The Neurotrophic Receptor TrkB in Anoikis Resistance and Metastasis: A Perspective

Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Cancer Research (Impact Factor: 9.33). 09/2005; 65(16):7033-6. DOI: 10.1158/0008-5472.CAN-05-0709
Source: PubMed

ABSTRACT Resistance to anoikis ("detachment-induced apoptosis") has been suggested to be a prerequisite for cancer cells to metastasize. In a functional screen for suppressors of anoikis, we identified the neurotrophic receptor TrkB. Upon s.c. inoculation in mice, TrkB-expressing cells formed highly invasive and metastatic tumors. Here, we discuss our findings within the context of the proposed role of TrkB in human malignancies and address the question of its feasibility as a target for cancer therapy.

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Available from: Thomas R Geiger, Jul 14, 2014
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    • "TrkB, which initiates the survival signal during neural development, may play a conflicting role such as regulating tumor suppressive functions, which are driven by apoptosis. As TrkB is also reported to be involved in regulating tumor invasion and metastasis in some adult cancers 26–28, these candidate compounds might also be used as drugs against the other advanced cancers with expression of TrkB. "
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    ABSTRACT: Neuroblastoma (NB) is one of the most frequent solid tumors in children and its prognosis is still poor. The neurotrophin receptor TrkB and its ligand brain-derived neurotrophic factor (BDNF) are expressed at high levels in high-risk NBs and are involved in defining the poor prognosis of the patients. However, the TrkB targeting therapy has never been realized in the clinic. We performed an in silico screening procedure utilizing an AutoDock/grid computing technology in order to identify novel small chemical compounds targeting the BDNF-binding domain of TrkB. For the first screening, a library of three million synthetic compounds was screened in silico and was ranked according to the Docking energy. The top-ranked 37 compounds were further functionally screened for cytotoxicity by using NB cell lines. We have finally identified seven compounds that kill NB cells with the IC50 values of 0.07–4.6 μmol/L. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed that these molecules induce apoptosis accompanied by p53 activation in NB cell lines. The candidate compounds and BDNF demonstrated an antagonistic effect on cell growth, invasion, and colony formation, possibly suggesting competition at the BDNF-binding site of TrkB. The candidate compounds had tumor-suppressive activity in xenograft and in vivo toxicity tests (oral and intravenous administrations) using mice, and did not show any abnormal signs. Using in silico Docking screening we have found new candidate TrkB inhibitors against high-risk NBs, which could lead to new anti-cancer drugs.
    Cancer Medicine 02/2014; 3(1). DOI:10.1002/cam4.175 · 2.50 Impact Factor
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    • "Treatment with BDNF promoted cell invasion of diverse cancer cells [10–14], whereas suppression of BDNF/TrkB signaling abrogated invasion of hepatocellular carcinoma cells [15], migration and invasion of head and neck squamous cell carcinoma [13], as well as transitional cell carcinoma [16]. Furthermore, TrkB signaling was shown to be a potent stimulator of angiogenesis [17], and this signaling mediates anoikis resistance, which is important for tumor metastasis [18, 19]. "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) acts through its cognate receptor tyrosine kinase-B (TrkB) to regulate diverse physiological functions in reproductive and other tissues. In normal and malignant trophoblastic cells, the BDNF/TrkB signaling promotes cell growth. Due to the highly malignant nature of choriocarcinoma, we investigated possible involvement of this system in choriocarcinoma cell invasion and metastasis. We demonstrated that treatment of cultured choriocarcinoma cells, known to express both BDNF and TrkB, with a soluble TrkB ectodomain or a Trk receptor inhibitor K252a suppressed cell invasion accompanied with decreased expression of matrix metalloproteinase-2, a cell invasion marker. In vivo studies using a tumor xenograft model in athymic nude mice further showed inhibition of cell invasion from tumors to surrounding tissues following the suppression of endogenous TrkB signaling. For an in vivo model of choriocarcinoma metastasis, we performed intravenous injections of JAR cells expressing firefly luciferase into severe combined immunodeficiency (SCID) mice. Treatment with K252a inhibited metastasis of tumors to distant organs. In vivo K252a treatment also suppressed metastatic tumor growth as reflected by decreased cell proliferation and increased apoptosis and caspases-3/7 activities, together with reduced tissue levels of a tumor marker, human chorionic gonadotropin-β. In vivo suppression of TrkB signaling also led to decreased expression of angiogenic markers in metastatic tumor, including cluster of differentiation 31 and vascular endothelial growth factor A. Our findings suggested essential autocrine/paracrine roles of the BDNF/TrkB signaling system in choriocarcinoma invasion and metastasis. Inhibition of this signaling could serve as the basis to develop a novel therapy for patients with choriocarcinoma.
    Cancer Medicine 12/2013; 2(6):849-861. DOI:10.1002/cam4.158 · 2.50 Impact Factor
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    • "For example, β-blockers are being considered to be a novel adjuvant to existing therapeutic strategies in clinical oncology (73). Finally, as important modulators in the nervous system and cancer, neurotrophic factors, neuropilins, axonal guidance molecules, neurotransmitters and their receptors are being considered to exploit new drugs to be used to treat metastasis (78,82,111,165,234,246–250). "
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    ABSTRACT: The notion that tumors lack innervation was proposed several years ago. However, nerve fibers are irregulatedly found in some tumor tissues. Their terminals interaction with cancer cells are considered to be neuro-neoplastic synapses. Moreover, neural-related factors, which are important players in the development and activity of the nervous system, have been found in cancer cells. Thus, they establish a direct connection between the nervous system and tumor cells. They modulate the process of metastasis, including degradation of base membranes, cancer cell invasion, migration, extravasation and colonization. Peripheral nerve invasion provides another pathway for the spread of cancer cells when blood and lymphatic metastases are absent, which is based on the interactions between the microenvironments of nerve fibers and tumor cells. The nervous system also modulates angiogenesis, the tumor microenvironment, bone marrow, immune functions and inflammatory pathways to influence metastases. Denervation of the tumor has been reported to enhance cancer metastasis. Stress, social isolation and other emotional factors may increase distant metastasis through releasing hormones from the brain, the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Disruption of circadian rhythms will also promote cancer metastasis through direct and indirect actions of the nervous system. Therefore, the nervous system plays an important role in cancer metastasis.
    Oncology letters 04/2013; 5(4):1101-1111. DOI:10.3892/ol.2013.1168 · 1.55 Impact Factor
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