Changes in the blood-brain barrier properties in vitro after treatment with sera from breast cancer patients with primary cancer and visceral, bone or cerebral metastases.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2026-2026
Author(s):  
Carolin Julia Curtaz ◽  
Schmitt Constanze ◽  
Patrick Meybohm ◽  
Achim Wöckel ◽  
Malgorzata Burek
Keyword(s):  
Breast Cancer ◽  
Bone Metastases ◽  
Cancer Patients ◽  
Blood Brain Barrier ◽  
Cerebral Metastases ◽  
Brain Barrier ◽  
Primary Cancer ◽  
Breast Cancer Patients ◽  
Blood Brain

2026 Background: The progression of brain metastases during breast cancer correlates with poor overall survival, but also with a reduced quality of life. During the metastatic progression of breast cancer, the key event for entry into the brain is the migration of cancer cells across the blood-brain barrier (BBB). To date, it is still controversial which serum factors play a role in cerebral expansion and what effects they have on the BBB. We hypothesize that sera from breast cancer patients with cerebral metastases contain unique factors that can affect BBB integrity. Methods: We used the CD34+ cells-derived human in vitro BBB model (brain-like endothelial cells, BLECs) in co-culture with brain pericytes, which was validated in our previous studies, to analyse the BBB properties after patient sera treatment. We used paracellular permeability measurements for fluorescein (400 Da), immunofluorescence staining, Western blot and mRNA analysis to examine the effects of patient sera on the properties of BBB in vitro. We collected serum samples from five patient cohorts (30 patient per group planned/150 in total/ current recruited patients 130): 1) healthy donors (current recruited patients- 23), 2) breast cancer patients with primary cancer (recruited patients- 30), 3) breast cancer patients with bone metastases (recruited patients- 29), 4) visceral metastases (recruited patients- 30), or 5) cerebral metastases (current recruited patients- 18). We then used 2% patient sera in cell culture medium to treat the cells for 24 hours. Results: Sera from breast cancer patients with cerebral and bone metastases led to a significant increase in the paracellular permeability for fluorescein. This could also be visualized by immunostaining cells with anti-claudin-5 antibody. Tight junction protein claudin-5 and occludin mRNA was reduced in BLECs, while mRNA of efflux pumps Breast cancer resistance protein (BCRP) and P-glycoprotein (P-GP) was induced in BLECs treated with serum from breast cancer patients with primary cancer, cerebral and visceral metastases. At the protein level, efflux pumps BCRP and P-GP were induced in cells treated with sera from breast cancer patients with cerebral metastases, while they were reduced in cells treated with sera from breast cancer patients with bone metastases. Conclusions: Sera from breast cancer patients with primary cancer and breast cancer metastases have an effect on the integrity of BBB in vitro. Reduced barrier properties of brain endothelial cells can contribute to the formation of cerebral metastases in advanced stages of breast cancer. Keywords: metastatic breast cancer, blood-brain barrier, in vitro models

scholarly journals SNORA71B promotes breast cancer cells across blood–brain barrier by inducing epithelial-mesenchymal transition

Breast Cancer ◽  
2020 ◽  
Vol 27 (6) ◽  
pp. 1072-1081
Author(s):  
Sijia Duan ◽  
Xuliang Luo ◽  
Huihui Zeng ◽  
Xiang Zhan ◽  
Chunlei Yuan
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Blood Brain Barrier ◽  
Epithelial Mesenchymal Transition ◽  
Brain Barrier ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Blood Brain

Abstract Background Brain metastasis (BM) is a dreadful complication that significantly impacts the quality of life in breast cancer patients. A key process during brain metastasis is the migration of cancer cells across blood–brain barrier (BBB). However, the role of snoRNAs regulating BBB in BM is still unknown. Methods Here SNORic and GEO databases were used to identify differentially expressed snoRNAs between brain metastatic and non-metastatic breast cancer (BC) tissues. The effects of SNORA71B on the capacities of proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and BBB invasion of BC cells were evaluated by CCK8, transwell, western blot, and BBB model, respectively. Results SNORA71B was highly expressed in high BM BC tissues and cells compared to low BM BC controls. Survival analysis revealed high expression of SNORA71B was significantly associated with poor PPS and OS in breast cancer patients. ROC curve showed that SNORA71B might act as biomarker for breast cancer. Moreover, SNORA71B significantly promoted proliferation, migration, and invasion of BC cells with different BM abilities. Importantly, SNORA71B promoted the EMT process of low BM BC cells. SNORA71B knockdown inhibited the high BM BC cells across BBB, while EMT activator dramatically abrogated this inhibited effect. Conclusions In conclusion, SNORA71B promotes BC cells across the BBB partly via inducing EMT.

scholarly journals Bisphenol A Inhibits the Transporter Function of the Blood-Brain Barrier by Directly Interacting with the ABC Transporter Breast Cancer Resistance Protein (BCRP)

