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BDNF and its signaling in cancer

  • Review
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Brain-derived neurotrophic factor (BDNF) belongs to the family of neurotrophic factors that can potentially increase cancer cell growth, survival, proliferation, anoikis, and migration by tyrosine kinase receptors TrkB and the p75NTR death receptor. The activation of BDNF/TrkB pathways leads to several downstream signaling pathways, including PI3K/Akt, Jak/STAT, PLCγ, Ras-Raf-MEK-ERK, NF-kB, and transactivation of EGFR. The current review aimed to provide an overview of the role of BDNF and its signaling in cancer.

Methods

We searched a major medical database, PubMed, to identify eligible studies for a narrative synthesis.

Results

Pathological examinations demonstrate BDNF overexpression in human cancer, notably involving the prostate, lung, breast, and underlying tissues, associated with a higher death rate and poor prognosis. Therefore, measurement of BDNF, either for identifying the disease or predicting response to therapy, can be helpful in cancer patients. Expression profiling studies have recognized the role of microRNAs (miR) in modulating BDNF/TrkB pathways, such as miR-101, miR-107, miR-134, miR-147, miR-191, miR-200a/c, miR-204, miR-206, miR-210, miR-214, miR-382, miR-496, miR-497, miR-744, and miR-10a-5p, providing a potential biological mechanism by which targeted therapies may correlate with decreased BDNF expression in cancers. Clinical studies investigating the use of agents targeting BDNF receptors and related signaling pathways and interfering with the related oncogenic effect, including Entrectinib, Larotrectinib, Cabozantinib, Repotrectinib, Lestaurtinib, and Selitrectinib, are in progress.

Conclusion

The aberrant signaling of BDNF is implicated in various cancers. Well-designed clinical trials are needed to clarify the BDNF role in cancer progression and target it as a therapeutic method.

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References

  • Aili A, Chen Y, Zhang H (2016) MicroRNA-10b suppresses the migration and invasion of chondrosarcoma cells by targeting brain-derived neurotrophic factor. Mol Med Rep 13(1):441–446

    Article  CAS  PubMed  Google Scholar 

  • Aloe L et al (1986) Aggressive behavior induces release of nerve growth factor from mouse salivary gland into the bloodstream. Proc Natl Acad Sci 83(16):6184–6187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aoki M, Blazek E, Vogt PK (2001) A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc Natl Acad Sci 98(1):136–141

    Article  CAS  PubMed  Google Scholar 

  • Au CW et al (2009) Tyrosine kinase B receptor and BDNF expression in ovarian cancers–Effect on cell migration, angiogenesis and clinical outcome. Cancer Lett 281(2):151–161

    Article  CAS  PubMed  Google Scholar 

  • Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64(2):238–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bailey JJ et al (2020) Tropomyosin receptor kinase inhibitors: an updated patent review for 2016–2019. Expert Opin Ther Pat 30(5):325–339

    Article  CAS  PubMed  Google Scholar 

  • Banerjee K, Resat H (2016) Constitutive activation of STAT 3 in breast cancer cells: a review. Int J Cancer 138(11):2570–2578

    Article  CAS  PubMed  Google Scholar 

  • Bao W et al (2013) A TrkB-STAT3-miR-204–5p regulatory circuitry controls proliferation and invasion of endometrial carcinoma cells. Mol Cancer. https://doi.org/10.1186/1476-4598-12-155

    Article  PubMed  PubMed Central  Google Scholar 

  • Bao Y et al (2014) PAR2-mediated upregulation of BDNF contributes to central sensitization in bone cancer pain. Mol Pain. https://doi.org/10.1186/1744-8069-10-28

    Article  PubMed  PubMed Central  Google Scholar 

  • Barde YA, Edgar D, Thoenen H (1982) Purification of a new neurotrophic factor from mammalian brain. EMBO J 1(5):549–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berridge MJ, Irvine RF (1989) Inositol phosphates and cell signalling. Nature 341(6239):197–205

    Article  CAS  PubMed  Google Scholar 

  • Binder DK, Scharfman HE (2004) Brain-derived neurotrophic factor. Growth Factors (chur, Switzerland) 22(3):123–131

    Article  CAS  PubMed  Google Scholar 

  • Bishop JL, Thaper D, Zoubeidi A (2014) The multifaceted roles of STAT3 signaling in the progression of prostate cancer. Cancers 6(2):829–859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burak K et al (2018) MicroRNA-16 targets mRNA involved in neurite extension and branching in hippocampal neurons during presymptomatic prion disease. Neurobiol Dis 112:1–13

