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Alterations in Pericyte Subpopulations Are Associated with Elevated Blood-Tumor Barrier Permeability in Experimental Brain Metastasis of Breast Cancer.

ABSTRACT: The blood-brain barrier (BBB) is modified to a blood-tumor barrier (BTB) as a brain metastasis develops from breast or other cancers. We (i) quantified the permeability of experimental brain metastases, (ii) determined the composition of the BTB, and (iii) identified which elements of the BTB distinguished metastases of lower permeability from those with higher permeability.A SUM190-BR3 experimental inflammatory breast cancer brain metastasis subline was established. Experimental brain metastases from this model system and two previously reported models (triple-negative MDA-231-BR6, HER2+ JIMT-1-BR3) were serially sectioned; low- and high-permeability lesions were identified with systemic 3-kDa Texas Red dextran dye. Adjoining sections were used for quantitative immunofluorescence to known BBB and neuroinflammatory components. One-sample comparisons against a hypothesized value of one were performed with the Wilcoxon signed-rank test.When uninvolved brain was compared with any brain metastasis, alterations in endothelial, pericytic, astrocytic, and microglial components were observed. When metastases with relatively low and high permeability were compared, increased expression of a desmin+ subpopulation of pericytes was associated with higher permeability (231-BR6 P = 0.0002; JIMT-1-BR3 P = 0.004; SUM190-BR3 P = 0.008); desmin+ pericytes were also identified in human craniotomy specimens. Trends of reduced CD13+ pericytes (231-BR6 P = 0.014; JIMT-1-BR3 P = 0.002, SUM190-BR3, NS) and laminin ?2 (231-BR6 P = 0.001; JIMT-1-BR3 P = 0.049; SUM190-BR3 P = 0.023) were also observed with increased permeability.We provide the first account of the composition of the BTB in experimental brain metastasis. Desmin+ pericytes and laminin ?2 are potential targets for the development of novel approaches to increase chemotherapeutic efficacy. Clin Cancer Res; 22(21); 5287-99. ©2016 AACR.

SUBMITTER: Lyle LT 

PROVIDER: S-EPMC5093086 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Alterations in Pericyte Subpopulations Are Associated with Elevated Blood-Tumor Barrier Permeability in Experimental Brain Metastasis of Breast Cancer.

Lyle L Tiffany LT   Lockman Paul R PR   Adkins Chris E CE   Mohammad Afroz Shareef AS   Sechrest Emily E   Hua Emily E   Palmieri Diane D   Liewehr David J DJ   Steinberg Seth M SM   Kloc Wojciech W   Izycka-Swieszewska Ewa E   Duchnowska Renata R   Nayyar Naema N   Brastianos Priscilla K PK   Steeg Patricia S PS   Gril Brunilde B  

Clinical cancer research : an official journal of the American Association for Cancer Research 20160531 21

<h4>Purpose</h4>The blood-brain barrier (BBB) is modified to a blood-tumor barrier (BTB) as a brain metastasis develops from breast or other cancers. We (i) quantified the permeability of experimental brain metastases, (ii) determined the composition of the BTB, and (iii) identified which elements of the BTB distinguished metastases of lower permeability from those with higher permeability.<h4>Experimental design</h4>A SUM190-BR3 experimental inflammatory breast cancer brain metastasis subline w  ...[more]