Targeting the BDNF/TrkB pathway for the treatment of tumors (Review)

Abstract

Neurotrophins are a family of growth factors that regulate neural survival, development, function and plasticity in the central and the peripheral nervous system. There are four neurotrophins: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4. Among them, BDNF is the most studied due to its high expression in the brain. Over the past two decades, BDNF and its receptor tropomyosin receptor kinase B (TrkB) have been reported to be upregulated in a wide range of tumors. This activated signal stimulates a series of downstream pathways, including phosphoinositide 3-kinase/protein kinase B, Ras-Raf-mitogen activated protein kinase kinase-extracellular signal-regulated kinases, the phospholipase-C-γ pathway and the transactivation of epidermal growth factor receptor. Activation of these signaling pathways induces oncogenic effects by increasing cancer cell growth, proliferation, survival, migration and epithelial to mesenchymal transition, and decreasing anoikis, relapse and chemotherapeutic sensitivity. The present review summarizes recent findings to discuss the role of BDNF in tumors, the underlying molecular mechanism, targeting Trk receptors for treatment of cancers and its potential risk.

Licochalcone A Inhibits BDNF and TrkB Gene Expression and Hypoxic Growth of Human Tumor Cell Lines

“…TrkB has been reported to regulate cellular proliferation in various cancer cells (reviewed in [12,27]). In accordance with this notion, TrkB knockdown in the SK-N-SH cell line in hypoxia caused inhibition of cellular proliferation in this study ( Figure 2I).…”

“…It has been reported that TrkB activation initiates three downstream signaling cascades, namely PI3K/AKT/mTOR, Ras/extracellular signal-regulated kinase (ERK), and phospholipase C-γ/protein kinase C (PLCγ/PKC) [12,27]. The activating mutations of the K-ras gene constitutively turn on the downstream K-ras-transduced signaling pathways, Ras/ERK and PI3K/AKT.…”

Neuroprotective effect of poly(lactic-co-glycolic acid) nanoparticle-bound brain-derived neurotrophic factor in a permanent middle cerebral artery occlusion model of ischemia in rats

“…It exerts its effects on brain function, including neuroprotection, vascular remodelling, neurogenesis, neuronal survival, and neuroplasticity, following injury to brain cells, particularly after ischemic insults (Chao, 2003;Ohira and Hayashi, 2009;Lu et al, 2013). Additionally, BDNF regulates neuronal survival, cell migration, and synaptic function (Thoenen, 1995;Murer et al, 2001;Baydyuk and Xu, 2014;Lu et al, 2014;Meng et al, 2019).…”

Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer

“…NTRK2 was shown to serve as an oncogene in multiple cancers (19)(20)(21)(22), and its increased expression was associated with poor outcome (23,24). Based on this, inhibition of NTRK2-encoded TRKB was shown to induce antitumor effects and cellular apoptosis (25,26). Similar to NTRK1, NTRK3 has been demonstrated to be an oncogene in breast cancer and gastric cancer (27,28), but it acts as a tumor suppressor gene in CRC, neuroblastomas, and head and neck squamous cell carcinoma (10,29,30).…”