Abstract:Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that was first known as responsible for sustain the growth, function, and plasticity of neural cells. BDNF exerts its effects by binding to the tyrosine kinase receptor B (TrkB). The BDNF/TrkB axis has been reported to be overexpressed in several neurogenic and non-neurogenic tumors. Its higher expression was associated with a poor prognosis to patients affected by different human malignancies, tumor growth, invas… Show more
“…NTRK1 fusions are now known to occur in many other solid tumor types, including lung adenocarcinoma, papillary thyroid carcinoma, secretory breast carcinoma, and glioblastoma (GBM) [ 45 , 46 ]. In addition, evidence indicating that NGF/TrkA, BDNF/TrkB, TrkC, or p75NTR play a role in cancer has rapidly accumulated over the past few years, with most studies showing that neurotrophins and their receptors are expressed in cancer cells and influence experimental tumor growth, cellular survival, proliferation, migration, invasion, neovascularization, metastasis, and treatment resistance in many peripheral solid tumor types including colorectal, breast, small cell and non-small cell lung, cervical, bladder, gallbladder, laryngeal, renal, head and neck, and oral squamous cell cancers [ 3 , 5 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ].…”
Section: Neurotrophin Signaling In Cancermentioning
Neurotrophins are a family of secreted proteins that act by binding to tropomyosin receptor kinase (Trk) or p75NTR receptors to regulate nervous system development and plasticity. Increasing evidence indicates that neurotrophins and their receptors in cancer cells play a role in tumor growth and resistance to treatment. In this review, we summarize evidence indicating that neurotrophin signaling influences medulloblastoma (MB), the most common type of malignant brain cancer afflicting children. We discuss the potential of neurotrophin receptors as new therapeutic targets for the treatment of MB. Overall, activation of TrkA and TrkC types of receptors seem to promote cell death, whereas TrkB might stimulate MB growth, and TrkB inhibition displays antitumor effects. Importantly, we show analyses of the gene expression profile of neurotrophins and their receptors in MB primary tumors, which indicate, among other findings, that higher levels of NTRK1 or NTRK2 are associated with reduced overall survival (OS) of patients with SHH MB tumors.
“…NTRK1 fusions are now known to occur in many other solid tumor types, including lung adenocarcinoma, papillary thyroid carcinoma, secretory breast carcinoma, and glioblastoma (GBM) [ 45 , 46 ]. In addition, evidence indicating that NGF/TrkA, BDNF/TrkB, TrkC, or p75NTR play a role in cancer has rapidly accumulated over the past few years, with most studies showing that neurotrophins and their receptors are expressed in cancer cells and influence experimental tumor growth, cellular survival, proliferation, migration, invasion, neovascularization, metastasis, and treatment resistance in many peripheral solid tumor types including colorectal, breast, small cell and non-small cell lung, cervical, bladder, gallbladder, laryngeal, renal, head and neck, and oral squamous cell cancers [ 3 , 5 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ].…”
Section: Neurotrophin Signaling In Cancermentioning
Neurotrophins are a family of secreted proteins that act by binding to tropomyosin receptor kinase (Trk) or p75NTR receptors to regulate nervous system development and plasticity. Increasing evidence indicates that neurotrophins and their receptors in cancer cells play a role in tumor growth and resistance to treatment. In this review, we summarize evidence indicating that neurotrophin signaling influences medulloblastoma (MB), the most common type of malignant brain cancer afflicting children. We discuss the potential of neurotrophin receptors as new therapeutic targets for the treatment of MB. Overall, activation of TrkA and TrkC types of receptors seem to promote cell death, whereas TrkB might stimulate MB growth, and TrkB inhibition displays antitumor effects. Importantly, we show analyses of the gene expression profile of neurotrophins and their receptors in MB primary tumors, which indicate, among other findings, that higher levels of NTRK1 or NTRK2 are associated with reduced overall survival (OS) of patients with SHH MB tumors.
