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

• Published in: Clinical cancer research Vol. 22; no. 21; pp. 5287 - 5299
• Main Authors: Lyle, L Tiffany, Lockman, Paul R, Adkins, Chris E, Mohammad, Afroz Shareef, Sechrest, Emily, Hua, Emily, Palmieri, Diane, Liewehr, David J, Steinberg, Seth M, Kloc, Wojciech, Izycka-Swieszewska, Ewa, Duchnowska, Renata, Nayyar, Naema, Brastianos, Priscilla K, Steeg, Patricia S, Gril, Brunilde
• Format: Journal Article
• Language: English
• Published: United States 01-11-2016
• Subjects: Animals; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Brain - metabolism; Brain - pathology; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Female; Humans; Pericytes - metabolism; Pericytes - pathology; Permeability
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-15-1836

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 α2 (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 α2 are potential targets for the development of novel approaches to increase chemotherapeutic efficacy. Clin Cancer Res; 22(21); 5287-99. ©2016 AACR.