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PFDA promotes cancer metastasis through macrophage M2 polarization mediated by Wnt/β-catenin signaling

Zhenyan Cui1, Zekun Liu1, Xiaoyu Yuan1

  • 1Department of Toxicology of School of Public Health, Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Chemosphere
|July 5, 2024
PubMed

Insights

Perfluoroundecanoic acid (PFDA) exposure shifts macrophages to a tumor-promoting M2 state by activating beta-catenin. This promotes cancer cell migration, invasion, and metastasis, highlighting a Wnt/beta-catenin-dependent mechanism.

Area of Science:

  • Environmental Toxicology
  • Cancer Biology
  • Immunology

Background:

  • Perfluoroundecanoic acid (PFDA) is a widely used industrial chemical with potential tumor-promoting effects.
  • Macrophages are critical regulators of the tumor microenvironment and immune responses.
  • The specific mechanisms by which PFDA influences macrophage function and tumor progression remain unclear.

Purpose of the Study:

  • To investigate the effects of PFDA on macrophage polarization.
  • To elucidate the role of the Wnt/beta-catenin pathway in PFDA-induced macrophage alterations.
  • To determine the impact of PFDA-modulated macrophages on cancer cell behavior and tumor metastasis.

Main Methods:

  • Treatment of RAW264.7 macrophage cell line with PFDA.
  • Bioinformatic analysis and molecular assays to assess beta-catenin activation and nuclear translocation.
  • Assessment of cancer cell migration and invasion using conditioned medium from PFDA-treated macrophages.
  • In vivo studies using mouse models to evaluate tumor metastasis, with and without beta-catenin inhibition (ICG001).

Main Results:

  • PFDA induced M2 polarization in RAW264.7 macrophages, a phenotype associated with tumor promotion.
  • PFDA activated beta-catenin signaling and enhanced its nuclear translocation in macrophages.
  • Inhibition of beta-catenin nuclear translocation partially reversed PFDA-induced M2 polarization.
  • Conditioned medium from PFDA-treated macrophages promoted ovarian cancer cell migration and invasion.
  • In vivo, PFDA-treated macrophages promoted tumor metastasis, an effect reduced by beta-catenin inhibition.

Conclusions:

  • PFDA promotes cancer metastasis by inducing M2 polarization in macrophages via the Wnt/beta-catenin pathway.
  • Targeting the Wnt/beta-catenin pathway may offer a therapeutic strategy to mitigate PFDA-driven tumor progression.
  • This study reveals a novel mechanism linking environmental chemical exposure to macrophage-mediated cancer metastasis.
Keywords:
M2 macrophageOvarian cancerPFDA

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