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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Am+J+Pathol
2013 ; 182
(6
): 2368-79
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Pazopanib inhibits the activation of PDGFR?-expressing astrocytes in the brain
metastatic microenvironment of breast cancer cells
#MMPMID23583652
Gril B
; Palmieri D
; Qian Y
; Anwar T
; Liewehr DJ
; Steinberg SM
; Andreu Z
; Masana D
; Fernández P
; Steeg PS
; Vidal-Vanaclocha F
Am J Pathol
2013[Jun]; 182
(6
): 2368-79
PMID23583652
show ga
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 ? (at tyrosine
751; p751-PDGFR?) was identified around perivascular brain micrometastases.
p751-PDGFR?(+) 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-PDGFR?(+) 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.
|Animals
[MESH]
|Antineoplastic Agents/*pharmacology/therapeutic use
[MESH]