PMID- 30550822
OWN - NLM
STAT- MEDLINE
DCOM- 20190503
LR  - 20190503
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Linking)
VI  - 156
IP  - 5
DP  - 2019 Apr
TI  - Neutrophils Restrict Tumor-Associated Microbiota to Reduce Growth and Invasion of
      Colon Tumors in Mice.
PG  - 1467-1482
LID - S0016-5085(18)35399-X [pii]
LID - 10.1053/j.gastro.2018.12.003 [doi]
AB  - BACKGROUND & AIMS: Neutrophils are among the most prevalent immune cells in the
      microenvironment of colon tumors; they are believed to promote growth of colon
      tumors, and their numbers correlate with outcomes of patients with colon cancer. 
      Trials of inhibitors of neutrophil trafficking are underway in patients with
      cancer, but it is not clear how neutrophils contribute to colon tumorigenesis.
      METHODS: Colitis-associated colon cancer was induced in mice with conditional
      deletion of neutrophils (LysMCre;Mcl1(fl/fl)) and wild-type littermates
      (LysMCre;Mcl1(wt/wt), control mice) by administration of azoxythmethane and/or
      dextran sulfate sodium. Sporadic colon tumorigenesis was assessed in
      neutrophil-deficient and neutrophil-replete mice with conditional deletion of
      colon epithelial Apc (Cdx2-CreERT2;Apc(fl/fl)). Primary colon tumor tissues from 
      these mice were assessed by histology, RNA sequencing, quantitative polymerase
      chain reaction, and fluorescence in situ hybridization analyses. Fecal and
      tumor-associated microbiota were assessed by 16s ribosomal RNA sequencing.
      RESULTS: In mice with inflammation-induced and sporadic colon tumors, depletion
      of neutrophils increased the growth, proliferation, and invasiveness of the
      tumors. RNA sequencing analysis identified genes that regulate antimicrobial and 
      inflammatory processes that were dysregulated in neutrophil-deficient colon
      tumors compared with colon tumors from control mice. Neutrophil depletion
      correlated with increased numbers of bacteria in tumors and proliferation of
      tumor cells, tumor-cell DNA damage, and an inflammatory response mediated by
      interleukin 17 (IL17). The 16s ribosomal RNA sequencing identified significant
      differences in the composition of the microbiota between colon tumors from
      neutrophil-deficient vs control mice. Administration of antibiotics or a
      neutralizing antibody against IL17 to neutrophil-deficient mice resulted in
      development of less-invasive tumors compared with mice given vehicle. We found
      bacteria in tumors to induce production of IL17, which promotes influx of
      intratumor B cells that promote tumor growth and progression. CONCLUSIONS: In
      comparisons of mice with vs without neutrophils, we found neutrophils to slow
      colon tumor growth and progression by restricting numbers of bacteria and
      tumor-associated inflammatory responses.
CI  - Copyright (c) 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Triner, Daniel
AU  - Triner D
AD  - Molecular and Integrative Physiology, University of Michigan Medical School, Ann 
      Arbor, Michigan.
FAU - Devenport, Samantha N
AU  - Devenport SN
AD  - Molecular and Integrative Physiology, University of Michigan Medical School, Ann 
      Arbor, Michigan.
FAU - Ramakrishnan, Sadeesh K
AU  - Ramakrishnan SK
AD  - Molecular and Integrative Physiology, University of Michigan Medical School, Ann 
      Arbor, Michigan.
FAU - Ma, Xiaoya
AU  - Ma X
AD  - Molecular and Integrative Physiology, University of Michigan Medical School, Ann 
      Arbor, Michigan.
FAU - Frieler, Ryan A
AU  - Frieler RA
AD  - Molecular and Integrative Physiology, University of Michigan Medical School, Ann 
      Arbor, Michigan.
FAU - Greenson, Joel K
AU  - Greenson JK
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor,
      Michigan.
FAU - Inohara, Naohiro
AU  - Inohara N
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor,
      Michigan.
FAU - Nunez, Gabriel
AU  - Nunez G
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor,
      Michigan; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, 
      Michigan.
FAU - Colacino, Justin A
AU  - Colacino JA
AD  - Department of Environmental Health Sciences, University of Michigan School of
      Public Health, Ann Arbor, Michigan; Department of Nutritional Sciences,
      University of Michigan School of Public Health, Ann Arbor, Michigan.
FAU - Mortensen, Richard M
AU  - Mortensen RM
AD  - Molecular and Integrative Physiology, University of Michigan Medical School, Ann 
      Arbor, Michigan; Internal Medicine Division of Metabolism, Endocrinology, and
      Diabetes, University of Michigan Medical School, Ann Arbor, Michigan.
FAU - Shah, Yatrik M
AU  - Shah YM
AD  - Molecular and Integrative Physiology, University of Michigan Medical School, Ann 
      Arbor, Michigan; Rogel Cancer Center, University of Michigan Medical School, Ann 
      Arbor, Michigan; Internal Medicine Division of Gastroenterology, University of
      Michigan Medical School, Ann Arbor, Michigan. Electronic address:
      shahy@umich.edu.
LA  - eng
GR  - K99 DK110537/DK/NIDDK NIH HHS/United States
GR  - R01 CA148828/CA/NCI NIH HHS/United States
GR  - R01 DK095201/DK/NIDDK NIH HHS/United States
GR  - F30 CA213664/CA/NCI NIH HHS/United States
GR  - R01 ES028802/ES/NIEHS NIH HHS/United States
GR  - P50 CA130810/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, N.I.H., Extramural
DEP - 20181211
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Interleukin-17)
RN  - 9042-14-2 (Dextran Sulfate)
RN  - MO0N1J0SEN (Azoxymethane)
SB  - AIM
SB  - IM
MH  - Adenocarcinoma/genetics/*immunology/microbiology/pathology
MH  - Animals
MH  - Anti-Bacterial Agents/pharmacology
MH  - Antibodies, Neutralizing/pharmacology
MH  - Azoxymethane
MH  - Bacteria/drug effects/*growth & development/immunology
MH  - *Cell Movement/drug effects
MH  - *Cell Proliferation/drug effects
MH  - Cell Transformation, Neoplastic/genetics/immunology/pathology
MH  - Colonic Neoplasms/genetics/*immunology/microbiology/pathology
MH  - Dextran Sulfate
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Female
MH  - Host-Pathogen Interactions
MH  - Interleukin-17/antagonists & inhibitors/immunology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neoplasm Invasiveness
MH  - Neutrophils/drug effects/*immunology
MH  - Tumor Burden
MH  - Tumor Microenvironment
PMC - PMC6441634
MID - NIHMS1516483
OTO - NOTNLM
OT  - *Antitumor Immune Response
OT  - *Cytotoxic
OT  - *Genetic
OT  - *PMNs
EDAT- 2018/12/15 06:00
MHDA- 2019/05/06 06:00
CRDT- 2018/12/15 06:00
PMCR- 2020/04/01 00:00
PHST- 2018/05/16 00:00 [received]
PHST- 2018/11/26 00:00 [revised]
PHST- 2018/12/05 00:00 [accepted]
PHST- 2020/04/01 00:00 [pmc-release]
PHST- 2018/12/15 06:00 [pubmed]
PHST- 2019/05/06 06:00 [medline]
PHST- 2018/12/15 06:00 [entrez]
AID - S0016-5085(18)35399-X [pii]
AID - 10.1053/j.gastro.2018.12.003 [doi]
PST - ppublish
SO  - Gastroenterology. 2019 Apr;156(5):1467-1482. doi: 10.1053/j.gastro.2018.12.003.
      Epub 2018 Dec 11.