor cases separated by microsatellite instability/stability

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Abstract

Different genetic routes account for colonic carcinogenesis. However, when analyzing colon cancer specimens, separation into different groups based on genetic alterations is commonly not performed. Thus, we here initiate the comparative phenotyping considering microsatellite instability/stability for clinical specimens. The focus is given to glycan epitopes, expression of which is known to be modulated by signal-transducing proteins that act as key regulators of normal colon epithelial growth and differentiation. In addition to six plant lectins used as sensors, the presence of two adhesion/growth-regulatory galectins is studied. Overall, a considerable level of intra- and interindividual heterogeneity is revealed. Alterations in the proportion of stained cells between tumor-adjacent and malignant epithelia concerned plant lectins, which bind substituted N-glycan cores, α2,6-sialylated branch ends, core 1 O-glycans and N-acetylgalactosamine. A tendency for changes was noted between microsatellite-unstable and microsatellite-stable cases for core substitution (bisected N-glycan, presence of β1,6-branching) and status of α2,6-sialylation. Statistical significance was reached for presence of galectin-3, found to be elevated in microsatellite-stable compared to microsatellite-unstable tumors. These results emphasize the potential of distinct signaling pathways to regulate certain aspects of the glycophenotype in vivo and thus delineate a perspective to discern functionally relevant deviations in expression of endogenous lectins and their counter-receptors.

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References

  • André S, Unverzagt C, Kojima S, Frank M, Seifert J, Fink C, Kayser K, von der Lieth C-W, Gabius H-J (2004) Determination of modulation of ligand properties of synthetic complex-type biantennary N-glycans by introduction of bisecting GlcNac in silico, in vitro and in vivo. Eur J Biochem 271:118–134

    Article  PubMed  Google Scholar 

  • André S, Kojima S, Gundel G, Russwurm R, Schratt X, Unverzagt C, Gabius H-J (2006) Branching mode in complex-type triantennary N-glycans as regulatory element of their ligand properties. Biochim Biophys Acta 1760:768–782

    Article  PubMed  Google Scholar 

  • André S, Sanchez-Ruderisch H, Nakagawa H, Buchholz M, Kopitz J, Forberich P, Kemmner W, Böck C, Deguchi K, Detjen KM, Wiedenmann B, von Knebel-Döberitz M, Gress TM, Nishimura S-I, Rosewicz S, Gabius H-J (2007) Tumor suppressor p16INK4a: modulator of glycomic profile and galectin-1 expression to increase susceptibility to carbohydrate-dependent induction of anoikis in pancreatic carcinoma cells. FEBS J 274:3233–3256

    Article  PubMed  Google Scholar 

  • André S, Kozár T, Kojima S, Unverzagt C, Gabius H-J (2009) From structural to functional glycomics: core substitutions as molecular switches for shape and lectin affinity of N-glycans. Biol Chem 390:557–565

    Article  PubMed  Google Scholar 

  • Bi S, Baum LG (2009) Sialic acids in T cell development and function. Biochim Biophys Acta 1790:1599–1610

    Article  PubMed  CAS  Google Scholar 

  • Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S (1998) A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257

    PubMed  CAS  Google Scholar 

  • Boscher C, Dennis JW, Nabi IR (2011) Glycosylation, galectins and cellular signaling. Curr Opin Cell Biol 23:383–392

    Article  PubMed  CAS  Google Scholar 

  • Bresalier RS, Boland CR, Kim YS (1985) Regional differences in normal and cancer-associated glycoconjugates of the human colon. J Natl Cancer Inst 75:249–260

    PubMed  CAS  Google Scholar 

  • Chokhawala HA, Huang S, Lau K, Yu H, Cheng J, Thon V, Hurtado-Ziola N, Guerrero JA, Varki A, Chen X (2008) Combinatorial chemoenzymatic synthesis and high-throughput screening of sialosides. ACS Chem Biol 3:567–756

    Article  PubMed  CAS  Google Scholar 

  • Dall’Olio F, Malagolini N, Di Stefano G, Ciambella M, Serafini-Cessi F (1991) α2,6-Sialylation of N-acetyllactosaminic sequences in human colorectal cancer cell lines. Relationship with non-adherent growth. Int J Cancer 47:291–297

