Aim:
The aim of the current work is to assess the role of proBDNF/BDNF in the interaction between brain microvascular endothelial cells and MDA-MB-231 breast cancer cell line that has been consistently reported to cause brain
metastasis.
Background:
Breast cancer brain metastasis (BM) is a significant health problem with limited therapeutic options. The development of BM is a multistep process that requires constant interaction with brain vasculature and development of tumor
blood supply. The benefits of antiangiogenic modalities based on antagonizing vascular endothelial growth factor in breast
cancer metastasis did not prove to be effective. Brain derived neurotrophic factor (BDNF) is a neurotrophin with reported
angiogenic effect. There is a lack of data regarding the involvement of BDNF in metastatic breast cancer interaction with
brain microvascular endothelial cells (HBEC-5i).
Objectives:
To determine the role of the pro form of BDNF in the interaction between MDA-MB-231 cells and brain endothelial cells.
Methods:
using an adaptive transfer design, the cross talk between HBEC-5i and MDA-MB-231 was investigated. HBEC-5i
were treated with MDA-MB-231-conditioned media and the involvement of BDNF/proBDNF in the interaction was assessed using both release and inhibitor-based assays in migration and in vitro tube formation assay.
Results:
MDA-MB-231 and HBEC-5i released total BDNF (250 vs. 80 pg/ml, respectively). MDA-MB-231 conditioned
media inhibited the migration of HBEC-5i by more than 80% (p<0.05) and tube formation by 75% (p<0.05). Neutralizing
mature BDNF did not alter the MDA-MB-231 induced antiangiogenic effect which was completely blunted by antagonizing
proBDNF. MDA-MB-231 released proBDNF (131.5 pg/ml) and more that 60% of total BDNF released was in the pro-form.
Conclusion:
proBDNF is a novel mediator of the breast cancer induced antiangiogenic effect in brain endothelial cells.
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