Downregulation of hematopoietic MUC1 during Experimental colitis increases tumor-promoting myeloid-derived suppressor cells

Tze Wei Poh, Cathy S. Madsen, Jessica E. Gorman, Ronald J Marler, Jonathan A Leighton, Peter A Cohen, Sandra J Gendler

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: To mechanistically confirm the linkage between Muc1 downregulation and MDSCexpansion, 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). Results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)5039-5052
Number of pages14
JournalClinical Cancer Research
Volume19
Issue number18
DOIs
StatePublished - Sep 15 2013

Fingerprint

Colitis
Down-Regulation
Neoplasms
Inflammatory Bowel Diseases
Colon
Myeloid-Derived Suppressor Cells
Defensins
Metalloproteases
Neoplasm Antigens
Collagenases
Chemokines
Intercellular Signaling Peptides and Proteins
Research Design
Up-Regulation
RNA
Cytokines
Inflammation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Downregulation of hematopoietic MUC1 during Experimental colitis increases tumor-promoting myeloid-derived suppressor cells. / Poh, Tze Wei; Madsen, Cathy S.; Gorman, Jessica E.; Marler, Ronald J; Leighton, Jonathan A; Cohen, Peter A; Gendler, Sandra J.

In: Clinical Cancer Research, Vol. 19, No. 18, 15.09.2013, p. 5039-5052.

Research output: Contribution to journalArticle

@article{8c2ac18acd6345e886d3f03eca8d9695,
title = "Downregulation of hematopoietic MUC1 during Experimental colitis increases tumor-promoting myeloid-derived suppressor cells",
abstract = "Purpose: 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. Experimental Design: To mechanistically confirm the linkage between Muc1 downregulation and MDSCexpansion, 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). Results: 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. Conclusion: 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.",
author = "Poh, {Tze Wei} and Madsen, {Cathy S.} and Gorman, {Jessica E.} and Marler, {Ronald J} and Leighton, {Jonathan A} and Cohen, {Peter A} and Gendler, {Sandra J}",
year = "2013",
month = "9",
day = "15",
doi = "10.1158/1078-0432.CCR-13-0278",
language = "English (US)",
volume = "19",
pages = "5039--5052",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - Downregulation of hematopoietic MUC1 during Experimental colitis increases tumor-promoting myeloid-derived suppressor cells

AU - Poh, Tze Wei

AU - Madsen, Cathy S.

AU - Gorman, Jessica E.

AU - Marler, Ronald J

AU - Leighton, Jonathan A

AU - Cohen, Peter A

AU - Gendler, Sandra J

PY - 2013/9/15

Y1 - 2013/9/15

N2 - Purpose: 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. Experimental Design: To mechanistically confirm the linkage between Muc1 downregulation and MDSCexpansion, 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). Results: 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. Conclusion: 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.

AB - Purpose: 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. Experimental Design: To mechanistically confirm the linkage between Muc1 downregulation and MDSCexpansion, 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). Results: 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. Conclusion: 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.

UR - http://www.scopus.com/inward/record.url?scp=84884570755&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884570755&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-13-0278

DO - 10.1158/1078-0432.CCR-13-0278

M3 - Article

VL - 19

SP - 5039

EP - 5052

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 18

ER -