    Article  PubMed  Google Scholar 

  • El-Bchiri J, Buhard O, Penard-Lacronique V, Thomas G, Hamelin R, Duval A (2005) Differential nonsense mediated decay of mutated mRNAs in mismatch repair deficient colorectal cancers. Hum Mol Genet 14:2435–2442

    Article  PubMed  CAS  Google Scholar 

  • Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767

    Article  PubMed  CAS  Google Scholar 

  • Findeisen P, Kloor M, Merx S, Sutter C, Woerner SM, Dostmann N, Benner A, Dondog B, Pawlita M, Dippold W, Wagner R, Gebert J, von Knebel Doeberitz M (2005) T25 repeat in the 3′ untranslated region of the CASP2 gene: a sensitive and specific marker for microsatellite instability in colorectal cancer. Cancer Res 65:8072–8078

    Article  PubMed  CAS  Google Scholar 

  • Fischer C, Sanchez-Ruderisch H, Welzel M, Wiedenmann B, Sakai T, André S, Gabius H-J, Khachigian L, Detjen K, Rosewicz S (2005) Galectin-1 interacts with the α5β1 fibronectin receptor to restrict carcinoma cell growth via induction of p21 and p27. J Biol Chem 280:37266–37277

    Article  PubMed  CAS  Google Scholar 

  • Gabius H-J, André S, Jiménez-Barbero J, Romero A, Solís D (2011) From lectin structure to functional glycomics: principles of the sugar code. Trends Biochem Sci 36:298–313

    Article  PubMed  CAS  Google Scholar 

  • Huang MC, Chen HY, Huang HC, Huang J, Liang JT, Shen TL, Lin NY, Ho CC, Cho IM, Hsu SM (2006) C2GnT-M is downregulated in colorectal cancer and its re-expression causes growth inhibition of colon cancer cells. Oncogene 25:3267–3276

    Article  PubMed  CAS  Google Scholar 

  • Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561

    Article  PubMed  CAS  Google Scholar 

  • Ionov Y, Nowak N, Perucho M, Markowitz S, Cowell JK (2004) Manipulation of nonsense mediated decay identifies gene mutations in colon cancer cells with microsatellite instability. Oncogene 23:639–645

    Article  PubMed  CAS  Google Scholar 

  • Itzkowitz SH, Yuan M, Montgomery CK, Kjeldsen T, Takahashi HK, Bigbee WL, Kim YS (1989) Expression of Tn, sialosyl-Tn, and T antigens in human colon cancer. Cancer Res 49:197–204

    PubMed  CAS  Google Scholar 

  • Kaltner H, Gabius H-J (2012) A toolbox of lectins for translating the sugar code: the galectin network in phylogenesis and tumors. Histol Histopathol 27:397–416

    PubMed  CAS  Google Scholar 

  • Knibbs RN, Goldstein IJ, Ratcliffe RM, Shibuya N (1991) Characterization of the carbohydrate binding specificity of the leukoagglutinating lectin from Maackia amurensis. Comparison with other sialic acid-specific lectins. J Biol Chem 266:83–88

    PubMed  CAS  Google Scholar 

  • Krzeminski M, Singh T, André S, Lensch M, Wu AM, Bonvin AMJJ, Gabius H-J (2011) Human galectin-3 (Mac-2 antigen): defining molecular switches of affinity to natural glycoproteins, structural and dynamic aspects of glycan binding by flexible ligand docking and putative regulatory sequences in the proximal promoter region. Biochim Biophys Acta 1810:150–161

    Article  PubMed  CAS  Google Scholar 

  • Lahm H, André S, Höflich A, Fischer JR, Sordat B, Kaltner H, Wolf E, Gabius H-J (2001) Comprehensive galectin fingerprinting in a panel of 61 human tumor cell lines by RT-PCR and its implications for diagnostic and therapeutic procedures. J Cancer Res Clin Oncol 127:375–386

    Article  PubMed  CAS  Google Scholar 

  • Langbein S, Brade J, Badawi JK, Hatzinger M, Kaltner H, Lensch M, Specht K, André S, Brinck U, Alken P, Gabius H-J (2007) Gene-expression signature of adhesion/growth-regulatory tissue lectins (galectins) in transitional cell cancer and its prognostic relevance. Histopathology 51:681–690

