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Endothelial-Mesenchymal Transition in Tumor Microenvironment Promotes Neuroendocrine Differentiation of Prostate Cancer

  • 0Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Tsu, Japan.
Cancer Science +

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July 24, 2025

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July 24, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Treatment for prostate cancer may paradoxically drive a more aggressive form, neuroendocrine prostate cancer (NEPC). This occurs via a mechanism involving endothelial-mesenchymal transition (EndoMT) and granulocyte-macrophage colony-stimulating factor (GM-CSF).

Area Of Science

  • Oncology
  • Cancer Biology
  • Tumor Microenvironment

Background

  • Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of castration-resistant prostate cancer (CRPC).
  • NEPC often arises during treatment with androgen-receptor (AR) pathway inhibitors.
  • The tumor microenvironment's role in NEPC development, particularly endothelial-mesenchymal transition (EndoMT), is not well understood.

Purpose Of The Study

  • To investigate the potential contribution of EndoMT to the development of NEPC.
  • To elucidate the molecular mechanisms linking EndoMT to NEPC.
  • To identify therapeutic targets for preventing NEPC development.

Main Methods

  • Human umbilical vein endothelial cells (HUVEC) were induced to undergo EndoMT using IL-1β and TGF-β2.
  • EndoMTed HUVEC were co-cultured with LNCaP prostate cancer cells.
  • Transcriptome analysis, GM-CSF neutralization (mavrilimumab), CSF2RA knockdown (siRNA), and GM-CSF stimulation were employed.
  • Reciprocal signaling loops between prostate cancer cells and endothelial cells were assessed.

Main Results

  • EndoMTed HUVEC promoted neuroendocrine differentiation and functional changes in LNCaP cells.
  • EndoMTed HUVEC significantly upregulated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression.
  • Neutralizing GM-CSF signaling or targeting its receptor (CSF2RA) suppressed NEPC phenotypes and STAT3 signaling in LNCaP cells.
  • GM-CSF alone induced NEPC features in LNCaP cells.
  • Enzalutamide-treated LNCaP cells secreted IL-1β and TGF-β2, inducing EndoMT in endothelial cells, establishing a feedback loop.

Conclusions

  • Endothelial-mesenchymal transition (EndoMT) driven by tumor-derived cytokines contributes to neuroendocrine prostate cancer (NEPC) development.
  • A paracrine loop involving endothelial GM-CSF secretion, triggered by anti-androgen therapy, promotes NEPC.
  • Targeting EndoMT or GM-CSF signaling represents a potential strategy to overcome treatment resistance in prostate cancer.

Keywords:

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