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Infiltrating macrophages promote prostate tumorigenesis via modulating androgen receptor-mediated CCL4-STAT3

Lei-Ya Fang1, Kouji Izumi, Kuo-Pao Lai

  • 1Authors' Affiliations: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York; Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli County, and Sex Hormone Research Center, China Medical University and Hospital, Taichung, Taiwan.

Cancer Research
|July 24, 2013
PubMed

Insights

Macrophages promote prostate cancer by activating the androgen receptor (AR)-CCL4-STAT3 pathway. This process involves epithelial-to-mesenchymal transition and tumor suppressor downregulation, highlighting inflammation

Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • Infiltrating macrophages are implicated in inflammation during tumorigenesis.
  • Direct evidence linking macrophages to prostate cancer initiation is limited.
  • The molecular mechanisms underlying macrophage-driven prostate tumorigenesis require elucidation.

Purpose of the Study:

  • To investigate the role of persistent macrophage-epithelial cell co-culture in inducing prostate tumorigenesis.
  • To elucidate the signaling pathways involved in macrophage-mediated prostate cancer initiation.
  • To explore therapeutic strategies targeting macrophage-driven prostate tumor development.

Main Methods:

  • Persistent co-culture of immortalized prostate epithelial cells with macrophages.
  • Analysis of signaling pathways including androgen receptor (AR), CCL4, STAT3, and epithelial-to-mesenchymal transition (EMT).
  • In vivo studies using PTEN(+/-) mice and xenograft models; administration of CCL4-neutralizing antibody and AR-degradation enhancer ASC-J9.

Main Results:

  • Macrophage co-culture induced prostate tumorigenesis without carcinogens, involving AR-CCL4-STAT3 signaling, EMT, and p53/PTEN downregulation.
  • Macrophage AR deficiency in PTEN(+/-) mice significantly reduced prostatic intraepithelial neoplasia (PIN) lesions.
  • Targeting AR with ASC-J9 reduced CCL4 expression and xenograft tumor growth; CCL4 upregulation correlated with Snail, decreased p53/PTEN in high-grade PIN and prostate cancer.

Conclusions:

  • The AR-CCL4-STAT3 axis is identified as a key regulator in prostate tumor initiation.
  • Infiltrating macrophages and inflammatory cytokines play critical roles in prostate tumorigenesis.
  • Targeting macrophage AR and CCL4 presents a potential therapeutic strategy for prostate cancer.

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