    Article  PubMed  CAS  Google Scholar 

  • Lawes DA, SenGupta S, Boulos PB (2003) The clinical importance and prognostic implications of microsatellite instability in sporadic cancer. Eur J Surg Oncol 29:201–212

    Article  PubMed  CAS  Google Scholar 

  • Lohr M, Kaltner H, Lensch M, André S, Sinowatz F, Gabius H-J (2008) Cell-type-specific expression of murine multifunctional galectin-3 and its association with follicular atresia/luteolysis in contrast to pro-apoptotic galectins-1 and -7. Histochem Cell Biol 130:567–581

    Article  PubMed  CAS  Google Scholar 

  • Lohr M, Kaltner H, Schwartz-Albiez R, Sinowatz F, Gabius H-J (2010) Towards functional glycomics by lectin histochemistry: strategic probe selection to monitor core and branch-end substitutions and detection of cell-type and regional selectivity in adult mouse testis and epididymis. Anat Histol Embryol 39:481–493

    Article  PubMed  CAS  Google Scholar 

  • Lundin M, Nordling S, Roberts PJ, Lundin J, Carpelan-Holmstrom M, von Boguslawsky K, Haglund C (1999) Sialyl Tn is a frequently expressed antigen in colorectal cancer: no correlation with patient prognosis. Oncology 57:70–76

    Article  PubMed  CAS  Google Scholar 

  • Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B et al (1995) Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268:1336–1338

    Article  PubMed  CAS  Google Scholar 

  • Morelle W, Stechly L, André S, van Seuningen I, Porchet N, Gabius H-J, Michalski JC, Huet G (2009) Glycosylation pattern of brush border-associated glycoproteins in enterocyte-like cells: involvement of complex-type N-glycans in apical trafficking. Biol Chem 390:529–544

    Article  PubMed  CAS  Google Scholar 

  • Murayama T, Zuber C, Seelentag WK, Li WP, Kemmner W, Heitz PU, Roth J (1997) Colon carcinoma glycoproteins carrying α2,6-linked sialic acid reactive with Sambucus nigra agglutinin are not constitutively expressed in normal human colon mucosa and are distinct from sialyl-Tn antigen. Int J Cancer 70:575–581

    Article  PubMed  CAS  Google Scholar 

  • Nagy N, Legendre H, Engels O, André S, Kaltner H, Wasano K, Zick Y, Pector J-C, Decaestecker C, Gabius H-J, Salmon I, Kiss R (2003) Refined prognostic evaluation in colon cancer using immunohistochemical galectin fingerprinting. Cancer 97:1849–1858

    Article  PubMed  Google Scholar 

  • Ohannesian DW, Lotan D, Thomas P, Jessup JM, Fukuda M, Gabius H-J, Lotan R (1995) Carcinoembryonic antigen and other glycoconjugates act as ligands for galectin-3 in human colon carcinoma cells. Cancer Res 55:2191–2199

    PubMed  CAS  Google Scholar 

  • Patsos G, Corfield A (2009) O-glycosylation: structural diversity and function. In: Gabius H-J (ed) The sugar code. Fundamentals of glycosciences. Wiley-VCH, Weinheim, pp 111–137

    Google Scholar 

  • Patsos G, André S, Roeckel N, Gromes R, Gebert J, Kopitz J, Gabius H-J (2009) Compensation of loss of protein function in microsatellite-unstable colon cancer cells (HCT116): a gene-dependent effect on the cell surface glycan profile. Glycobiology 19:726–734

    Article  PubMed  CAS  Google Scholar 

  • Qiu Y, Patwa TH, Xu L, Shedden K, Misek DE, Tuck M, Jin G, Ruffin MT, Turgeon DK, Synal S, Bresalier R, Marcon N, Brenner DE, Lubman DM (2008) Plasma glycoprotein profiling for colorectal cancer biomarker identification by lectin glycoarray and lectin blot. J Proteome Res 7:1693–1703

    Article  PubMed  CAS  Google Scholar 

  • Roth J (2011) Lectins for histochemical demonstration of glycans. Histochem Cell Biol 136:117–130

    Article  PubMed  CAS  Google Scholar 

  • Royrvik EC, Ahlquist T, Rognes T, Lothe RA (2007) Slip slidin’ away: a duodecennial review of targeted genes in mismatch repair deficient colorectal cancer. Crit Rev Oncog 13:229–257

