Downregulation of Hematopoietic MUC1 during Experimental Colitis Increases Tumor-Promoting Myeloid-Derived Suppressor Cells

• Published in: Clinical cancer research Vol. 19; no. 18; pp. 5039 - 5052
• Main Authors: WEI POH, Tze, MADSEN, Cathy S, GORMAN, Jessica E, MARLER, Ronald J, LEIGHTON, Jonathan A, COHEN, Peter A, GENDLER, Sandra J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-09-2013
• Subjects: Animals; Antineoplastic agents; Azoxymethane - toxicity; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Bone Marrow Transplantation; Carcinogens - toxicity; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - complications; Colitis, Ulcerative - metabolism; Colonic Neoplasms - etiology; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Crohn Disease - genetics; Crohn Disease - metabolism; Crohn Disease - pathology; Female; Flow Cytometry; Gene Expression Profiling; Humans; Immunoenzyme Techniques; Medical sciences; Mice; Mice, Knockout; Mucin-1 - physiology; Myeloid Cells - metabolism; Myeloid Cells - pathology; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Digestive diseases; Intestinal disease; Mucin 1; Colitis; Myeloid derived suppressor cell; Experimental tumor
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-0278

MUC1 is a tumor-associated antigen that is aberrantly expressed in cancer and inflammatory bowel disease (IBD). Even though immune cells express low MUC1 levels, their modulations of MUC1 are important in tumor progression. Consistent with previous clinical data that show increased myeloid-derived suppressor cells (MDSCs) in IBD, we now show that downregulation of MUC1 on hematopoietic cells increases MDSCs in IBD, similar to our data in tumor-bearing mice. We hypothesize that MDSC expansion in IBD is critical for tumor progression.
To mechanistically confirm the linkage between Muc1 downregulation and MDSC expansion, we generated chimeric mice that did not express Muc1 in the hematopoietic compartment (KO→WT). These mice were used in two models of colitis and colitis-associated cancer (CAC) and their responses were compared with wild-type (WT) chimeras (WT→WT).
KO→WT mice show increased levels of MDSCs during colitis and increased protumorigenic signaling in the colon during CAC, resulting in larger colon tumors. RNA and protein analysis show increased upregulation of metalloproteinases, collagenases, defensins, complements, growth factors, cytokines, and chemokines in KO→WT mice as compared with WT→WT mice. Antibody-mediated depletion of MDSCs in mice during colitis reduced colon tumor formation during CAC.
Development of CAC is a serious complication of colitis and our data highlight MDSCs as a targetable link between inflammation and cancer. In addition, the lack of MUC1 expression on MDSCs can be a novel marker for MDSCs, given that MDSCs are still not well characterized in human cancers.