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: Brunilde Gril, Diane Palmieri, Yongzhen Qian, Talha Anwar, David J Liewehr, Seth M Steinberg, Zoraida Andreu, Daniel Masana, Paloma Fernández, Patricia S Steeg, Fernando Vidal-Vanaclocha
• Journal: The American journal of pathology (Am J Pathol) Vol. 182 Issue 6 Pg. 2368-79 (Jun 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23583652 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Indazoles
• Neoplasm Proteins
• Pyrimidines
• Sulfonamides
• pazopanib
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Astrocytes (drug effects, metabolism)
• Brain Neoplasms (metabolism, pathology, prevention & control, secondary)
• Breast Neoplasms (metabolism, pathology)
• Drug Evaluation, Preclinical (methods)
• Female
• Humans
• Indazoles
• Mice
• Neoplasm Micrometastasis (pathology)
• Neoplasm Proteins (metabolism)
• Neoplasm Transplantation
• Neuroglia (drug effects, metabolism)
• Phosphorylation (drug effects)
• Pyrimidines (pharmacology, therapeutic use)
• Receptor, Platelet-Derived Growth Factor beta (antagonists & inhibitors, metabolism)
• Sulfonamides (pharmacology, therapeutic use)
• Tumor Cells, Cultured
• Tumor Microenvironment