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.
Highlights
Breast cancer is the most common cancer in women worldwide and is the second leading cause of cancer death among females [1]
We aimed to investigate the roles of exosomal long noncoding RNA (lncRNA) in the brain metastasis of breast cancer
With GS1-600G8.5 deficiency in the exosome, the expressions of ZO-1, Claudin-5, and N-cadherin proteins were increased in the brain microvascular endothelial cells (BMECs). These results suggested that exosomes containing lncRNA GS1-600G8.5 may destroy blood-brain barrier (BBB) by the tight junction proteins
Summary
Breast cancer is the most common cancer in women worldwide and is the second leading cause of cancer death among females [1]. Metastasis is the leading cause of morbidity and mortality in breast cancer patients. Brain metastasis occurs in approximately 15 to 30% of breast cancer patients, with the highest incidence in breast cancer patients with trinegative or basal tumors and Her-2 positive tumors [2, 3]. Promising advances have recently been made in the treatment of breast cancer, the prognosis of breast cancer patients with brain metastasis remains poor. Novel insights into the process of brain metastasis in breast cancer are urgently needed. The BBB is comprised of brain microvascular endothelial cells (BMECs), pericytes, astrocytes, endothelial basement membranes, and adjacent neurons [4]. How the cancer cells across the BBB to cause brain metastasis is unclear
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