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

EMBO Mol Med. 2013 Mar;5(3):384-96. doi: 10.1002/emmm.201201623.

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.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / prevention & control
  • Brain Neoplasms / secondary*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cell Communication
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Culture Media, Conditioned / metabolism
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Jagged-1 Protein
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • NIH 3T3 Cells
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • RNA Interference
  • Rats
  • Receptors, Notch / antagonists & inhibitors
  • Receptors, Notch / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Serrate-Jagged Proteins
  • Signal Transduction* / drug effects
  • Stem Cell Niche
  • Time Factors
  • Transfection
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Calcium-Binding Proteins
  • Culture Media, Conditioned
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-1beta
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jag1 protein, rat
  • Jagged-1 Protein
  • Membrane Proteins
  • Receptors, Notch
  • Repressor Proteins
  • Serrate-Jagged Proteins
  • HES5 protein, human