title: Pazopanib inhibits the activation of PDGFRβ-expressing astrocytes in the brain metastatic microenvironment of breast cancer cells.
abstract: Brain metastases occur in more than one-third of metastatic breast cancer patients whose tumors overexpress HER2 or are triple negative. Brain colonization of cancer cells occurs in a unique environment, containing microglia, oligodendrocytes, astrocytes, and neurons. Although a neuroinflammatory response has been documented in brain metastasis, its contribution to cancer progression and therapy remains poorly understood. Using an experimental brain metastasis model, we characterized the brain metastatic microenvironment of brain tropic, HER2-transfected MDA-MB-231 human breast carcinoma cells (231-BR-HER2). A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor β (at tyrosine 751; p751-PDGFRβ) was identified around perivascular brain micrometastases. p751-PDGFRβ(+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte-enriched glial cells. Previously, we reported that pazopanib, a multispecific tyrosine kinase inhibitor, prevented the outgrowth of 231-BR-HER2 large brain metastases by 73%. Here, we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment. Pazopanib treatment resulted in 70% (P = 0.023) decrease of the p751-PDGFRβ(+) astrocyte population, at the lowest dose of 30 mg/kg, twice daily. Collectively, the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib, suggesting its potential to prevent the development of brain micrometastases in breast cancer patients.
authors.affiliation: Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. grilbrun@mail.nih.gov
authors.forename: Brunilde
authors.initials: B
authors.lastname: Gril
authors.forename: Diane
authors.initials: D
authors.lastname: Palmieri
authors.forename: Yongzhen
authors.initials: Y
authors.lastname: Qian
authors.forename: Talha
authors.initials: T
authors.lastname: Anwar
authors.forename: David J
authors.initials: DJ
authors.lastname: Liewehr
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Zoraida
authors.initials: Z
authors.lastname: Andreu
authors.forename: Daniel
authors.initials: D
authors.lastname: Masana
authors.forename: Paloma
authors.initials: P
authors.lastname: Fernández
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.forename: Fernando
authors.initials: F
authors.lastname: Vidal-Vanaclocha
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D007191:Indazoles; D051379:Mice; D061206:Neoplasm Micrometastasis / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D009363:Neoplasm Proteins; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D020797:Receptor, Platelet-Derived Growth Factor beta