Brain-derived neurotrophic factor (BDNF) -TrKB signaling modulates cancer-endothelial cells interaction and affects the outcomes of triple negative breast cancer

Abstract

AimsThere is good evidence that the tumor microenvironment plays an important role in cancer metastasis and progression. Our previous studies have shown that brain-derived neurotrophic factor (BDNF) participates in the process of metastasis and in the migration of cancer cells. The aim of this study was to investigate the role of BDNF on the tumor cell microenvironment, namely, the cancer cell-endothelial cell interaction of TNBC cells.MethodsWe conducted oligoneucleotide microarray analysis of potential biomarkers that are able to differentiate recurrent TNBC from non-recurrent TNBC. The MDA-MB-231 and human endothelial HUVEC lines were used for this study and our approaches included functional studies, such as migration assay, as well as Western blot and real-time PCR analysis of migration and angiogenic signaling. In addition, we analyzed the survival outcome of TNBC breast cancer patients according to their expression level of BDNF using clinical samples.ResultsThe results demonstrated that BDNF was able to bring about autocrinal (MDA-MB-231) and paracrinal (HUVECs) regulation of BDNF-TrkB gene expression and this affected cell migratory activity. The BDNF-induced migratory activity was blocked by inhibitors of ERK, PI3K and TrkB when MDA-MB-231 cells were examined, but only an inhibitor of ERK blocked this activity when HUVEC cells were used. Furthermore, decreased migratory activity was found for △BDNF and △TrkB cell lines. Ingenuity pathway analysis (IPA) of MDA-MB-231 cells showed that BDNF is a key factor that is able to regulate a network made up of metalloproteases and calmodulin. Protein expression levels in a tissue array of tumor slices were found to be correlated with patient prognosis and the results showed that there was significant correlation of TrkB expression, but not of BDNF. expressionwith patient DFS and OS.ConclusionOur study demonstrates that up-regulation of the BDNF signaling pathway seems tobe involved in the mechanism associated with early recurrence in triple negative breast cancer cell. In addition, BDNF can function in either an autocrine or a paracrine manner to increase the migration ability of both MDA-MB-231 cells and HUVEC cells. Finally, overexpression of TrkB, but not of BDNF, is significantly associated with a poor survival outcome for TNBC patients.

Neurotrophin‐3 acts on the endothelial‐mesenchymal transition of heterotopic ossification in rats

“…As NT-3 and its TrkC receptor were observed during formation of HO ( Figure 2), thus we tried to further explore role of NT-3 on the induction of EndMT in HO. GNF5837, the inhibitor of TrkC receptor 25 Figure 7C, 7), which was similar with the effect of Dorsomorphin.…”

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

“…Due to their great importance during metastasis development, targeting these proteases has been considered an important objective of anti-tumoral therapy, resulting in the development of a great variety of MMP inhibitors (reviewed in [278]). In this context, it has been shown by ingenuity pathway analysis that the BDNF/TrkA (tropomyosin receptor kinase A) pathway regulates the network of MMPs and CaM in triple-negative human breast carcinoma cells modulating the interaction of tumor cells with endothelial cells [279]. HRPAP20 (hormone-regulated proliferation-associated protein 20) is a CaM-binding proliferation-associated protein highly expressed in invasive breast cancer cells and is implicated in matrix metalloprotease-9 (MMP-9) secretion [280].…”

Immunity against cancer cells may promote their proliferation and metastasis

“…As a result, these pathways showed oncogenic effects by increasing cancer cell growth, proliferation, migration, epithelial-mesenchymal transition, and resistance to anoikis. These findings indicate that TrkB may be a useful target for therapeutic interventions for cancer cells (20)(21)(22)(23).…”