Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Lung inflammatory injury and tissue repair (Jul 2023)
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma
Hideaki Ijichi, … , Masao Omata, Harold L. Moses
Hideaki Ijichi, … , Masao Omata, Harold L. Moses
Published September 19, 2011
Citation Information: J Clin Invest. 2011;121(10):4106-4117. https://doi.org/10.1172/JCI42754.
View: Text | PDF
Research Article Oncology

Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma

  • Text
  • PDF
Abstract

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized by an expanded stroma with marked fibrosis (desmoplasia). We previously generated pancreas epithelium–specific TGF-β receptor type II (Tgfbr2) knockout mice in the context of Kras activation (mice referred to herein as Kras+Tgfbr2KO mice) and found that they developed aggressive PDAC that recapitulated the histological manifestations of the human disease. The mouse PDAC tissue showed strong expression of connective tissue growth factor (Ctgf), a profibrotic and tumor-promoting factor, especially in the tumor-stromal border area, suggesting an active tumor-stromal interaction. Here we show that the PDAC cells in Kras+Tgfbr2KO mice secreted much higher levels of several Cxc chemokines compared with mouse pancreatic intraepithelial neoplasia cells, which are preinvasive. The Cxc chemokines induced Ctgf expression in the pancreatic stromal fibroblasts, not in the PDAC cells themselves. Subcutaneous grafting studies revealed that the fibroblasts enhanced growth of PDAC cell allografts, which was attenuated by Cxcr2 inhibition. Moreover, treating the Kras+Tgfbr2KO mice with the CXCR2 inhibitor reduced tumor progression. The decreased tumor progression correlated with reduced Ctgf expression and angiogenesis and increased overall survival. Taken together, our data indicate that tumor-stromal interactions via a Cxcr2-dependent chemokine and Ctgf axis can regulate PDAC progression. Further, our results suggest that inhibiting tumor-stromal interactions might be a promising therapeutic strategy for PDAC.

Authors

Hideaki Ijichi, Anna Chytil, Agnieszka E. Gorska, Mary E. Aakre, Brian Bierie, Motohisa Tada, Dai Mohri, Koji Miyabayashi, Yoshinari Asaoka, Shin Maeda, Tsuneo Ikenoue, Keisuke Tateishi, Christopher V.E. Wright, Kazuhiko Koike, Masao Omata, Harold L. Moses

×

Figure 1

Stromal components in Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox PDAC and Ptf1acre/+;LSL-KrasG12D/+ mPanIN tissue.

Options: View larger image (or click on image) Download as PowerPoint
Stromal components in Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox PDAC and...
(A) Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox PDAC stroma demonstrated prominent collagen deposition with Trichrome Blue staining and abundant macrophage and histiocyte infiltration with F4-80 immunostaining. PDAC also showed positive vascular endothelial cell staining with von Willebrand factor immunostaining, specifically in the invasion front area. Ptf1acre/+;LSL-KrasG12D/+ mPanIN stroma also showed stromal expansion to a lesser extent. (B) Fibroblast antigens (S100a4, Ng2, α-SMA) were abundantly observed in the stroma of both mPanIN and PDAC. Scale bars: 125 μm.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts