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

作者：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^*

来源：Clinical Cancer Research, 2016, 22(21): 5287-5299.

DOI：10.1158/1078-0432.CCR-15-1836

Purpose: 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.
Experimental Design: 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.
Results: 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 alpha 2 (231-BR6 P = 0.001; JIMT-1-BR3 P = 0.049; SUM190-BR3 P = 0.023) were also observed with increased permeability.
Conclusions: We provide the first account of the composition of the BTB in experimental brain metastasis. Desmin(+) pericytes and laminin a2 are potential targets for the development of novel approaches to increase chemotherapeutic efficacy.

• 出版日期2016-11-1
• 单位NIH; 河北医科大学