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Alterations in Pericyte Subpopulations Are Associated with Elevated Blood-Tumor Barrier Permeability in Experimental Brain Metastasis of Breast Cancer.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2016 Nov 01; Vol. 22 (21), pp. 5287-5299. Date of Electronic Publication: 2016 May 31. - Publication Year :
- 2016
-
Abstract
- 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.<br />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 <superscript>+</superscript> 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.<br />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 <superscript>+</superscript> 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 <superscript>+</superscript> pericytes were also identified in human craniotomy specimens. Trends of reduced CD13 <superscript>+</superscript> 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.<br />Conclusions: We provide the first account of the composition of the BTB in experimental brain metastasis. Desmin <superscript>+</superscript> 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.<br />Competing Interests: Dr. PSS receives research funding from Sanofi-Aventis and Genentech. The other authors have no conflicts of interest to declare.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Animals
Brain metabolism
Brain Neoplasms metabolism
Breast Neoplasms metabolism
Cell Line, Tumor
Female
Humans
Permeability
Blood-Brain Barrier metabolism
Blood-Brain Barrier pathology
Brain pathology
Brain Neoplasms pathology
Breast Neoplasms pathology
Pericytes metabolism
Pericytes pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 22
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 27245829
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-15-1836