Uncovering the role of brain‐derived neurotrophic factor/tyrosine kinase receptor B signaling in head and neck malignancies

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In the past years, the paradigm for cancer therapy evolved from conventional non‐specific treatments to highly selective, mechanism‐based drugs.1 Therefore, the identification of deregulated molecular networks in different types of tumors became a primordial goal in the challenging battle to beat cancer. Among these, growth factor signaling pathways, neurotrophins and their receptors represent emerging targets for the development of novel anticancer therapies.2
Brain‐derived neurotrophic factor (BDNF) is a growth factor member of a family of functionally and structurally related proteins called neurotrophins that also includes nerve growth factor (NGF), neurotrophin 3 (NT‐3), and neurotrophin 4/5 (NT‐4/5). BDNF is expressed mainly involved in the differentiation of neurons, responsible for sustain the growth and function of neuronal synapses, proliferation, plasticity, and survival of neural adulthood cells in the central and peripheral nervous system. This protein was identified and isolated for the first time in 1982 by Barde et al. from the pig brain as a survival factor for embryonic sensory neurons of chickens in culture. Since 1991, it was identified as a ligand for tyrosine receptor kinase B (TrkB).2
Both BDNF and TrkB are expressed by T and B lymphocytes, platelets, macrophages, vascular endothelial cells, epidermal, and other non‐neural cells.5 In oral cavity, BDNF is necessary for the development of the dental papilla/pulp ‐ beginning of the dental innervation; modulation of proliferation, and differentiation of epithelial and mesenchymal cells; formation and maintenance of the sensory apparatus of the tongue (morphogenesis of the gustatory epithelium). BDNF‐derived gustatory epithelium is required for gustatory axons to correctly locate and innervate fungiform papillae with BDNF‐mediated target being restricted to a critical period of development.6
Current research has shown that BDNF/TrkB pathway facilitates tumor progression stimulating invasion, metastasis, and angiogenesis. BDNF/TrkB system has also been reported to be responsible for chemoresistance, through Akt/PI‐3K and MAPK signaling pathways, in selected models of cancer. It has been shown to be overexpressed in various cancer types like head and neck squamous cell carcinoma (HNSCC), pancreas, Wilms’ tumors, lung, breast, gastric, hepatocellular, and also myelomas and lymphoid cancers. In addition, in various types of tumors the overexpression of these proteins was associated with more aggressive behavior and poor prognosis.7 Our group was the first to identify and explore the role of BDNF and TrkB in colorectal cancer23 and has been evaluating this pathway in other cancers such as acute leukemia,25 Ewing sarcoma,26 medulloblastoma,27 and breast and gynecologic cancer.29
Brain‐derived neurotrophic factor and its receptor represent promising targets for the development of novel anticancer therapies.10 Several series of Trk inhibitors with excellent in vitro therapeutic potential have been reported and a number of compounds have gone into the clinic.30 Some undergoing clinical trials are evaluating the efficacy of Trk protein‐target drugs in different types of solid tumors.31 The most favorable results concerning Trk inhibitors were observed in tumors that harbor NTRK gene fusions.31 Trk inhibitors Entrectinib and LOXO‐101, for example, demonstrated sustained clinical responses among patients with metastatic or unresectable solid tumors with NTRK mutations.31
To date, few groups have evaluated the BDNF/TrkB pathway in head and neck malignancies. Therefore, in this study, we aimed to review the literature concerning the role of BDNF/TrkB activation in these tumors, as well as to discuss future perspectives of BDNF/TrkB‐target therapy.
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