Oncotarget

Research Papers:

MGL ligand expression is correlated to BRAF mutation and associated with poor survival of stage III colon cancer patients

Kristiaan Lenos, Jeroen A.C.M. Goos, Ilona M. Vuist, Sjoerd H. den Uil, Pien M. Delis-van Diemen, Eric J.Th. Belt, Hein B.A.C. Stockmann, Herman Bril, Meike de Wit, Beatriz Carvalho, Susan Giblett, Catrin A. Pritchard, Gerrit A. Meijer, Yvette van Kooyk, Remond J.A. Fijneman and Sandra J. van Vliet _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2015; 6:26278-26290. https://doi.org/10.18632/oncotarget.4495

Metrics: PDF 2617 views  |   HTML 3694 views  |   ?  


Abstract

Kristiaan Lenos1,2, Jeroen A.C.M. Goos3, Ilona M. Vuist1,4, Sjoerd H. den Uil3,5, Pien M. Delis-van Diemen3,6, Eric J.Th. Belt7, Hein B.A.C. Stockmann5, Herman Bril8, Meike de Wit9,6, Beatriz Carvalho3,6, Susan Giblett10, Catrin A. Pritchard10, Gerrit A. Meijer3,6, Yvette van Kooyk1, Remond J.A. Fijneman3,6, Sandra J. van Vliet1

1Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands

2Current address: Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands

3Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

4Current address: Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands

5Department of Surgery, Spaarne Gasthuis, Haarlem, The Netherlands

6Current address: Netherlands Cancer Institute, Amsterdam, The Netherlands

7Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands

8Department of Pathology, Spaarne Gasthuis, Haarlem, The Netherlands

9Department of Medical Oncology, VU University Medical Center Amsterdam, The Netherlands

10Department of Biochemistry, University of Leicester, Leicester, UK

Correspondence to:

Sandra J. van Vliet, e-mail: [email protected]

Keywords: colorectal cancer, BRAF, glycosylation, MGL, C-type lectin

Received: May 06, 2015     Accepted: June 18, 2015     Published: July 02, 2015

ABSTRACT

Colorectal cancer (CRC) is the third most prevalent cancer type worldwide with a mortality rate of approximately 50%. Elevated cell-surface expression of truncated carbohydrate structures such as Tn antigen (GalNAcα-Ser/Thr) is frequently observed during tumor progression. We have previously demonstrated that the C-type lectin macrophage galactose-type lectin (MGL), expressed by human antigen presenting cells, can distinguish healthy tissue from CRC through its specific recognition of Tn antigen. Both MGL binding and oncogenic BRAF mutations have been implicated in establishing an immunosuppressive microenvironment. Here we aimed to evaluate whether MGL ligand expression has prognostic value and whether this was correlated to BRAFV600E mutation status. Using a cohort of 386 colon cancer patients we demonstrate that high MGL binding to stage III tumors is associated with poor disease-free survival, independent of microsatellite instability or adjuvant chemotherapy. In vitro studies using CRC cell lines showed an association between MGL ligand expression and the presence of BRAFV600E. Administration of specific BRAFV600E inhibitors resulted in decreased expression of MGL-binding glycans. Moreover, a positive correlation between induction of BRAFV600E and MGL binding to epithelial cells of the gastrointestinal tract was found in vivo using an inducible BRAFV600E mouse model. We conclude that the BRAFV600E mutation induces MGL ligand expression, thereby providing a direct link between oncogenic transformation and aberrant expression of immunosuppressive glycans. The strong prognostic value of MGL ligands in stage III colon cancer patients, i.e. when tumor cells disseminate to lymph nodes, further supports the putative immune evasive role of MGL ligands in metastatic disease.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 4495