Reactive astrocytes promote the metastatic growth of breast cancer stem‐like cells by activating Notch signalling in brain

EMBO Molecular Medicine

Fei Xing⁴  Aya Kobayashi⁴  Hiroshi Okuda⁴  Misako Watabe⁴  Sudha K. Pai⁴  Puspa R. Pandey⁴  Shigeru Hirota¹  Andrew Wilber⁴  Yin-Yuan Mo⁴  Brian E. Moore²  Wen Liu⁴  Koji Fukuda⁴  Megumi Iiizumi⁴  Sambad Sharma³  Yin Liu³  Kerui Wu³  Elizabeth Peralta⁵ 

[1] Department of Internal Medicine, Iwate Medical University, Morioka, Japan;Department of Pathology, Southern Illinois University School of Medicine, Springfield, IL, USA;Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA;Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA;Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA

关键词: cancer stem‐like cell;    IL‐1β;    metastasis;    notch;    reactive astrocytes;   

DOI  :  10.1002/emmm.201201623

来源: Wiley

【 摘 要 】

Abstract

Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL-1β which then ‘activated’ surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem-like cells (CSCs) significantly stimulated Notch signalling in CSCs. We also found that the activated Notch signalling in CSCs up-regulated HES5 followed by promoting self-renewal of CSCs. Furthermore, we have shown that the blood-brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis in vivo. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease.

【 授权许可】

Unknown   
Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.