Tumor-initiating cells establish an IL-33-TGF-β niche signaling loop to promote cancer progression

Science. 2020 Jul 17;369(6501):eaay1813. doi: 10.1126/science.aay1813.

Abstract

Targeting the cross-talk between tumor-initiating cells (TICs) and the niche microenvironment is an attractive avenue for cancer therapy. We show here, using a mouse model of squamous cell carcinoma, that TICs play a crucial role in creating a niche microenvironment that is required for tumor progression and drug resistance. Antioxidant activity in TICs, mediated by the transcription factor NRF2, facilitates the release of a nuclear cytokine, interleukin-33 (IL-33). This cytokine promotes differentiation of macrophages that express the high-affinity immunoglobulin E receptor FcεRIα and are in close proximity to TICs. In turn, these IL-33-responding FcεRIα+ macrophages send paracrine transforming growth factor β (TGF-β) signals to TICs, inducing invasive and drug-resistant properties and further upregulating IL-33 expression. This TIC-driven, IL-33-TGF-β feedforward loop could potentially be exploited for cancer treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology*
  • Disease Progression
  • Humans
  • Interleukin-33 / metabolism*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism*
  • Tumor Microenvironment

Substances

  • IL33 protein, human
  • Interleukin-33
  • Transforming Growth Factor beta