Alterations in pericyte subpopulations are associated with elevated blood-tumor barrier permeability in experimental brain metastasis of breast cancer

L. Tiffany Lyle, Paul R. Lockman, Chris E. Adkins, Afroz Shareef Mohammad, Emily Sechrest, Emily Hua, Diane Palmieri, David J. Liewehr, Seth M. Steinberg, Wojciech Kloc, Ewa Izycka-Swieszewska, Renata Duchnowska, Naema Nayyar, Priscilla K. Brastianos, Patricia S. Steeg, Brunilde Gril

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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. 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 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.

Original languageEnglish (US)
Pages (from-to)5287-5299
Number of pages13
JournalClinical Cancer Research
Volume22
Issue number21
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

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Pericytes
Permeability
Breast Neoplasms
Neoplasm Metastasis
Brain
Desmin
Neoplasms
Laminin
Blood-Brain Barrier
Inflammatory Breast Neoplasms
Craniotomy
Nonparametric Statistics
Dextrans
Brain Neoplasms
Fluorescent Antibody Technique
Breast
Research Design
Coloring Agents

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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; 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.

In: Clinical Cancer Research, Vol. 22, No. 21, 01.11.2016, p. 5287-5299.

Research output: Contribution to journalArticle

Lyle, LT, Lockman, PR, Adkins, CE, Mohammad, AS, Sechrest, E, Hua, E, Palmieri, D, Liewehr, DJ, Steinberg, SM, Kloc, W, Izycka-Swieszewska, E, Duchnowska, R, Nayyar, N, Brastianos, PK, Steeg, PS & Gril, B 2016, 'Alterations in pericyte subpopulations are associated with elevated blood-tumor barrier permeability in experimental brain metastasis of breast cancer', Clinical Cancer Research, vol. 22, no. 21, pp. 5287-5299. https://doi.org/10.1158/1078-0432.CCR-15-1836
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. / Alterations in pericyte subpopulations are associated with elevated blood-tumor barrier permeability in experimental brain metastasis of breast cancer. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 21. pp. 5287-5299.
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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. 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 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.",
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T1 - Alterations in pericyte subpopulations are associated with elevated blood-tumor barrier permeability in experimental brain metastasis of breast cancer

AU - Lyle, L. Tiffany

AU - Lockman, Paul R.

AU - Adkins, Chris E.

AU - Mohammad, Afroz Shareef

AU - Sechrest, Emily

AU - Hua, Emily

AU - Palmieri, Diane

AU - Liewehr, David J.

AU - Steinberg, Seth M.

AU - Kloc, Wojciech

AU - Izycka-Swieszewska, Ewa

AU - Duchnowska, Renata

AU - Nayyar, Naema

AU - Brastianos, Priscilla K.

AU - Steeg, Patricia S.

AU - Gril, Brunilde

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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 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.

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