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Jagged1 upregulation in prostate epithelial cells promotes formation of reactive stroma in the Pten null mouse model for prostate cancer

Oncogene volume 36, pages 618–627 (2017)Cite this article

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Abstract

The role of Notch signaling in prostate cancer has not been defined definitively. Several large scale tissue microarray studies have revealed that the expression of some Notch signaling components including the Jagged1 ligand are upregulated in advanced human prostate cancer specimens. Jagged1 expressed by tumor cells may activate Notch signaling in both adjacent tumor cells and cells in tumor microenvironment. However, it remains undetermined whether increased Jagged1 expression reflects a cause for or a consequence of tumor progression in vivo. To address this question, we generated a novel R26-LSL-JAG1 mouse model that enables spatiotemporal Jagged1 expression. Prostate specific upregulation of Jagged1 neither interferes with prostate epithelial homeostasis nor significantly accelerates tumor initiation or progression in the prostate-specific Pten deletion mouse model for prostate cancer. However, Jagged1 upregulation results in increased inflammatory foci in tumors and incidence of intracystic adenocarcinoma. In addition, Jagged1 overexpression upregulates Tgfβ signaling in prostate stromal cells and promotes progression of a reactive stromal microenvironment in the Pten null prostate cancer model. Collectively, Jagged1 overexpression does not significantly accelerate prostate cancer initiation and progression in the context of loss-of-function of Pten, but alters tumor histopathology and microenvironment. Our study also highlights an understudied role of Notch signaling in regulating prostatic stromal homeostasis.

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Acknowledgements

We thank Dr Spyros Artavanis-Tsakonas for providing the human Jagged1 cDNA, the technical support by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH (P30 AI036211, P30 CA125123 and S10 RR024574) and the expert assistance of Joel M. Sederstrom. This work is supported by NIH R01 CA190378 (L.X.), CA196570 (L.X.), NIH P30 CA125123 (the Cancer Center Shared Resources Grant), the Mouse Embryonic Stem Cell Core at Baylor College of Medicine and NCI.

Author contributions

QS, BZ, LZ and TD: collection and assembly of the data, data analysis and interpretation. DR and MI: data analysis and interpretation. LX: conception and design, manuscript writing, collection and/or assembly of the data, data analysis and interpretation, and final approval of manuscript.

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Authors and Affiliations

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

    Q Su, B Zhang, L Zhang, T Dang, D Rowley & L Xin

  2. Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX, USA

    Q Su

  3. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    D Rowley, M Ittmann & L Xin

  4. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

    M Ittmann

  5. Michael E. DeBakey Department of Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX, USA

    M Ittmann

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Correspondence to L Xin.

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Su, Q., Zhang, B., Zhang, L. et al. Jagged1 upregulation in prostate epithelial cells promotes formation of reactive stroma in the Pten null mouse model for prostate cancer. Oncogene 36, 618–627 (2017). https://doi.org/10.1038/onc.2016.232

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