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C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation

Numerous factors have been claimed to play important roles in colorectal cancer (CRC) tumorigenesis, including myeloid-derived suppressor cells (MDSCs) and other immune cells, cytokines, and chemokines; however, the precise mechanisms of colorectal tumorigenesis remain elusive, and there is a lack o...

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Autores principales: Ding, Peipei, Li, Ling, Li, Luying, Lv, Xinyue, Zhou, Danlei, Wang, Qingkai, Chen, Jianfeng, Yang, Chaoqun, Xu, Enjie, Dai, Weixing, Zhang, Xin, Wang, Na, Wang, Qi, Zhang, Wei, Zhang, Long, Zhou, Yuzhen, Gu, Hongyu, Lei, Qunying, Zhou, Xuhui, Hu, Weiguo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392014/
https://www.ncbi.nlm.nih.gov/pubmed/32754267
http://dx.doi.org/10.7150/thno.45058
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author Ding, Peipei
Li, Ling
Li, Luying
Lv, Xinyue
Zhou, Danlei
Wang, Qingkai
Chen, Jianfeng
Yang, Chaoqun
Xu, Enjie
Dai, Weixing
Zhang, Xin
Wang, Na
Wang, Qi
Zhang, Wei
Zhang, Long
Zhou, Yuzhen
Gu, Hongyu
Lei, Qunying
Zhou, Xuhui
Hu, Weiguo
author_facet Ding, Peipei
Li, Ling
Li, Luying
Lv, Xinyue
Zhou, Danlei
Wang, Qingkai
Chen, Jianfeng
Yang, Chaoqun
Xu, Enjie
Dai, Weixing
Zhang, Xin
Wang, Na
Wang, Qi
Zhang, Wei
Zhang, Long
Zhou, Yuzhen
Gu, Hongyu
Lei, Qunying
Zhou, Xuhui
Hu, Weiguo
author_sort Ding, Peipei
collection PubMed
description Numerous factors have been claimed to play important roles in colorectal cancer (CRC) tumorigenesis, including myeloid-derived suppressor cells (MDSCs) and other immune cells, cytokines, and chemokines; however, the precise mechanisms of colorectal tumorigenesis remain elusive, and there is a lack of effective preventive treatments. Here, we investigated the role of complement system, a key regulator of immune surveillance and homeostasis, in colorectal tumorigenesis. Methods: The prototypical CRC model was induced by combined administration of azoxymethane (AOM)/ dextran sulfate sodium (DSS) in Wild-type (WT), C3-, C5-, C5ar1-, and C5ar2-deficient mice. Using flow cytometry, immunohistochemical staining and multiplex bead assay, we profiled the immune cells, cytokines and chemokines. Bone marrow transplantation was employed to determine the contribution of immune cells in colorectal tumorigenesis. Further, we used C5aR1 antagonist PMX205 to investigate the protective role in colorectal tumorigenesis. Results: Complement was extensively activated in inflamed tissues of AOM/DSS-induced murine CRC model, leading to multifaceted consequences. The deficiency of complement C5 or especially C5ar1, but not C3 almost completely prevented CRC tumorigenesis. C5a/C5aR1 signaling recruited MDSCs into the inflamed colorectum to impair CD8(+) T cells, and modulated the production of critical cytokines and chemokines, thus initiating CRC. Moreover, the C5aR1 antagonist PMX205 strongly impeded colorectal tumorigenesis. Bone marrow transplantation further revealed that C5aR1 expression by immune cells was critical for colorectal tumorigenesis. Conclusion: Our study identifies C5a/C5aR1 signaling as a vital immunomodulatory program in CRC tumorigenesis and suggests a feasible preventive strategy.
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spelling pubmed-73920142020-08-03 C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation Ding, Peipei Li, Ling Li, Luying Lv, Xinyue Zhou, Danlei Wang, Qingkai Chen, Jianfeng Yang, Chaoqun Xu, Enjie Dai, Weixing Zhang, Xin Wang, Na Wang, Qi Zhang, Wei Zhang, Long Zhou, Yuzhen Gu, Hongyu Lei, Qunying Zhou, Xuhui Hu, Weiguo Theranostics Research Paper Numerous factors have been claimed to play important roles in colorectal cancer (CRC) tumorigenesis, including myeloid-derived suppressor cells (MDSCs) and other immune cells, cytokines, and chemokines; however, the precise mechanisms of colorectal tumorigenesis remain elusive, and there is a lack of effective preventive treatments. Here, we investigated the role of complement system, a key regulator of immune surveillance and homeostasis, in colorectal tumorigenesis. Methods: The prototypical CRC model was induced by combined administration of azoxymethane (AOM)/ dextran sulfate sodium (DSS) in Wild-type (WT), C3-, C5-, C5ar1-, and C5ar2-deficient mice. Using flow cytometry, immunohistochemical staining and multiplex bead assay, we profiled the immune cells, cytokines and chemokines. Bone marrow transplantation was employed to determine the contribution of immune cells in colorectal tumorigenesis. Further, we used C5aR1 antagonist PMX205 to investigate the protective role in colorectal tumorigenesis. Results: Complement was extensively activated in inflamed tissues of AOM/DSS-induced murine CRC model, leading to multifaceted consequences. The deficiency of complement C5 or especially C5ar1, but not C3 almost completely prevented CRC tumorigenesis. C5a/C5aR1 signaling recruited MDSCs into the inflamed colorectum to impair CD8(+) T cells, and modulated the production of critical cytokines and chemokines, thus initiating CRC. Moreover, the C5aR1 antagonist PMX205 strongly impeded colorectal tumorigenesis. Bone marrow transplantation further revealed that C5aR1 expression by immune cells was critical for colorectal tumorigenesis. Conclusion: Our study identifies C5a/C5aR1 signaling as a vital immunomodulatory program in CRC tumorigenesis and suggests a feasible preventive strategy. Ivyspring International Publisher 2020-07-09 /pmc/articles/PMC7392014/ /pubmed/32754267 http://dx.doi.org/10.7150/thno.45058 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Ding, Peipei
Li, Ling
Li, Luying
Lv, Xinyue
Zhou, Danlei
Wang, Qingkai
Chen, Jianfeng
Yang, Chaoqun
Xu, Enjie
Dai, Weixing
Zhang, Xin
Wang, Na
Wang, Qi
Zhang, Wei
Zhang, Long
Zhou, Yuzhen
Gu, Hongyu
Lei, Qunying
Zhou, Xuhui
Hu, Weiguo
C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation
title C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation
title_full C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation
title_fullStr C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation
title_full_unstemmed C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation
title_short C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation
title_sort c5ar1 is a master regulator in colorectal tumorigenesis via immune modulation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392014/
https://www.ncbi.nlm.nih.gov/pubmed/32754267
http://dx.doi.org/10.7150/thno.45058
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