PMID- 30517646
OWN - NLM
STAT- MEDLINE
DCOM- 20200214
LR  - 20200214
IS  - 1536-4844 (Electronic)
IS  - 1078-0998 (Linking)
VI  - 25
IP  - 4
DP  - 2019 Mar 14
TI  - Tenascin-C Produced by Intestinal Myofibroblasts Promotes Colitis-associated 
      Cancer Development Through Angiogenesis.
PG  - 732-741
LID - 10.1093/ibd/izy368 [doi]
AB  - BACKGROUND: Colitis-associated cancer (CAC) is one of the prognostic factors in 
      inflammatory bowel disease (IBD), and prevention of CAC is a critical concern for 
      patients with IBD. Component cells of the microenvironment, especially 
      myofibroblasts, are known to affect tumor development, but the role of intestinal 
      myofibroblasts (IMFs) in CAC has not been clarified. Here, we explored the role 
      of IMFs in CAC and sought to identify candidate genes as novel therapeutic 
      targets for the prevention of CAC. METHODS: We used the azoxymethane 
      (AOM)/dextran sodium sulfate (DSS) model for dysplasia and CAC. Flow cytometry 
      and RNA sequencing (RNA-seq) were performed to obtain an unbiased gene expression 
      profile of IMFs. The transcriptome of significantly differentially expressed 
      genes was analyzed by RNA-seq, quantitative reverse transcriptase polymerase 
      chain reaction, and immunohistochemistry. RESULTS: Comparison of normal 
      intestinal fibroblasts and IMFs revealed 1045 genes with significantly 
      differential expression. Among them, we focused on tenascin-C (TNC; q = 0.00232, 
      Log2(Fold Change) = 3.87). Tenascin-C gene expression was markedly increased in 
      the dysplasia model compared with control and CAC model (P < 0.05). Tenascin-C 
      protein was barely expressed in normal and nondysplastic mucosa but strongly 
      expressed in the stroma around dysplastic lesions. Moreover, TNC surrounded and 
      enclosed integrin alphavbeta3-positive microvessels. Administration of ATN-161, an 
      antagonist of alphavbeta3-integrin, significantly suppressed tumorigenesis of CAC 
      through inhibition of angiogenesis (P < 0.05). CONCLUSIONS: In the early stages 
      of CAC, TNC produced by IMFs affects tumor development via integrin alphavbeta3-mediated 
      angiogenesis. Intestinal myofibroblasts might be a novel therapeutic target for 
      preventing CAC.
CI  - (c) 2018 Crohn's & Colitis Foundation. Published by Oxford University Press. All 
      rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
FAU - Kawamura, Takafumi
AU  - Kawamura T
AD  - Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, 
      Japan.
FAU - Yamamoto, Masayoshi
AU  - Yamamoto M
AD  - Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, 
      Japan.
FAU - Suzuki, Katsunori
AU  - Suzuki K
AD  - Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, 
      Japan.
FAU - Suzuki, Yuhi
AU  - Suzuki Y
AD  - Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, 
      Japan.
FAU - Kamishima, Megumu
AU  - Kamishima M
AD  - Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, 
      Japan.
FAU - Sakata, Mayu
AU  - Sakata M
AD  - Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, 
      Japan.
FAU - Kurachi, Kiyotaka
AU  - Kurachi K
AD  - Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, 
      Japan.
FAU - Setoh, Mitsutoshi
AU  - Setoh M
AD  - Department of Cellular and Molecular Anatomy, International Mass Imaging Center, 
      Hamamatsu University School of Medicine, Hamamatsu, Japan.
FAU - Konno, Hiroyuki
AU  - Konno H
AD  - Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, 
      Japan.
FAU - Takeuchi, Hiroya
AU  - Takeuchi H
AD  - Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, 
      Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Inflamm Bowel Dis
JT  - Inflammatory bowel diseases
JID - 9508162
RN  - 0 (Tenascin)
RN  - 0 (Tnc protein, mouse)
RN  - 9042-14-2 (Dextran Sulfate)
RN  - MO0N1J0SEN (Azoxymethane)
SB  - IM
MH  - Animals
MH  - Azoxymethane/toxicity
MH  - Cell Transformation, Neoplastic/metabolism/*pathology
MH  - Colitis/chemically induced/*complications/metabolism
MH  - Colonic Neoplasms/blood supply/etiology/metabolism/*pathology
MH  - Dextran Sulfate/toxicity
MH  - Gene Expression Profiling
MH  - Intestinal Mucosa/*metabolism/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Myofibroblasts/*metabolism/pathology
MH  - Neovascularization, Pathologic/etiology/metabolism/*pathology
MH  - Tenascin/genetics/*metabolism
OTO - NOTNLM
OT  - ATN-161
OT  - angiogenesis
OT  - colitis-associated cancer
OT  - intestinal myofibroblasts
OT  - tenascin-C
EDAT- 2018/12/06 06:00
MHDA- 2020/02/15 06:00
CRDT- 2018/12/06 06:00
PHST- 2018/09/05 00:00 [received]
PHST- 2018/12/06 06:00 [pubmed]
PHST- 2020/02/15 06:00 [medline]
PHST- 2018/12/06 06:00 [entrez]
AID - 5230928 [pii]
AID - 10.1093/ibd/izy368 [doi]
PST - ppublish
SO  - Inflamm Bowel Dis. 2019 Mar 14;25(4):732-741. doi: 10.1093/ibd/izy368.