2021 ◽  
Vol 22 (11) ◽  
pp. 5534
Author(s):  
Elin Engdahl ◽  
Maarten van Schijndel ◽  
Dimitrios Voulgaris ◽  
Michela Di Criscio ◽  
Kerry Ramsbottom ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bisphenol A ◽  
Blood Brain Barrier ◽  
Breast Cancer Resistance Protein ◽  
Brain Barrier ◽  
Production Volume ◽  
Cancer Resistance ◽  
Blood Brain ◽  
Resistance Protein

The breast cancer resistance protein (BCRP) is an important efflux transporter in the blood-brain barrier (BBB), protecting the brain from a wide range of substances. In this study, we investigated if BCRP function is affected by bisphenol A (BPA), a high production volume chemical used in common consumer products, as well as by bisphenol F (BPF) and bisphenol S (BPS), which are used to substitute BPA. We employed a transwell-based in vitro cell model of iPSC-derived brain microvascular endothelial cells, where BCRP function was assessed by measuring the intracellular accumulation of its substrate Hoechst 33342. Additionally, we used in silico modelling to predict if the bisphenols could directly interact with BCRP. Our results showed that BPA significantly inhibits the transport function of BCRP. Additionally, BPA was predicted to bind to the cavity that is targeted by known BCRP inhibitors. Taken together, our findings demonstrate that BPA inhibits BCRP function in vitro, probably by direct interaction with the transporter. This effect might contribute to BPA’s known impact on neurodevelopment.

scholarly journals Impact of Docetaxel on blood-brain barrier function and formation of breast cancer brain metastases

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Simon Bernatz ◽  
Elena I. Ilina ◽  
Kavi Devraj ◽  
Patrick N. Harter ◽  
Klaus Mueller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Brain Barrier ◽  
Patient Cohort ◽  
Blood Brain ◽  
Metastatic Setting ◽  
The Impact

Abstract Background Breast cancer (BC) is the most frequent malignant tumor in females and the 2nd most common cause of brain metastasis (BM), that are associated with a fatal prognosis. The increasing incidence from 10% up to 40% is due to more effective treatments of extracerebral sites with improved prognosis and increasing use of MRI in diagnostics. A frequently administered, potent chemotherapeutic group of drugs for BC treatment are taxanes usually used in the adjuvant and metastatic setting, which, however, have been suspected to be associated with a higher incidence of BM. The aim of our study was to experimentally analyze the impact of the taxane docetaxel (DTX) on brain metastasis formation, and to elucidate the underlying molecular mechanism. Methods A monocentric patient cohort was analyzed to determine the association of taxane treatment and BM formation. To identify the specific impact of DTX, a murine brain metastatic model upon intracardial injection of breast cancer cells was conducted. To approach the functional mechanism, dynamic contrast-enhanced MRI and electron microscopy of mice as well as in-vitro transendothelial electrical resistance (TEER) and tracer permeability assays using brain endothelial cells (EC) were carried out. PCR-based, immunohistochemical and immunoblotting analyses with additional RNA sequencing of murine and human ECs were performed to explore the molecular mechanisms by DTX treatment. Results Taxane treatment was associated with an increased rate of BM formation in the patient cohort and the murine metastatic model. Functional studies did not show unequivocal alterations of blood-brain barrier properties upon DTX treatment in-vivo, but in-vitro assays revealed a temporary DTX-related barrier disruption. We found disturbance of tubulin structure and upregulation of tight junction marker claudin-5 in ECs. Furthermore, upregulation of several members of the tubulin family and downregulation of tetraspanin-2 in both, murine and human ECs, was induced. Conclusion In summary, a higher incidence of BM was associated with prior taxane treatment in both a patient cohort and a murine mouse model. We could identify tubulin family members and tetraspanin-2 as potential contributors for the destabilization of the blood-brain barrier. Further analyses are needed to decipher the exact role of those alterations on tumor metastatic processes in the brain.

scholarly journals Circulating MicroRNAs and Blood-Brain-Barrier Function in Breast Cancer Metastasis

2020 ◽  
Vol 26 (13) ◽  
pp. 1417-1427 ◽  
Author(s):  
Carolin J. Curtaz ◽  
Constanze Schmitt ◽  
Kinga G. Blecharz-Lang ◽  
Norbert Roewer ◽  
Achim Wöckel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Brain Barrier ◽  
Target Cells ◽  
Breast Cancer Patients ◽  
Blood Brain ◽  
The Brain

Brain metastases are a major cause of death in breast cancer patients. A key event in the metastatic progression of breast cancer in the brain is the migration of cancer cells across the blood-brain barrier (BBB). The BBB is a natural barrier with specialized functions that protect the brain from harmful substances, including antitumor drugs. Extracellular vesicles (EVs) sequestered by cells are mediators of cell-cell communication. EVs carry cellular components, including microRNAs that affect the cellular processes of target cells. Here, we summarize the knowledge about microRNAs known to play a significant role in breast cancer and/or in the BBB function. In addition, we describe previously established in vitro BBB models, which are a useful tool for studying molecular mechanisms involved in the formation of brain metastases.

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