title: MGL ligand expression is correlated to BRAF mutation and associated with poor survival of stage III colon cancer patients.
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 BRAF(V600E) 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 BRAF(V600E). Administration of specific BRAF(V600E) inhibitors resulted in decreased expression of MGL-binding glycans. Moreover, a positive correlation between induction of BRAF(V600E) and MGL binding to epithelial cells of the gastrointestinal tract was found in vivo using an inducible BRAF(V600E) mouse model. We conclude that the BRAF(V600E) 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.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.|Current address: Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Lenos
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jeroen A C M
authors.initials: JA
authors.lastname: Goos
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.|Current address: Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ilona M
authors.initials: IM
authors.lastname: Vuist
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Surgery, Spaarne Gasthuis, Haarlem, The Netherlands.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: den Uil
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Current address: Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Pien M
authors.initials: PM
authors.lastname: Delis-van Diemen
authors.affiliation: Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Eric J Th
authors.initials: EJ
authors.lastname: Belt
authors.affiliation: Department of Surgery, Spaarne Gasthuis, Haarlem, The Netherlands.
authors.forename: Hein B A C
authors.initials: HB
authors.lastname: Stockmann
authors.affiliation: Department of Pathology, Spaarne Gasthuis, Haarlem, The Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Bril
authors.affiliation: Department of Medical Oncology, VU University Medical Center Amsterdam, The Netherlands.|Current address: Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Meike
authors.initials: M
authors.lastname: de Wit
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Current address: Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Giblett
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: Catrin A
authors.initials: CA
authors.lastname: Pritchard
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Current address: Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Current address: Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Remond J A
authors.initials: RJ
authors.lastname: Fijneman
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: van Vliet
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D019073:HT29 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D037181:Lectins, C-Type / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010641:Phenotype; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015398:Signal Transduction; D013997:Time Factors; D016896:Treatment Outcome; D019139:Tumor Escape; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D008024:Ligands; C506225:MGL lectin, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; C-type lectin; MGL; colorectal cancer; glycosylation