    Article  CAS  PubMed  Google Scholar 

  • Burbach GJ et al (2004) Induction of brain-derived neurotrophic factor in plaque-associated glial cells of aged APP23 transgenic mice. J Neurosci 24(10):2421–2430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butler DE et al (2017) Inhibition of the PI3K/AKT/mTOR pathway activates autophagy and compensatory Ras/Raf/MEK/ERK signalling in prostate cancer. Oncotarget 8(34):56698

    Article  PubMed  PubMed Central  Google Scholar 

  • Cacialli P et al (2016) BDNF expression in larval and adult zebrafish brain: distribution and cell identification. PLoS ONE 11(6):e0158057

    Article  PubMed  PubMed Central  Google Scholar 

  • Cacialli P et al (2018) Morpho-functional features of the gonads of Danio rerio: the role of brain-derived neurotrophic factor. Anat Rec 301(1):140–147

    Article  CAS  Google Scholar 

  • Ceccanti M et al (2013) NGF and BDNF long-term variations in the thyroid, testis and adrenal glands of a mouse model of fetal alcohol spectrum disorders. Ann Ist Super Sanita 49:383–390

    CAS  PubMed  Google Scholar 

  • Chao MV, Bothwell M (2002) Neurotrophins: to cleave or not to cleave. Neuron 33(1):9–12

    Article  CAS  PubMed  Google Scholar 

  • Chen B et al (2016) Autocrine activity of BDNF induced by the STAT3 signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation. Sci Rep 6:30404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng F et al (2018) microRNA-107 inhibits gastric cancer cell proliferation and metastasis by targeting PI3K/AKT pathway. Microb Pathog 121:110–114

    Article  CAS  PubMed  Google Scholar 

  • Cheung Y et al (2012) Cognitive changes in multiethnic Asian breast cancer patients: a focus group study. Ann Oncol 23(10):2547–2552

    Article  CAS  PubMed  Google Scholar 

  • Cocco E, Scaltriti M, Drilon A (2018) NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 15(12):731–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Degirmenci U, Wang M, Hu J (2020) Targeting aberrant RAS/RAF/MEK/ERK signaling for cancer therapy. Cells 9(1):198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Derogatis LR et al (1983) The prevalence of psychiatric disorders among cancer patients. JAMA 249(6):751–757

    Article  CAS  PubMed  Google Scholar 

  • Desmet C, Peeper DS (2006) The neurotrophic receptor TrkB: a drug target in anti-cancer therapy? Cell Mol Life Sci CMLS 63(7–8):755–759

    Article  CAS  PubMed  Google Scholar 

  • DeWitt J et al (2014) Constitutively active TrkB confers an aggressive transformed phenotype to a neural crest-derived cell line. Oncogene 33(8):977–985

    Article  CAS  PubMed  Google Scholar 

  • Ding D et al (2018) miR-613 inhibits gastric cancer progression through repressing brain derived neurotrophic factor. Exp Ther Med 15(2):1735–1741

    CAS  PubMed  Google Scholar 

  • Doebele RC et al (2020) Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol 21(2):271–282

    Article  CAS  PubMed  Google Scholar 

  • Dong X et al (2020) Long intergenic non-protein coding RNA 1094 promotes initiation and progression of glioblastoma by promoting microRNA-577-regulated stabilization of brain-derived neurotrophic factor. Cancer Manag Res 12:5619–5631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drilon A et al (2018) Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. N Engl J Med 378(8):731–739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duprey-Díaz MV et al (2002) Changes in brain-derived neurotrophic factor and trkB receptor in the adult Rana pipiens retina and optic tectum after optic nerve injury. J CompNeurol 454(4):456–469

    Google Scholar 

  • Fang F et al (2012) Suicide and cardiovascular death after a cancer diagnosis. N Engl J Med 366:1310–1318

    Article  PubMed  Google Scholar 

  • Fei X et al (2020) Hsa-mir-10a-5p promotes pancreatic cancer growth by bdnf/sema4c pathway. J Biol Regul Homeost Agents 34(3):927–934

    CAS  PubMed  Google Scholar 

  • Gao B et al (2017) MicroRNA-107 is downregulated and having tumor suppressive effect in breast cancer by negatively regulating brain-derived neurotrophic factor. J Gene Med 19(12):e2932

    Article  Google Scholar 

  • Gao B et al (2017) MicroRNA-107 is downregulated and having tumor suppressive effect in breast cancer by negatively regulating brain-derived neurotrophic factor. J Gene Med. https://doi.org/10.1002/jgm.2932

