title: Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain.
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.
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Xing
authors.forename: Aya
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okuda
authors.forename: Misako
authors.initials: M
authors.lastname: Watabe
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Pai
authors.forename: Puspa R
authors.initials: PR
authors.lastname: Pandey
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hirota
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilber
authors.forename: Yin-Yuan
authors.initials: YY
authors.lastname: Mo
authors.forename: Brian E
authors.initials: BE
authors.lastname: Moore
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Koji
authors.initials: K
authors.lastname: Fukuda
authors.forename: Megumi
authors.initials: M
authors.lastname: Iiizumi
authors.forename: Sambad
authors.initials: S
authors.lastname: Sharma
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Kerui
authors.initials: K
authors.lastname: Wu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Peralta
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Watabe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000378:metabolism; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D051381:Rats; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects; D055153:Stem Cell Niche; D013997:Time Factors; D014162:Transfection; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C000606275:Jag1 protein, rat; C077478:HES5 protein, human