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Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma
Open accessAbstract
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.
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“Notably, data from various mouse models indicate that disrupting the CXCR1/2–MDSC axis in tumours is therapeutically efficacious across a wide variety of solid cancers166–172.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [169]
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“Moreover, the important role of CXCR2 in pancreatic adenocarcinoma models (Ijichi et al., 2011) and of S100A8/9 in colorectal cancer (Ichikawa et al., 2011) suggest that the relevance of targeting the CXCL1/2–S100A8/9 axis may extend beyond breast cancer.”
From A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis (2012) · cites this paper as Ijichi et al., 2011
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Metadata
- Authors
- Ijichi, H., Chytil, A., Gorska, A. E., Aakre, M. E., Bierie, B., Tada, M., Mohri, D., Miyabayashi, K., Asaoka, Y., Maeda, S., Ikenoue, T., Tateishi, K., Wright, C. V. E., Koike, K., Omata, M., & Moses, H. L.
- Affiliations
- The University of Tokyo (JP)
- Vanderbilt University (US)
- Whitehead Institute for Biomedical Research (US)
- Chiba University (JP)
- Yokohama City University (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Yamanashi Prefectural Central Hospital (JP)
- Corresponding author
- Ijichi, Hideaki
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2011-10-03
- Volume
- 121
- Issue
- 10
- Pages
- 4106-4117
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3195452
- OpenAlex
- W2014434319
- Cited by
- 256
- References
- 50
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 8 · 2023: 9 · 2022: 13 · 2021: 31 · 2020: 19 · 2019: 17 · 2018: 7 · 2017: 20 · 2016: 20 · 2015: 20 · 2014: 22 · 2013: 27 · 2012: 24
- FWCI
- 11.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Funders
- Vanderbilt University
- Ministry of Education, Culture, Sports, Science and Technology
- Foundation for Promotion of Cancer Research
- National Institutes of Health
- U.S. Public Health Service (U54126505)
- Japan Society for the Promotion of Science (23591011, 22501004)
- National Cancer Institute (CA 085492, R01CA085492, CA102162, R01CA102162)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Keywords
- pancreatic ductal adenocarcinoma, tumor-stroma interactions, connective tissue growth factor, CXCR2, CXCL chemokines, desmoplasia, TGFBR2, tumor angiogenesis, tumor growth, overall survival, pancreatic intraepithelial neoplasia
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type II, Animals, Female, Humans, Mice, Inbred C57BL, Mice, Nude, Pancreatic Neoplasms, Signal Transduction, Gene Expression, Proto-Oncogene Proteins p21(ras), Stromal Cells, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Mice, Knockout, Chemokines, CXC, Carcinoma, Pancreatic Ductal, Receptors, Interleukin-8B, Mice, Connective Tissue Growth Factor, Tumor Microenvironment
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