Back to Search
Start Over
STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis
- Source :
- Nature medicine. 24(7)
- Publication Year :
- 2017
-
Abstract
- The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors. Reactive astrocytes expressing STAT3 support the metastatic growth of tumor cells colonizing the brain and can be pharmacologically targeted to improve the clinical management of patients with secondary brain tumors.
- Subjects :
- Genetics and Molecular Biology (all)
0301 basic medicine
STAT3 Transcription Factor
Cell Survival
Central nervous system
Biochemistry
General Biochemistry, Genetics and Molecular Biology
Lesion
03 medical and health sciences
Mice
Glial Fibrillary Acidic Protein
Tumor Microenvironment
Medicine
Animals
Humans
Phosphorylation
STAT3
Tumor microenvironment
Biochemistry, Genetics and Molecular Biology (all)
biology
business.industry
Brain Neoplasms
Brain
General Medicine
medicine.disease
Acquired immune system
Primary tumor
Immunity, Innate
Editorial Commentary
030104 developmental biology
medicine.anatomical_structure
Astrocytes
Gene Targeting
Cancer research
biology.protein
STAT protein
medicine.symptom
business
Brain metastasis
Subjects
Details
- ISSN :
- 1546170X
- Volume :
- 24
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Nature medicine
- Accession number :
- edsair.doi.dedup.....c6e56eff85fe535456625716c5c389f7