Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology (JUST), Irbid, 22110, Jordan.
Curr Mol Med. 2021;21(10):914-921. doi: 10.2174/1566524020666201120142717.
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.
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).
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.
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.
proBDNF is a novel mediator of breast cancer-induced anti-angiogenic effect in brain endothelial cells.
本研究旨在评估前脑源性神经营养因子（proBDNF）/脑源性神经营养因子（BDNF）在脑微血管内皮细胞与 MDA-MB-231 乳腺癌细胞系之间相互作用中的作用，后者一直被报道可导致脑转移。
乳腺癌脑转移（BM）是一个严重的健康问题，治疗选择有限。BM 的发展是一个多步骤的过程，需要与脑脉管系统不断相互作用，并发展肿瘤血液供应。基于拮抗乳腺癌转移中血管内皮生长因子的抗血管生成方式的益处并未被证明是有效的。脑源性神经营养因子（BDNF）是一种具有报道的血管生成作用的神经营养因子。关于 BDNF 在转移性乳腺癌与脑微血管内皮细胞（HBEC-5i）相互作用中的参与，数据不足。
使用自适应转移设计，研究了 HBEC-5i 与 MDA-MB-231 细胞之间的串扰。用 MDA-MB-231 条件培养基处理 HBEC-5i，使用释放和抑制剂为基础的测定法，在迁移和体外管形成测定中评估 BDNF/proBDNF 在相互作用中的作用。
MDA-MB-231 和 HBEC-5i 分别释放总 BDNF（分别为 250 与 80pg/ml）。MDA-MB-231 条件培养基抑制 HBEC-5i 的迁移超过 80%（p<0.05）和管形成 75%（p<0.05）。中和成熟 BDNF 不会改变 MDA-MB-231 诱导的抗血管生成作用，而拮抗 proBDNF 则完全阻断了该作用。MDA-MB-231 释放 proBDNF（131.5pg/ml），释放的总 BDNF 中超过 60%处于前体形式。
proBDNF 是乳腺癌诱导脑内皮细胞抗血管生成作用的新型介质。
