Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis
Open accessAbstract
The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development. However, CXCR2 influences tumors through multiple mechanisms and might promote or inhibit tumor development depending on context. Here, we used several mouse models of spontaneous and inflammation-driven neoplasia to define indispensable roles for CXCR2 in benign and malignant tumors. CXCR2-activating chemokines were part of the secretome of cultured primary benign intestinal adenomas (ApcMin/+) and highly expressed by all tumors in all models. CXCR2 deficiency profoundly suppressed inflammation-driven tumorigenesis in skin and intestine as well as spontaneous adenocarcinoma formation in a model of invasive intestinal adenocarcinoma (AhCreER;Apcfl/+;Ptenfl/fl mice). Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in ApcMin/+ mice. Ly6G+ neutrophils were the dominant source of CXCR2 in blood, and CXCR2 deficiency attenuated neutrophil recruitment. Moreover, systemic Ly6G+ cell depletion purged CXCR2-dependent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis, and reduced ApcMin/+ adenoma formation. CXCR2 is thus a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues during tumor-inducing and tumor-driven inflammation. Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Data from various mouse models indicate that disrupting the CXCR1/2-MDSC axis is therapeutically efficacious across a wide variety of solid cancers.
“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 [170]
Cites
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204 · see citing works
Cancer and the chemokine network
Balkwill, F. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1388 · Cited by 2,343 · see citing works
Chemokine signaling via the CXCR2 receptor reinforces senescence
Acosta, J. C., O'Loghlen, A., Banito, A., Guijarro, M. V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., et al. (2008) · Cell · doi:10.1016/j.cell.2008.03.038 · Cited by 1,801 · cited 5× · see citing works
“O -tetradecanoyl phorbol-13-acetate (TPA), generates inflammation-driven prema-lignant lesions that express high levels of senescence markers (21, 29).”
InfluentialYang, L., Huang, J., Ren, X., Gorska, A. E., Chytil, A., Aakre, M., Carbone, D. P., Matrisian, L. M., Richmond, A., Lin, P. C., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2007.12.004 · Cited by 918 · see citing works
Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis
Moore, R. J., Owens, D. M., Stamp, G., Arnott, C., Burke, F., East, N., Holdsworth, H., Turner, L., Rollins, B., Pasparakis, M., et al. (1999) · Nature Medicine · doi:10.1038/10552 · Cited by 839 · see citing works
Ijichi, H., Chytil, A., Gorska, A. E., Aakre, M. E., Bierie, B., Tada, M., Mohri, D., Miyabayashi, K., Asaoka, Y., Maeda, S., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci42754 · Cited by 256 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Understanding the tumor immune microenvironment (TIME) for effective therapy
Binnewies, M., Roberts, E. W., Kersten, K., Chan, V., Fearon, D. F., Merad, M., Coussens, L. M., Gabrilovich, D. I., Ostrand-Rosenberg, S., Hedrick, C. C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0014-x · Cited by 6,145 · see citing works
Roles of the immune system in cancer: From tumor initiation to metastatic progression
Gonzalez, H., Hagerling, C., & Werb, Z. (2018) · Genes & Development · doi:10.1101/gad.314617.118 · Cited by 2,111 · see citing works
Neutrophils in cancer: Neutral no more
Coffelt, S. B., Wellenstein, M. D., & de Visser, K. E. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.52 · Cited by 1,830 · see citing works
Neutrophil chemoattractant receptors in health and disease: Double-edged swords
Metzemaekers, M., Gouwy, M., & Proost, P. (2020) · Cellular & Molecular Immunology · doi:10.1038/s41423-020-0412-0 · Cited by 570 · see citing works
The current state of the art and future trends in RAS-targeted cancer therapies
