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Elevated expression of the colony-stimulating factor 1 (CSF1) induces prostatic intraepithelial neoplasia dependent of epithelial-Gp130

Oncogene volume 41, pages 1309–1323 (2022)Cite this article

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Abstract

Macrophages are increased in human benign prostatic hyperplasia and prostate cancer. We generate a Pb-Csf1 mouse model with prostate-specific overexpression of macrophage colony-stimulating factor (M-Csf/Csf1). Csf1 overexpression promotes immune cell infiltration into the prostate, modulates the macrophage polarity in a lobe-specific manner, and induces senescence and low-grade prostatic intraepithelial neoplasia (PIN). The Pb-Csf1 prostate luminal cells exhibit increased stem cell features and undergo an epithelial-to-mesenchymal transition. Human prostate cancer patients with high CSF-1 expression display similar transcriptional alterations with the Pb-Csf1 model. P53 knockout alleviates senescence but fails to progress PIN lesions. Ablating epithelial Gp130 but not Il1r1 substantially blocks PIN lesion formation. The androgen receptor (AR) is downregulated in Pb-Csf1 mice. ChIP-Seq analysis reveals altered AR binding in 2482 genes although there is no significant widespread change in global AR transcriptional activity. Collectively, our study demonstrates that increased macrophage infiltration causes PIN formation but fails to transform prostate cells.

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Fig. 1: Csf1 overexpression recruits immune cells and alters polarization of macrophage in mouse prostate.
Fig. 2: Csf1 overexpression causes prostatic intraepithelial neoplasia.
Fig. 3: RNA-seq reveals inflammation-induced molecular changes in prostate luminal cells.
Fig. 4: Csf1 overexpression increases EMT and progenitor activity-related gene signatures.
Fig. 5: Attenuating p53-mediated senescence promotes initiation of PIN lesions.
Fig. 6: Il6-Gp130 signaling is necessary for formation of Csf1-induced prostate intraepithelial neoplasia.
Fig. 7: Prostate inflammation alters AR transcriptome.

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Code availability

RNA-Seq data have been deposited to GEO: GSA134326.

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Acknowledgements

We thank Dr. Fen Wang for the ARR2PB-Cre mice, Dr. Rodger McEver for the Gp130fl/fl mice, and Dr. Richard Stanley for the mouse Csf-1 cDNA. This work is supported by R01CA190378, R01DK092202 and R01DK107436 (L.X.).

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  1. These authors contributed equally: Oh-Joon Kwon, Boyu Zhang.

Authors and Affiliations

  1. Department of Urology, University of Washington, Seattle, WA, 98109, USA

    Oh-Joon Kwon, Deyong Jia, Li Zhang, Xing Wei, Zhicheng Zhou, Kai Zhang & Li Xin

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Boyu Zhang

  3. Sandra and Edward Meyer Cancer Center and Department of Urology, Weill Cornell Medicine, New York, NY, USA

    Deli Liu, Andrea Sboner & Chris Barbieri

  4. Department of Biology, University of Washington, Seattle, WA, 98109, USA

    Khoi Trung Huynh

  5. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Yiqun Zhang & Chad J. Creighton

  6. Active Motif, San Diego, CA, USA

    Paul Labhart

  7. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98109, USA

    Michael C. Haffner

  8. Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, 98109, USA

    Li Xin

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Contributions

LX, BZ, and OK designed the experiments. OK, BZ, LZ, XW, ZZ, DJ, KTH, DL and KZ performed experiments. OK, BZ, YZ, PL, CJC, MH, AS, CB, and LX analyzed the data. LX wrote the manuscript with input from other authors. OK and BZ contributed equally to the work.

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Correspondence to Li Xin.

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Kwon, OJ., Zhang, B., Jia, D. et al. Elevated expression of the colony-stimulating factor 1 (CSF1) induces prostatic intraepithelial neoplasia dependent of epithelial-Gp130. Oncogene 41, 1309–1323 (2022). https://doi.org/10.1038/s41388-021-02169-7

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