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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]

PMID: 27245829

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Project description:RationalePericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive.ObjectiveTo map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level and to correlate them with regional heterogeneities in BBB function and vascular phenotype.Methods and resultsWe reveal transcriptional, morphological, and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses, and immunofluorescent detection of protein expression in pericyte-deficient adult Pdgfbret/ret mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult Pdgfbret/ret brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB.ConclusionsBy elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence, and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 (angiopoietin 2) is paradoxical given its wider role as TIE2 (TEK receptor tyrosine kinase) receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.

Project description:Disruption of the blood-brain barrier has been proposed to be important in vascular cognitive impairment. Increased cerebrospinal fluid albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the blood-brain barrier permeability in patients with vascular cognitive impairment is lacking. Therefore, we acquired dynamic contrast-enhanced MRI to quantify blood-brain barrier permeability in vascular cognitive impairment. Method- We studied 60 patients with suspected vascular cognitive impairment. They had neurological and neuropsychological testing, permeability measurements with dynamic contrast-enhanced MRI, and lumbar puncture to measure albumin index. Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts, and leukoaraiosis. Twenty volunteers were controls for the dynamic contrast-enhanced MRI studies, and control cerebrospinal fluid was obtained from 20 individuals undergoing spinal anesthesia for nonneurological problems.Thirty-six patients were classified as SIVD, 8 as multiple and lacunar infarcts, and 9 as leukoaraiosis. The albumin index was significantly increased in the SIVD group compared with 20 control subjects. Permeabilities for the patients with vascular cognitive impairment measured by dynamic contrast-enhanced MRI were significantly increased over control subjects (P<0.05). Patient age did not correlate with either the blood-brain barrier permeability or albumin index. Highest albumin index values were seen in the SIVD group (P<0.05) and were significantly increased over multiple and lacunar infarcts. K(i) values were elevated over control subjects in SIVD but were similar to multiple and lacunar infarcts.There was abnormal permeability in white matter in patients with SIVD as shown by dynamic contrast-enhanced MRI and albumin index. Future studies will be needed to determine the relationship of blood-brain barrier damage and development of white matter hyperintensities.

Dataset Information

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

Publications

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

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