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Neurotrophin Signaling in Cancer

  • Reference work entry
  • First Online:
Handbook of Neurotoxicity

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-γ (PLC-γ) 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-κB 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.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

ERK:

Extracellular signal-regulated kinase

Grb2:

Growth factor receptor-bound protein 2

HGF:

Hepatocyte growth factor

JNK:

c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinases

MEK:

MAP kinase kinase

mTOR:

Mammalian target of rapamycin

NGF:

Nerve growth factor

NSCLC:

Non-small cell lung cancer

NT-3:

Neurotrophin 3

NT-4/5:

Neurotrophin 4/5

P75NTR:

P75 neurotrophin receptor

PI3K:

Phosphatidylinositol-3 kinase

PLC-γ:

Phospholipase C-γ

PTB domain:

Phosphotyrosine-binding domain

SCLC:

Small cell lung cancer

Shc:

Src-homology collagen protein

SOS:

Son of sevenless

Trk:

Tropomyosin-related kinase

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Authors and Affiliations

  1. Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, 110004, China

    Fei Tan

  2. Cellular and Molecular Biology, Pediatric Oncology Branch, National Cancer Institute, National Institute of Health, 10 Center Dr. MSC-1105, Bethesda, MD, 20892, USA

    Carol J. Thiele & Zhijie Li

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  1. Fei Tan
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  2. Carol J. Thiele
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  3. Zhijie Li
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Correspondence to Fei Tan .

Editor information

Editors and Affiliations

  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, USA

    Richard M. Kostrzewa

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Tan, F., Thiele, C.J., Li, Z. (2014). Neurotrophin Signaling in Cancer. In: Kostrzewa, R. (eds) Handbook of Neurotoxicity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5836-4_49

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