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Exosomes Derived from Brain Metastatic Breast Cancer Cells Destroy the Blood-Brain Barrier by Carrying lncRNA GS1-600G8.5.

ABSTRACT: Brain metastasis is a major cause of death in breast cancer patients. The greatest event for brain metastasis is the breaching of the blood-brain barrier (BBB) by cancer cells. The role of exosomes in cancer metastasis is clear, whereas the role of exosomes in the integrity of the BBB is unknown. Here, we established a highly brain metastatic breast cancer cell line by three cycles of in vivo selection. The effect of exosomes on the BBB was evaluated in vitro by tracking, transepithelial/transendothelial electrical resistance (TEER), and permeability assays. BBB-associated exosomal long noncoding RNA (lncRNA) was selected from the GEO dataset and verified by real-time PCR, TEER, permeability, and Transwell assays. The cells obtained by the in vivo selection showed higher brain metastatic capacity in vivo and higher migration and invasion in vitro compared to the parental cells. Exosomes from the highly brain metastatic cells were internalized by brain microvascular endothelial cells (BMECs), which reduced TEER and increased permeability of BBB. The exosomes derived from the highly metastatic cells promoted invasion of the breast cancer cells in the BBB model. lncRNA GS1-600G8.5 was highly expressed in the highly brain metastatic cells and their exosomes, as compared to the samples with reduced metastatic behavior. Silencing of GS1-600G8.5 significantly abrogated the BBB destructive effect of exosomes. GS1-600G8.5-deficient exosomes failed to promote the infiltration of cancer cells through the BBB. Furthermore, BMECs treated with GS1-600G8.5-deprived exosomes expressed higher tight junction proteins than those treated with the control exosomes. These data suggest the exosomes derived from highly brain metastatic breast cancer cells might destroy the BBB system and promote the passage of cancer cells across the BBB, by transferring lncRNA GS1-600G8.5.

SUBMITTER: Lu Y

PROVIDER: S-EPMC7165326 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Exosomes Derived from Brain Metastatic Breast Cancer Cells Destroy the Blood-Brain Barrier by Carrying lncRNA GS1-600G8.5.

Lu Yunhe Y Chen Lei L Li Liangdong L Cao Yiqun Y Cao Yiqun Y

BioMed research international 20200406

Brain metastasis is a major cause of death in breast cancer patients. The greatest event for brain metastasis is the breaching of the blood-brain barrier (BBB) by cancer cells. The role of exosomes in cancer metastasis is clear, whereas the role of exosomes in the integrity of the BBB is unknown. Here, we established a highly brain metastatic breast cancer cell line by three cycles of <i>in vivo</i> selection. The effect of exosomes on the BBB was evaluated <i>in vitro</i> by tracking, transepit ...[more]

PMID: 32337272

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Project description:Microglia are implicated in the neuropathogenesis of HIV. Tetraspanin 2 (Tspan2) is closely related to CD9 and CD81 proteins, and are expressed on microglia cells. They have been implicated in cell fusion and adhesion and in the immune response, and neuroinflammation. Developing therapeutics that target microglia remains a challenge as these therapeutics must cross the Blood-Brain Barrier (BBB). Our goal was to use microglia derived exosomes as a vehicle to deliver siRNA across the BBB to target human telomerase reverse transcriptase immortalized human microglial cells (HTHU) latently infected by HIV (HTHU-HIV) and to evaluate if the knockdown of Tspan2 gene expression in changes the activation state of microglia cells, thereby modulating the neuroinflammatory response. A blood brain barrier (BBB) model that closely mimics and accurately reflects the characteristics and functional properties of the in vivo BBB was used to examine HTHU microglia exosome effects on BBB permeability, and their ability to migrate across the and delivery small interfering RNA (siRNA) to cells on the CNS side of the BBB model. Exosomes were loaded with Texas-Red control siRNA (20 pmol) or Cy5-Tspan2 siRNA and then placed in the apical side of the BBB model, 24 h after incubation, HTHU-HIV cells microglial cells on the lower chamber were either imaged for siRNA uptake or analyzed for gene expression induced modifications. HTHU exosomes transmigrate from the apical side of the BBB to deliver Texas-Red control siRNA or Cy5-Tspan2 siRNA to HTHU-HIV microglia cells on the CNS side of the BBB model. A dose dependent (5-40 pmol) increase in Cy5-Tspan2 uptake with a corresponding decrease in gene expression for Tspan2 occurred in HTHU-HIV microglia. A decrease in Tspan2 gene expression as a consequence of knockdown with Tspan2 siRNA at both 20 and 40 pmol concentrations resulted in a significant decrease in C-X-C motif chemokine 12 (CXCL12) and C-X-C chemokine receptor type 4 (CXCR4) gene expression in HTHU-HIV microglia. Furthermore, a decrease in the gene expression levels of the Interleukins, IL-13 and IL-10 and an increase in the gene expression levels for the Fc gamma receptor 2A(FCGR2A) and TNF-α occurred in HTHU-HIV microglial cells These data demonstrate that HTHU exosomes cross the BBB and are efficient delivery vehicles to the CNS. Moreover, modifying the expression levels of Tspan2, has downstream consequences that includes alterations in cytokines and microglia biomarkers. Graphical Abstract Microglia-derived exosomes loaded with Tspan2 siRNA transmigrate across the BBB and knockdown Tspan2 gene expression in human microglial cells latently infected by HIV. This knockdown increases CXCL12, CXCR4, FCGR2A and TNF-α while decreasing IL-13 and IL-10 gene expression in HTHU-HIV microglial cells. Modulating Tspan2 modulates microglia cytokines and phenotype biomarkers.

Dataset Information

Exosomes Derived from Brain Metastatic Breast Cancer Cells Destroy the Blood-Brain Barrier by Carrying lncRNA GS1-600G8.5.

Publications

Exosomes Derived from Brain Metastatic Breast Cancer Cells Destroy the Blood-Brain Barrier by Carrying lncRNA GS1-600G8.5.

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