Genetic Deficiency of the Histamine H<sub>4</sub>-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice
Colorectal cancer (CRC), a severe complication of inflammatory bowel diseases, is a common type of cancer and accounts for high mortality. CRC can be modeled in mice by application of the tumor promoter, azoxymethane (AOM), in combination with dextran sodium sulfate (DSS), which are able to induce c...
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doaj-6fc268a173784a2e8d804477729b7fdb2020-11-25T02:23:41ZengMDPI AGCancers2072-66942020-04-011291291210.3390/cancers12040912Genetic Deficiency of the Histamine H<sub>4</sub>-Receptor Reduces Experimental Colorectal Carcinogenesis in MiceBastian Schirmer0Tamina Rother1Inga Bruesch2Andre Bleich3Christopher Werlein4Danny Jonigk5Roland Seifert6Detlef Neumann7Institute of Pharmacology, Hannover Medical School, 30625 Hannover, GermanyInstitute of Pharmacology, Hannover Medical School, 30625 Hannover, GermanyInstitute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, GermanyInstitute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, GermanyInstitute of Pathology and German Center of Lung Research (DZL), Partner site BREATH, Hannover Medical School, 30625 Hannover, GermanyInstitute of Pathology and German Center of Lung Research (DZL), Partner site BREATH, Hannover Medical School, 30625 Hannover, GermanyInstitute of Pharmacology, Hannover Medical School, 30625 Hannover, GermanyInstitute of Pharmacology, Hannover Medical School, 30625 Hannover, GermanyColorectal cancer (CRC), a severe complication of inflammatory bowel diseases, is a common type of cancer and accounts for high mortality. CRC can be modeled in mice by application of the tumor promoter, azoxymethane (AOM), in combination with dextran sodium sulfate (DSS), which are able to induce colitis-like manifestations. Active colitis correlates with high mucosal concentrations of histamine, which, together with the histamine receptor subtype 4 (H<sub>4</sub>R), provide a pro-inflammatory function in a mouse colitis model. Here, we analyzed whether H<sub>4</sub>R is involved in the pathogenesis of AOM/DSS-induced CRC in mice. As compared to wild type (WT) mice, AOM/DSS-treated mice lacking H<sub>4</sub>R expression (TM) demonstrate ameliorated signs of CRC, i.e., significantly reduced loss of body weight, stiffer stool consistency, and less severe perianal bleeding. Importantly, numbers and diameters of tumors and the degree of colonic inflammation are dramatically reduced in TM mice as compared to WT mice. This is concomitant with a reduced colonic inflammatory response involving expression of cyclooxygenase 2 and the production of C-X-C motif chemokine ligand 1 (CXCL1) and CXCL2. We conclude that H<sub>4</sub>R is involved in the tumorigenesis of chemically-induced CRC in mice via cyclooxygenase 2 expression and, probably, CXCL1 and CXCL2 as effector molecules.https://www.mdpi.com/2072-6694/12/4/912histamineH<sub>4</sub> receptorcolorectal cancermouse modelcyclooxygenase 2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bastian Schirmer Tamina Rother Inga Bruesch Andre Bleich Christopher Werlein Danny Jonigk Roland Seifert Detlef Neumann |
spellingShingle |
Bastian Schirmer Tamina Rother Inga Bruesch Andre Bleich Christopher Werlein Danny Jonigk Roland Seifert Detlef Neumann Genetic Deficiency of the Histamine H<sub>4</sub>-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice Cancers histamine H<sub>4</sub> receptor colorectal cancer mouse model cyclooxygenase 2 |
author_facet |
Bastian Schirmer Tamina Rother Inga Bruesch Andre Bleich Christopher Werlein Danny Jonigk Roland Seifert Detlef Neumann |
author_sort |
Bastian Schirmer |
title |
Genetic Deficiency of the Histamine H<sub>4</sub>-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice |
title_short |
Genetic Deficiency of the Histamine H<sub>4</sub>-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice |
title_full |
Genetic Deficiency of the Histamine H<sub>4</sub>-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice |
title_fullStr |
Genetic Deficiency of the Histamine H<sub>4</sub>-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice |
title_full_unstemmed |
Genetic Deficiency of the Histamine H<sub>4</sub>-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice |
title_sort |
genetic deficiency of the histamine h<sub>4</sub>-receptor reduces experimental colorectal carcinogenesis in mice |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-04-01 |
description |
Colorectal cancer (CRC), a severe complication of inflammatory bowel diseases, is a common type of cancer and accounts for high mortality. CRC can be modeled in mice by application of the tumor promoter, azoxymethane (AOM), in combination with dextran sodium sulfate (DSS), which are able to induce colitis-like manifestations. Active colitis correlates with high mucosal concentrations of histamine, which, together with the histamine receptor subtype 4 (H<sub>4</sub>R), provide a pro-inflammatory function in a mouse colitis model. Here, we analyzed whether H<sub>4</sub>R is involved in the pathogenesis of AOM/DSS-induced CRC in mice. As compared to wild type (WT) mice, AOM/DSS-treated mice lacking H<sub>4</sub>R expression (TM) demonstrate ameliorated signs of CRC, i.e., significantly reduced loss of body weight, stiffer stool consistency, and less severe perianal bleeding. Importantly, numbers and diameters of tumors and the degree of colonic inflammation are dramatically reduced in TM mice as compared to WT mice. This is concomitant with a reduced colonic inflammatory response involving expression of cyclooxygenase 2 and the production of C-X-C motif chemokine ligand 1 (CXCL1) and CXCL2. We conclude that H<sub>4</sub>R is involved in the tumorigenesis of chemically-induced CRC in mice via cyclooxygenase 2 expression and, probably, CXCL1 and CXCL2 as effector molecules. |
topic |
histamine H<sub>4</sub> receptor colorectal cancer mouse model cyclooxygenase 2 |
url |
https://www.mdpi.com/2072-6694/12/4/912 |
work_keys_str_mv |
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