“…The BDNF/TrkB axis is overexpressed in neurogenic and non-neurogenic tumors, as well, its higher expression was reported to be associated with unfavored prognosis in cancer patients. Mechanistic explanations for this issue are related to tumor growth, invasion, metastasis, epithelial-to-mesenchymal transition, and resistance to chemotherapy [12,13].…”
We hypothesized that in head and neck squamous cell carcinoma (HNSCC), the neurotrophin brain-derived neurotrophic factor (BDNF) and its high affinity receptor TrkB regulate tumor cell survival, invasion, and therapy resistance. We used in situ hybridization for BDNF and immunohistochemistry (IHC) for TrkB in 131 HNSCC samples. Brain-derived neurotrophic factor was highly expressed in normal mucosa in HNSCC tissue and in cell lines, whereas only 42.74% of HNSCC tissue was TrkB+. One fourth of HNSCC cases was human papilloma virus (HPV)− positive, but the TrkB IHC frequency was not different in HPV-positive (HPV+) and negative cases. The UPCI-SCC090 cells expressed constitutive levels of TrkB. Transforming-growth-factor-β1 (1 ng/mL TGF-β1) induced TrkB in a subpopulation of SCC-25 cells. A single 10-µg/mL mitomycin C treatment in UPCI-SCC090 cells induced apoptosis and BDNF did not rescue them. The SCC-25 cells were resistant to the MMC treatment, and their growth decreased after TGF-β1 treatment, but was restored by BDNF if it followed TGF-β1. Taken together, BDNF might be ineffective in HPV+ HNSCC patients. In HPV− HNSCC patients, tumor cells did not die after chemotherapeutic challenge and BDNF with TGF-β1 could improve tumor cell survival and contribute to worse patient prognosis.
“…PIKC3 gene copy number correlated weakly with TrkB-T1 RNA at r = 0.3 and r = 0.47 in LASC and OSCC cells respectively. Pikc3a is a key component of the AKT pathway which in turn has been shown to be regulated by TrkB proteins [17, 18]. Logistic regression revealed that, in LASC, activating mutations of the PIK3CA gene were associated with high TrkB-T1 expression (odds ratio 0.720; 95% confidence interval, 0.577 to 0.899; p = 0.0037).Fig.…”
Section: Resultsmentioning
confidence: 99%
“…In oral, head and neck, ovarian, pancreatic, colon, prostate, and gastric cancers and neuroblastomas, high TRKB protein levels correlate with worse patient outcomes [10–18]. Rare mutated versions of the NTRK2 gene, which encode proteins consisting of fusions of the TrkB kinase domain with domains of other signaling proteins, are drivers in a number of cancers [17, 19–22]. The intact NTRK2 gene is also a potential oncogene [12, 13, 23].…”
Background
The NTRK2 genetic locus encodes neurotrophin membrane receptors that play an important role in normal neural tissue plasticity, growth, and survival. One NTRK2-encoded protein is TrkB-FL, which can regulate multiple pathways relevant to cancer. A second NTRK2 gene mRNA isoform encodes TrkB-T1, a receptor that has a different cytoplasmic domain encoded in a mRNA with a unique 3′ terminal exon.
Method
Tumors from The Cancer Genome Atlas (TCGA) and other studies were classified according to the expression of a single form of NTRK2 mRNA, TrkB-T1, identified by its unique 3′ terminal exon. Analysis of differentially expressed genes in TrkB-T1 high expressers was done to determine if tumors enriched for TrkB-T1 mRNA were a uniform group independent of anatomic site.
Results
The mRNA for TrkB-T1 is the most abundant NTRK2 gene mRNA in all squamous cell carcinomas (SCCs) in the TCGA database. Comparison of larynx SCC high TrkB-T1 RNA expressers to low expressers (
n
= 96) revealed gene expression differences consistent with the high TrkB-T1 tumors being more neural-like. The upregulated genes in the TrkB-T1 RNA high expressers also showed enrichment of pathways involved in retinol metabolism, hedgehog signaling, and the Nfe2l2 response, among other pathways. An examination of oral, esophagus, and lung SCCs (
n
= 284, 97, 501) showed induction of the same pathways among tumors that expressed high levels of TrkB-T1 mRNA. Proteins associated with regulation of the sonic hedgehog pathway, and the Nfe2l2 response, Tp63, and Keap1 and p62/SQSTM1 proteins, showed differential expression in larynx, oral and lung high TrkB1-T1 expresser SCCs. Unexpectantly, the relationship of high level TrkB-T1 expression to patient outcomes was SCC anatomic site specific. High TrkB-T1 mRNA levels in laryngeal SCC correlated with poor survival, but the opposite was true for lung SCC. This may be because pathways enriched in the TrkB high expressers, like those involving oncogenes NFE2L2, PIK3CA, and SOX2, are known to have SCC anatomic site-specific effects on progression.
Conclusions
High level TrkB-T1 mRNA is a marker of a distinct SCC subtype enriched for at least 3 pathways relevant to tumor progression: Nfe2l2 response, retinol metabolism, and hedgehog signaling.
Electronic supplementary material
The online version of this article (10.1186/s12885-019-5789-8) contains supplementary material, which is available to authorized users.
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