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

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.

• Authors: Sachiko Taniguchi, Ajit Elhance, Avery Van Duzer, Sushil Kumar, Justin J Leitenberger, Naoki Oshimori
• Journal: Science (New York, N.Y.) (Science) Vol. 369 Issue 6501 (07 17 2020) ISSN: 1095-9203 [Electronic] United States
• PMID: 32675345 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

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

Topics

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