    Article  PubMed  Google Scholar 

  • Sams JS, Lynch HT, Burt RW, Lanspa SJ, Boland CR (1990) Abnormalities of lectin histochemistry in familial polyposis coli and hereditary nonpolyposis colorectal cancer. Cancer 66:502–508

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Ruderisch H, Fischer C, Detjen KM, Welzel M, Wimmel A, Manning JC, André S, Gabius H-J (2010) Tumor suppressor p16INK4a: downregulation of galectin-3, an endogenous competitor of the pro-anoikis effector galectin-1, in a pancreatic carcinoma model. FEBS J 277:3552–3563

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Ruderisch H, Detjen KM, Welzel M, André S, Fischer C, Gabius H-J, Rosewicz S (2011) Galectin-1 sensitizes carcinoma cells to anoikis via the fibronectin receptor α5β1-integrin. Cell Death Differ 18:806–816

    Article  PubMed  CAS  Google Scholar 

  • Sata T, Roth J, Zuber C, Stamm B, Heitz PU (1991) Expression of α2,6-linked sialic acid residues in neoplastic but not in normal human colonic mucosa. A lectin-gold cytochemical study with Sambucus nigra and Maackia amurensis lectins. Am J Pathol 139:1435–1448

    PubMed  CAS  Google Scholar 

  • Sata T, Roth J, Zuber C, Stamm B, Rinderle SJ, Goldstein IJ, Heitz PU (1992) Studies on the Thomsen–Friedenreich antigen in human colon with the lectin Amaranthin. Normal and neoplastic epithelium express only cryptic T antigen. Lab Invest 66:175–186

    PubMed  CAS  Google Scholar 

  • Saussez S, de Leval L, Decaestecker C, Sirtaine N, Cludts S, Duray A, Chevalier D, André S, Gabius H-J, Remmelink M, Leroy X (2010) Galectin fingerprinting in Warthin’s tumors: lectin-based approach to trace its origin? Histol Histopathol 25:541–550

    PubMed  Google Scholar 

  • Schwartz-Albiez R (2009) Inflammation and glycosciences. In: Gabius H-J (ed) The sugar code. Fundamentals of glycosciences. Wiley-VCH, Weinheim, pp 447–467

    Google Scholar 

  • Seales EC, Jurado GA, Brunson BA, Wakefield JK, Frost AR, Bellis SL (2005) Hypersialylation of β1 integrins, observed in colon adenocarcinoma, may contribute to cancer progression by up-regulating cell motility. Cancer Res 65:4645–4652

    Article  PubMed  CAS  Google Scholar 

  • Seelentag WK, Li WP, Schmitz SF, Metzger U, Aeberhard P, Heitz PU, Roth J (1998) Prognostic value of β1,6-branched oligosaccharides in human colorectal carcinoma. Cancer Res 58:5559–5564

    PubMed  CAS  Google Scholar 

  • Solís D, Maté MJ, Lohr M, Ribeiro JP, López-Merino L, André S, Buzamet E, Cañada FJ, Kaltner H, Lensch M, Ruiz FM, Haroske G, Wollina U, Kloor M, Kopitz J, Sáiz JL, Menéndez M, Jiménez-Barbero J, Romero A, Gabius H-J (2010) N-Domain of human adhesion/growth-regulatory galectin-9: preference for distinct conformers and non-sialylated N-glycans and detection of ligand-induced structural changes in crystal and solution. Int J Biochem Cell Biol 42:1019–1029

    Article  PubMed  Google Scholar 

  • Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819

    Article  PubMed  CAS  Google Scholar 

  • van de Wouwer M, André S, Gabius H-J, Villalobo A (2011) Nitric oxide changes distinct aspects of the glycophenotype of human neuroblastoma NB69 cells. Nitric Oxide 24:91–101

    Article  PubMed  Google Scholar 

  • Vazquez-Martin C, Gil-Martin E, Fernandez-Briera A (2005) Elevation of ST6Gal I activity in malignant and transitional tissue in human colorectal cancer. Oncology 69:436–444

