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MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with act...

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Autores principales: Hennenberg, Eva Maria, Eyking, Annette, Reis, Henning, Cario, Elke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501609/
https://www.ncbi.nlm.nih.gov/pubmed/28686677
http://dx.doi.org/10.1371/journal.pone.0180834
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author Hennenberg, Eva Maria
Eyking, Annette
Reis, Henning
Cario, Elke
author_facet Hennenberg, Eva Maria
Eyking, Annette
Reis, Henning
Cario, Elke
author_sort Hennenberg, Eva Maria
collection PubMed
description Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with active UC with or without CAC, but not in non-UC patients with sporadic colon cancer. We investigated the consequences of ABCB1/MDR1 loss-of-function in a common murine model for CAC (AOM/DSS). Mice deficient in MDR1A (MDR1A KO) showed enhanced intratumoral inflammation and cellular damage, which were associated with reduced colonic tumor size and decreased degree of dysplasia, when compared to wild-type (WT). Increased cell injury correlated with reduced capacity for growth of MDR1A KO tumor spheroids cultured ex-vivo. Gene expression analysis by microarray demonstrated that MDR1A deficiency shaped the inflammatory response towards an anti-tumorigenic microenvironment by downregulating genes known to be important mediators of cancer progression (PTGS2 (COX2), EREG, IL-11). MDR1A KO tumors showed increased gene expression of TNFSF10 (TRAIL), a known inducer of cancer cell death, and CCL12, a strong trigger of B cell chemotaxis. Abundant B220+ B lymphocyte infiltrates with interspersed CD138+ plasma cells were recruited to the MDR1A KO tumor microenvironment, concomitant with high levels of immunoglobulin light chain genes. In contrast, MDR1A deficiency in RAG2 KO mice that lack both B and T cells aggravated colonic tumor progression. MDR1A KO CD19+ B cells, but not WT CD19+ B cells, suppressed growth of colonic tumor-derived spheroids from AOM/DSS-WT mice in an ex-vivo co-culture system, implying that B-cell regulated immune responses contributed to delayed tumor development in MDR1A deficiency. In conclusion, we provide first evidence that loss of ABCB1/MDR1 function may represent an essential tumor-suppressive host defense mechanism in CAC.
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spelling pubmed-55016092017-07-25 MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis Hennenberg, Eva Maria Eyking, Annette Reis, Henning Cario, Elke PLoS One Research Article Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with active UC with or without CAC, but not in non-UC patients with sporadic colon cancer. We investigated the consequences of ABCB1/MDR1 loss-of-function in a common murine model for CAC (AOM/DSS). Mice deficient in MDR1A (MDR1A KO) showed enhanced intratumoral inflammation and cellular damage, which were associated with reduced colonic tumor size and decreased degree of dysplasia, when compared to wild-type (WT). Increased cell injury correlated with reduced capacity for growth of MDR1A KO tumor spheroids cultured ex-vivo. Gene expression analysis by microarray demonstrated that MDR1A deficiency shaped the inflammatory response towards an anti-tumorigenic microenvironment by downregulating genes known to be important mediators of cancer progression (PTGS2 (COX2), EREG, IL-11). MDR1A KO tumors showed increased gene expression of TNFSF10 (TRAIL), a known inducer of cancer cell death, and CCL12, a strong trigger of B cell chemotaxis. Abundant B220+ B lymphocyte infiltrates with interspersed CD138+ plasma cells were recruited to the MDR1A KO tumor microenvironment, concomitant with high levels of immunoglobulin light chain genes. In contrast, MDR1A deficiency in RAG2 KO mice that lack both B and T cells aggravated colonic tumor progression. MDR1A KO CD19+ B cells, but not WT CD19+ B cells, suppressed growth of colonic tumor-derived spheroids from AOM/DSS-WT mice in an ex-vivo co-culture system, implying that B-cell regulated immune responses contributed to delayed tumor development in MDR1A deficiency. In conclusion, we provide first evidence that loss of ABCB1/MDR1 function may represent an essential tumor-suppressive host defense mechanism in CAC. Public Library of Science 2017-07-07 /pmc/articles/PMC5501609/ /pubmed/28686677 http://dx.doi.org/10.1371/journal.pone.0180834 Text en © 2017 Hennenberg et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Hennenberg, Eva Maria
Eyking, Annette
Reis, Henning
Cario, Elke
MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis
title MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis
title_full MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis
title_fullStr MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis
title_full_unstemmed MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis
title_short MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis
title_sort mdr1a deficiency restrains tumor growth in murine colitis-associated carcinogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501609/
https://www.ncbi.nlm.nih.gov/pubmed/28686677
http://dx.doi.org/10.1371/journal.pone.0180834
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