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Updated: Dec 15, 2025

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

Published on: July 20, 2019

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Microenvironmental Activation of Nrf2 Restricts the Progression of Nrf2-Activated Malignant Tumors

Makiko Hayashi1, Ayumi Kuga1, Mikiko Suzuki2

  • 1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.

Cancer Research
|July 9, 2020
PubMed

Insights

Targeting the Nrf2 pathway in the tumor microenvironment, not just the tumor itself, can suppress cancer progression. Activating Nrf2 in host cells, particularly immune cells, offers a novel therapeutic strategy for Nrf2-activated cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Immunology

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that protects cells against oxidative and electrophilic stress by activating cytoprotective genes.
  • Keap1 normally regulates Nrf2 activity in a stress-dependent manner, but loss-of-function mutations in Keap1 lead to constitutive Nrf2 activation, common in lung adenocarcinomas and promoting tumor survival.
  • Current cancer therapies often target Nrf2 inhibition within tumors, but the role of Nrf2 in the tumor microenvironment remains less understood.

Purpose of the Study:

  • To investigate whether targeting Nrf2 activation within the tumor microenvironment can inhibit the progression of Nrf2-activated tumors.
  • To explore the therapeutic potential of modulating Nrf2 activity in the host's cellular environment to combat cancer.

Main Methods:

  • A Kras-driven lung adenocarcinoma model was combined with Keap1-flox mice to create tumors with varying Keap1 deficiency, surrounded by normal or Keap1-knockdown host cells.
  • The study analyzed the impact of microenvironmental Nrf2 activation on tumor burden, survival rates, and preinvasive lesion formation in a mouse model.
  • Investigated the contribution of bone marrow-derived cells and Nrf2 activity within these cells to the observed anti-tumor effects.

Main Results:

  • Activation of Nrf2 in the tumor microenvironment significantly prolonged the survival of mice bearing Nrf2-activated tumors.
  • A Nrf2-activated microenvironment was found to suppress overall tumor burden, with a notable reduction in preinvasive lesion development.
  • Loss of Nrf2 in bone marrow-derived cells partially counteracted the tumor-suppressive effects of microenvironmental Nrf2 activation, highlighting the role of immune cells.

Conclusions:

  • Microenvironmental Nrf2 activation demonstrates a potent suppressive effect on the progression of malignant Nrf2-activated tumors.
  • Nrf2 activation within the tumor microenvironment, particularly in immune cells, is crucial for inhibiting cancer growth.
  • These findings suggest that Nrf2 inducers targeting the tumor microenvironment represent a promising new avenue for cancer therapy.

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