    Article  PubMed  CAS  Google Scholar 

  • Wu AM, Wu JH, Liu J-H, Singh T, André S, Kaltner H, Gabius H-J (2004) Effects of polyvalency of glycotopes and natural modifications of human blood group ABH/Lewis sugars at the Galβ1-terminated core saccharides on the binding of domain-I of recombinant tandem-repeat-type galectin-4 from rat gastrointestinal tract (G4-N). Biochimie 86:317–326

    Article  PubMed  CAS  Google Scholar 

  • Yang JM, Byrd JC, Siddiki BB, Chung YS, Okuno M, Sowa M, Kim YS, Matta KL, Brockhausen I (1994) Alterations of O-glycan biosynthesis in human colon cancer tissues. Glycobiology 4:873–884

    Article  PubMed  CAS  Google Scholar 

  • Zhuo Y, Bellis SL (2011) Emerging role of α2,6-sialic acid as a negative regulator of galectin binding and function. J Biol Chem 286:5935–5941

    Article  PubMed  CAS  Google Scholar 

  • Zuber C, Roth J (2009) N-Glycosylation. In: Gabius H-J (ed) The sugar code. Fundamentals of glycosciences. Wiley-VCH, Weinheim, pp 87–110

    Google Scholar 

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Acknowledgments

The expert technical assistance of Marcel Karl and Katharina Liedtke, inspiring discussion with Dr. B. Friday and the helpful input of the reviewers are gratefully acknowledged. We appreciate the generous help of Niels Grabe and Bernd Lahrmann (BioQuant, Hamamatsu Tissue Imaging and Analysis Center, Institute of Medical Biometry and Informatics, University of Heidelberg) in slide scanning. This work was supported by DFG grant KO 1663/5-1 to J.K. and funding from the EU seventh framework program under grant agreement no. 26060 (“GlycoHIT”) to J.K. and H.-J.G.

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Authors and Affiliations

  1. Abteilung Angewandte Tumorbiologie, Universitaetsklinikum Heidelberg, Im Neuenheimer Feld 220/221, 69120, Heidelberg, Germany

    Johannes Gebert, Matthias Kloor, Jennifer Lee & Juergen Kopitz

  2. Institut fuer Physiologische Chemie, Tieraerztliche Fakultaet, Ludwig-Maximilians-Universitaet, Veterinaerstr. 13, 80539, Munich, Germany

    Michaela Lohr, Sabine André & Hans-Joachim Gabius

  3. Institut für Pathologie, Westpfalz Klinikum GmbH, Hellmut-Hartert-Str. 1, 67655, Kaiserslautern, Germany

    Rudolf Wagner

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  1. Johannes Gebert
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  2. Matthias Kloor
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  3. Jennifer Lee
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  4. Michaela Lohr
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  5. Sabine André
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  6. Rudolf Wagner
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  7. Juergen Kopitz
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  8. Hans-Joachim Gabius
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Corresponding author

Correspondence to Juergen Kopitz.

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J. Gebert and M. Kloor contributed equally to this work.

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418_2012_957_MOESM1_ESM.pdf

Suppl. Fig. 1 Representative whole-tissue scans of colon cancer specimens MSI-5 (a) and MSS-6 (b) with adjacent normal epithelium processed with biotinylated MAA-I and SNA, respectively. Magnification: 20×; scale bars are indicated (PDF 231 kb)

418_2012_957_MOESM2_ESM.ppt

Suppl. Fig. 2 Comparison of staining patterns for the plant lectins PNA/JAC (a, b, 40×) and the two anti-galectin antibodies GAL-3/-4 (c, d, 40×) in one selected region of specimen MSI-2 containing both normal and tumor epithelium. PNA staining (a) is observed in tumor cells (arrows) and colocalizes with JAC staining (arrows, b). Anti-GAL-3 reactivity (c, arrows) is seen in nonmalignant cells at the luminal border with a similar distribution to anti-GAL-4 staining (d, arrows). No similarities of staining patterns were observed on a regional level for PNA/GAL-3 (a, c) or JAC/GAL-4 (b, d), respectively. Scale bars are indicated (PPT 3192 kb)

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Gebert, J., Kloor, M., Lee, J. et al. Colonic carcinogenesis along different genetic routes: glycophenotyping of tumor cases separated by microsatellite instability/stability. Histochem Cell Biol 138, 339–350 (2012). https://doi.org/10.1007/s00418-012-0957-9

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