title: Alterations in Pericyte Subpopulations Are Associated with Elevated Blood-Tumor Barrier Permeability in Experimental Brain Metastasis of Breast Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 α2 (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 α2 are potential targets for the development of novel approaches to increase chemotherapeutic efficacy. Clin Cancer Res; 22(21); 5287-99. ©2016 AACR.
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: L Tiffany
authors.initials: LT
authors.lastname: Lyle
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lockman
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia.
authors.forename: Chris E
authors.initials: CE
authors.lastname: Adkins
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia.
authors.forename: Afroz Shareef
authors.initials: AS
authors.lastname: Mohammad
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia.
authors.forename: Emily
authors.initials: E
authors.lastname: Sechrest
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: Emily
authors.initials: E
authors.lastname: Hua
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: Diane
authors.initials: D
authors.lastname: Palmieri
authors.affiliation: Biostatistics and Data Management Section, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: David J
authors.initials: DJ
authors.lastname: Liewehr
authors.affiliation: Biostatistics and Data Management Section, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Departments of Neurology & Neurosurgery, University of Varmia & Masuria University, Olsztyn, Poland.|Department of Neurosurgery, Copernicus Hospital Gdańsk, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kloc
authors.affiliation: Departments of Pathology & Neuropathology, Medical University of Gdańsk, Poland.|Department of Pathomorphology, Copernicus Hospital, Gdańsk, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Izycka-Swieszewska
authors.affiliation: Department of Oncology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Duchnowska
authors.affiliation: Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Naema
authors.initials: N
authors.lastname: Nayyar
authors.affiliation: Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Priscilla K
authors.initials: PK
authors.lastname: Brastianos
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland. grilbrun@mail.nih.gov.
authors.forename: Brunilde
authors.initials: B
authors.lastname: Gril
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology*; D010539:Permeability