Aim: The current work aims to assess the role of proBDNF/BDNF in the
interaction between brain microvascular endothelial cells and the 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 the development of tumor blood supply.
The benefits of anti-angiogenic 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 a 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).
Methods: Using an adaptive transfer design, the cross-talk between HBEC-5i and MDAMB-
231 cell 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 anti-angiogenic effect, which was
completely blunted by antagonizing proBDNF. MDA-MB-231 released proBDNF (131.5
pg/ml), and more than 60% of total BDNF released was in the pro-form.
Conclusion: proBDNF is a novel mediator of breast cancer-induced anti-angiogenic
effect in brain endothelial cells.