Neurotrophin signaling in cancer

Abstract

Neurotrophins are growth factors that play a major role in neuron survival, proliferation, differentiation, and apoptosis. There are four neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) which function by interacting with Trk (tropomyosin-related kinase) tyrosine kinase receptors, TrkA, TrkB, TrkC, or p75NTR receptor. Binding of neurotrophins with their cognate Trk receptors activates Ras/mitogen-activated protein kinase (MAPK) pathway, Phosphatidylinositol-3 kinase (PI3K)/Akt pathway, and Phospholipase C-g (PLC-g) pathway which are involved in cell survival, proliferation, differentiation, and apoptosis. Activation of the pan-neurotrophin receptor, p75NTR, leads to JNK pathway activation that induces cell apoptosis or activates a NF-kB cell survival pathway. Although neurotrophins were originally found to act on neurons, studies indicate they also have activities in nonneuronal cells. Trk activation or mutation occurs in tumors of neuronal origin, like neuroblastoma and medulloblastoma, as well as in nonneuronal tumors like thyroid, breast, lung, and prostate cancer. In neuroblastoma, expression of TrkA occurs in tumors that are biologically favorable and prone to spontaneous regression or differentiation which may be due to the absence or presence of its ligand (NGF) in the microenvironment. Expression of TrkB and/or its ligand BDNF in neuroblastoma tumors is often associated with chemo-resistance, metastasis, and a poor prognosis. In breast cancer, overexpression of TrkA promotes cell growth, migration and invasion in vitro or tumor growth, metastasis, and angiogenesis. Based on these studies, small molecule inhibitors targeting Trk receptors or downstream targets in their signaling pathways have been developed. The Trk selective inhibitor CEP-701 (Cephalon) or the Akt inhibitor perifosine are both in phase 1 and 2 clinical trials. The effects of these small molecule inhibitors, alone or in combination with chemotherapeutic drugs, are discussed.