Brain metastases occur in approximately 35% of metastatic breast cancer patients whose tumors overexpress HER2. Brain colonization of cancer cells occurs in a unique environment, containing microglia, oligodendrocytes, astrocytes and neurons. While a neuroinflammatory response has been documented in brain metastasis, its contribution to cancer progression and therapy remains poorly understood. Using a model system to study experimental brain metastasis of breast cancer, we intensively characterized the brain metastatic microenvironment of a brain tropic, HER2-transfected MDA-MB-231 human breast carcinoma subline (231-BR-HER2). The 231-BR-HER2 cell line was injected into the left cardiac ventricle of immunocompromised mice; mice were treated with vehicle, 30mg/kg or 100mg/kg pazopanib twice a day beginning on day 3 post-injection, for 4 weeks. Pazopanib, a multispecific tyrosine kinase inhibitor targeting VEGFR-1, -2, and -3, PDGFR-α and β, and c-kit, directly targeted tumor cells through the disruption of B-Raf pathway, prevents the outgrowth of 231-BR-HER2 large brain metastases by 73% (p<0.0001). Here we evaluated the effect of pazopanib on the brain micro-environment microenvironment. A novel subpopulation of metastasis-associated astrocytes expressing phosphorylated (Y751) PDGFRβ was identified surrounding brain metastases. This subpopulation of p751-PDGFRβ + astrocytes was also identified in human brain metastases from five different craniotomy specimens. Expression of p751-PDGFRβ was studied in primary cultures of astrocyte-enriched glial cells. p751-PDGFRβ expression was increased in response to soluble factors from cultured breast cancer cells, and was inhibited by pazopanib treatment. In the mouse mode, pazopanib treatment resulted in a 70% (p=0.023) decrease of the p751-PDGFRβ+ astrocyte population, at the lowest dose of 30mg/kg, twice daily. In contrast, pazopanib did not have any effect on microglia expression. Collectively, the data identify a new subpopulation of activated astrocytes in the perivascular stage of subclinical brain metastases and demonstrate that they are inhibitable by pazopanib, suggesting its potential to prevent the development of brain metastases from breast cancer patients.
Citation Format: Brunilde M. Gril, Diane Palmieri, Yong Qian, David J. Liewehr, Seth M. Steinberg, Talha Anwar, Zoraida Andreu, Daniel Masana, Patricia S. Steeg, Fernando Vidal-Vanaclocha. PDGFRβ activation defines a subset of astrocytes in the neuroinflammatory microenvironment of breast cancer brain metastasis, inhibitable by pazopanib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1442. doi:10.1158/1538-7445.AM2013-1442