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Nrf2 expression in pancreatic stellate cells promotes progression of cancer

Yu Tanaka1, Shin Hamada1, Ryotaro Matsumoto1

  • 1Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.

American Journal of Physiology. Gastrointestinal and Liver Physiology
|August 18, 2021
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (Nrf2) promotes pancreatic stellate cell (PSC) activation, which drives pancreatic ductal adenocarcinoma progression. Inhibiting Nrf2 in PSCs may offer a novel therapeutic strategy for pancreatic cancer.

Area of Science:

  • Oncology
  • Cell Biology
  • Cancer Research

Background:

  • Systemic Nrf2 deletion was previously shown to slow pancreatic cancer growth in KPC mice.
  • The specific cell type mediating this effect remained unclear.

Purpose of the Study:

  • To identify the cell type responsible for Nrf2-mediated pancreatic cancer progression.
  • To investigate the role of Nrf2 in pancreatic stellate cells (PSCs) and their contribution to pancreatic cancer.

Main Methods:

  • Examined human pancreatic cancers for NRF2-target gene expression in α-smooth muscle actin-positive cells.
  • Cultured PSCs from Nrf2-deleted mice and assessed proliferation and migration.
  • Evaluated the effect of conditioned medium from Nrf2-deleted PSCs on pancreatic cancer cells.
  • Coinjected KPC mouse-derived cancer cells with wild-type or Nrf2-deleted PSCs in immunodeficient mice.

Main Results:

  • Elevated NRF2-target gene products were found in PSCs of human pancreatic cancers.
  • Nrf2-deleted PSCs exhibited reduced proliferation and migration.
  • Conditioned medium from Nrf2-deleted PSCs had diminished growth-stimulating effects on cancer cells.
  • Tumor growth was significantly smaller when cancer cells were coinjected with Nrf2-deleted PSCs compared to wild-type PSCs.

Conclusions:

  • Nrf2 actively promotes PSC function, sustaining KPC pancreatic cancer progression.
  • Nrf2 in PSCs is a potential therapeutic target for pancreatic cancer treatment.
Keywords:
Nrf2oxidative stresspancreatic fibrosispancreatic stellate cellstroma

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