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Neutrophils are mediators of metastatic prostate cancer progression in bone.

Authors
  • Costanzo-Garvey, Diane L1
  • Keeley, Tyler1
  • Case, Adam J2
  • Watson, Gabrielle F2
  • Alsamraae, Massar1
  • Yu, Yangsheng1
  • Su, Kaihong1, 3
  • Heim, Cortney E1
  • Kielian, Tammy1
  • Morrissey, Colm4
  • Frieling, Jeremy S5
  • Cook, Leah M6
  • 1 Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Med Center, Omaha, NE, 68192, USA.
  • 2 Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
  • 3 Department of Medical Education, California University of Science and Medicine, San Bernadino, CA, USA.
  • 4 Department of Urology, University of Washington, Seattle, WA, USA.
  • 5 Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
  • 6 Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Med Center, Omaha, NE, 68192, USA. [email protected]
Type
Published Article
Journal
Cancer Immunology Immunotherapy
Publisher
Springer-Verlag
Publication Date
Feb 29, 2020
Identifiers
DOI: 10.1007/s00262-020-02527-6
PMID: 32114681
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Bone metastatic prostate cancer (BM-PCa) significantly reduces overall patient survival and is currently incurable. Current standard immunotherapy showed promising results for PCa patients with metastatic, but less advanced, disease (i.e., fewer than 20 bone lesions) suggesting that PCa growth in bone contributes to response to immunotherapy. We found that: (1) PCa stimulates recruitment of neutrophils, the most abundant immune cell in bone, and (2) that neutrophils heavily infiltrate regions of prostate tumor in bone of BM-PCa patients. Based on these findings, we examined the impact of direct neutrophil-prostate cancer interactions on prostate cancer growth. Bone marrow neutrophils directly induced apoptosis of PCa in vitro and in vivo, such that neutrophil depletion in bone metastasis models enhanced BM-PCa growth. Neutrophil-mediated PCa killing was found to be mediated by suppression of STAT5, a transcription factor shown to promote PCa progression. However, as the tumor progressed in bone over time, neutrophils from late-stage bone tumors failed to elicit cytotoxic effector responses to PCa. These findings are the first to demonstrate that bone-resident neutrophils inhibit PCa and that BM-PCa are able to progress via evasion of neutrophil-mediated killing. Enhancing neutrophil cytotoxicity in bone may present a novel therapeutic option for bone metastatic prostate cancer.

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