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Cancer Immunology Research
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Cross-talk between Colon Cells and Macrophages Increases ST6GALNAC1 and MUC1-sTn Expression in Ulcerative Colitis and Colitis-Associated Colon Cancer

Michael Kvorjak, Yasmine Ahmed, Michelle L. Miller, Raahul Sriram, Claudia Coronnello, Jana G. Hashash, Douglas J. Hartman, Cheryl A. Telmer, Natasa Miskov-Zivanov, Olivera J. Finn and Sandra Cascio
Michael Kvorjak
1Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Yasmine Ahmed
2Department of Electrical and Computer Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Michelle L. Miller
1Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Raahul Sriram
1Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Claudia Coronnello
3Fondazione Ri.Med, Palermo, Italy.
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  • ORCID record for Claudia Coronnello
Jana G. Hashash
4Department of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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Douglas J. Hartman
5Department of Pathology University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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Cheryl A. Telmer
6Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, Pennsylvania.
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Natasa Miskov-Zivanov
2Department of Electrical and Computer Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Olivera J. Finn
1Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Sandra Cascio
1Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
3Fondazione Ri.Med, Palermo, Italy.
7Department of Obstetrics, Gynecology, & Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
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  • For correspondence: sac131@pitt.edu
DOI: 10.1158/2326-6066.CIR-19-0514 Published February 2020
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Abstract

Patients with ulcerative colitis have an increased risk of developing colitis-associated colon cancer (CACC). Changes in glycosylation of the oncoprotein MUC1 commonly occur in chronic inflammation, including ulcerative colitis, and this abnormally glycosylated MUC1 promotes cancer development and progression. It is not known what causes changes in glycosylation of MUC1. Gene expression profiling of myeloid cells in inflamed and malignant colon tissues showed increased expression levels of inflammatory macrophage–associated cytokines compared with normal tissues. We analyzed the involvement of macrophage-associated cytokines in the induction of aberrant MUC1 glycoforms. A coculture system was used to examine the effects of M1 and M2 macrophages on glycosylation-related enzymes in colon cancer cells. M2-like macrophages induced the expression of the glycosyltransferase ST6GALNAC1, an enzyme that adds sialic acid to O-linked GalNAc residues, promoting the formation of tumor-associated sialyl-Tn (sTn) O-glycans. Immunostaining of ulcerative colitis and CACC tissue samples confirmed the elevated number of M2-like macrophages as well as high expression of ST6GALNAC1 and the altered MUC1-sTn glycoform on colon cells. Cytokine arrays and blocking antibody experiments indicated that the macrophage-dependent ST6GALNAC1 activation was mediated by IL13 and CCL17. We demonstrated that IL13 promoted phosphorylation of STAT6 to activate transcription of ST6GALNAC1. A computational model of signaling pathways was assembled and used to test IL13 inhibition as a possible therapy. Our findings revealed a novel cellular cross-talk between colon cells and macrophages within the inflamed and malignant colon that contributes to the pathogenesis of ulcerative colitis and CACC.

See related Spotlight on p. 160

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2020;8:167–78

  • Received July 8, 2019.
  • Revision received October 3, 2019.
  • Accepted December 3, 2019.
  • Published first December 12, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Immunology Research: 8 (2)
February 2020
Volume 8, Issue 2
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Cross-talk between Colon Cells and Macrophages Increases ST6GALNAC1 and MUC1-sTn Expression in Ulcerative Colitis and Colitis-Associated Colon Cancer
Michael Kvorjak, Yasmine Ahmed, Michelle L. Miller, Raahul Sriram, Claudia Coronnello, Jana G. Hashash, Douglas J. Hartman, Cheryl A. Telmer, Natasa Miskov-Zivanov, Olivera J. Finn and Sandra Cascio
Cancer Immunol Res February 1 2020 (8) (2) 167-178; DOI: 10.1158/2326-6066.CIR-19-0514

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Cross-talk between Colon Cells and Macrophages Increases ST6GALNAC1 and MUC1-sTn Expression in Ulcerative Colitis and Colitis-Associated Colon Cancer
Michael Kvorjak, Yasmine Ahmed, Michelle L. Miller, Raahul Sriram, Claudia Coronnello, Jana G. Hashash, Douglas J. Hartman, Cheryl A. Telmer, Natasa Miskov-Zivanov, Olivera J. Finn and Sandra Cascio
Cancer Immunol Res February 1 2020 (8) (2) 167-178; DOI: 10.1158/2326-6066.CIR-19-0514
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