Punekar, S. R., Velcheti, V., Neel, B. G., & Wong, K.-K. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00671-9 · Cited by 549 · see citing works
Genetically engineered mouse models in oncology research and cancer medicine
Kersten, K., de Visser, K. E., van Miltenburg, M. H., & Jonkers, J. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201606857 · Cited by 502 · see citing works
Katoh, H., Wang, D., Daikoku, T., Sun, H., Dey, S. K., & DuBois, R. N. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.10.009 · Cited by 477 · see citing works
Immunity, Hypoxia, and Metabolism–the Ménage à Trois of Cancer: Implications for Immunotherapy
Riera-Domingo, C., Audigé, A., Granja, S., Cheng, W.-C., Ho, P.-C., Baltazar, F., Stockmann, C., & Mazzone, M. (2020) · Physiological Reviews · doi:10.1152/physrev.00018.2019 · Cited by 310 · see citing works
Bird, T. G., Müller, M., Boulter, L., Vincent, D. F., Ridgway, R. A., Lopez-Guadamillas, E., Lu, W.-Y., Jamieson, T., Govaere, O., Campbell, A. D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan1230 · Cited by 261 · see citing works
“Genomic DNA decontamination, reverse transcription, and real-time PCR were performed using reagents and primers (QuantiFast and QuantiTect, respectively; Qiagen) on an ABI Prism 7500 cycler, except for chemokine/ chemokine receptor analysis, which was performed as previously described (55).”
MethodSelf-citationNFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma
Wilson, C. L., Jurk, D., Fullard, N., Banks, P., Page, A., Luli, S., Elsharkawy, A. M., Gieling, R. G., Chakraborty, J. B., Fox, C., et al. (2015) · Nature Communications · doi:10.1038/ncomms7818 · Cited by 171 · see citing works
Bryce, S. A., Wilson, R. A. M., Tiplady, E. M., Asquith, D. L., Bromley, S. K., Luster, A. D., Graham, G. J., & Nibbs, R. J. B. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501542 · Cited by 71 · see citing works
Self-citationSenescence Can Be BETter without the SASP?
Vizioli, M. G., & Adams, P. D. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0485 · Cited by 6 · see citing works
- Authors
- Jamieson, T., Clarke, M., Steele, C. W., Samuel, M. S., Neumann, J., Jung, A., Huels, D., Olson, M. F., Das, S., Nibbs, R. J. B., & Sansom, O. J.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- University of Glasgow (GB)
- Pathologisches Institut (DE)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2012-09-04
- Volume
- 122
- Issue
- 9
- Pages
- 3127-3144
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3428079
- OpenAlex
- W2042355069
- Cited by
- 391
- References
- 6
- Citations by year
- 2026: 12 · 2025: 32 · 2024: 27 · 2023: 22 · 2022: 33 · 2021: 31 · 2020: 32 · 2019: 25 · 2018: 32 · 2017: 28 · 2016: 26 · 2015: 33 · 2014: 29 · 2013: 26 · 2012: 3
- FWCI
- 14.38
- 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)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- UniSA Research Outputs Repository (University of South Australia) (submittedVersion)
- Funders
- Wellcome Trust
- Cancer Research UK (12481)
- Medical Research Council
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- CXCR2, chemokine receptors, inflammation-driven tumorigenesis, spontaneous tumor development, neutrophil recruitment, intestinal adenoma, colitis-associated colorectal cancer, skin cancer, pepducins, ApcMin/+ mice, CXCR2 antagonist, chemokines
- MeSH terms
- Adenocarcinoma, Adenoma, Animals, Azoxymethane, Cell Transformation, Neoplastic, Colitis, Colonic Neoplasms, Dermatitis, Contact, Mice, Inbred BALB C, Mice, Inbred C57BL, Peroxidase, Neutrophils, Papilloma, Precancerous Conditions, Skin Neoplasms, Tetradecanoylphorbol Acetate, 9,10-Dimethyl-1,2-benzanthracene, Gene Expression, Dextran Sulfate, Animals, Inbred Strains, Mice, Knockout, Statistics, Nonparametric, Chemokines, CXC, Receptors, Interleukin-8B, Tumor Burden, Mice, Mice, 129 Strain
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