    Article  PubMed  Google Scholar 

  • Groner B, von Manstein V (2017) Jak stat signaling and cancer: opportunities, benefits and side effects of targeted inhibition. Elsevier

    Google Scholar 

  • Hajicek N et al (2019) Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations. Elife 8:e51700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harada D, Takigawa N, Kiura K (2014) The role of STAT3 in non-small cell lung cancer. Cancers 6(2):708–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He Z et al (2019) RGS4 regulates proliferation and apoptosis of NSCLC cells via microRNA-16 and brain-derived neurotrophic factor. Onco Targets Ther 12:8701–8714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hing B, Sathyaputri L, Potash JB (2018) A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 177(2):143–167

    Article  CAS  PubMed  Google Scholar 

  • Horneber M et al (2012) Cancer-related fatigue: epidemiology, pathogenesis, diagnosis, and treatment. Dtsch Arztebl Int 109(9):161

    PubMed  PubMed Central  Google Scholar 

  • Howe EN et al (2012) miR-200c targets a NF-κB up-regulated TrkB/NTF3 autocrine signaling loop to enhance anoikis sensitivity in triple negative breast cancer. PLoS ONE. https://doi.org/10.1371/journal.pone.0049987

    Article  PubMed  PubMed Central  Google Scholar 

  • Hu XM et al (2016) Downregulation of miR-219 enhances brain-derived neurotrophic factor production in mouse dorsal root ganglia to mediate morphine analgesic tolerance by upregulating CaMKII gamma. Mol Pain. https://doi.org/10.1177/1744806916666283

    Article  PubMed  PubMed Central  Google Scholar 

  • Hu J et al (2016) NTRK2 is an oncogene and associated with microRNA-22 regulation in human gastric cancer cell lines. Tumor Biol 37(11):15115–15123

    Article  CAS  Google Scholar 

  • Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72(1):609–642

    Article  CAS  PubMed  Google Scholar 

  • Huang T-L, Lee C-T, Liu Y-L (2008) Serum brain-derived neurotrophic factor levels in patients with major depression: effects of antidepressants. J Psychiatr Res 42(7):521–525

    Article  PubMed  Google Scholar 

  • Imam JS et al (2012) Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization. PLoS ONE 7(12):e52397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jehn CF et al (2015) Neurocognitive function, brain-derived neurotrophic factor (BDNF) and IL-6 levels in cancer patients with depression. J Neuroimmunol 287:88–92

    Article  CAS  PubMed  Google Scholar 

  • Jin H et al (2007) p75 neurotrophin receptor inhibits invasion and metastasis of gastric cancer. Mol Cancer Res 5(5):423–433

    Article  CAS  PubMed  Google Scholar 

  • Jin S et al (2020) TGF-β1 fucosylation enhances the autophagy and mitophagy via PI3K/Akt and Ras-Raf-MEK-ERK in ovarian carcinoma. Biochem Biophys Res Commun. https://doi.org/10.1016/j.bbrc.2020.02.028

    Article  PubMed  PubMed Central  Google Scholar 

  • Johnston AL et al (2007) The p75 neurotrophin receptor is a central regulator of glioma invasion. PLoS Biol 5(8):e212

    Article  PubMed  PubMed Central  Google Scholar 

  • Kang HJ et al (2015) A longitudinal study of BDNF promoter methylation and depression in breast cancer. Psychiatry Investig 12(4):523–531

    Article  PubMed  PubMed Central  Google Scholar 

  • Karar J, Maity A (2011) PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 4:51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawamura K et al (2005) Ovarian brain-derived neurotrophic factor (BDNF) promotes the development of oocytes into preimplantation embryos. Proc Natl Acad Sci 102(26):9206–9211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kenneth SK, Laura MK, Carol AP (1999) Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 156(6):837–841

    Article  Google Scholar 

  • Khwaja F, Djakiew D (2003) Inhibition of cell-cycle effectors of proliferation in bladder tumor epithelial cells by the p75NTR tumor suppressor. Mol Carcinog Publ Coop Univ Texas MD Anderson Cancer Center 36(3):153–160

    CAS  Google Scholar 

  • Kim Y-K et al (2007) Low plasma BDNF is associated with suicidal behavior in major depression. Prog Neuropsychopharmacol Biol Psychiatry 31(1):78–85

    Article  CAS  PubMed  Google Scholar 

  • Kim JE et al (2014) STAT3 activation in glioblastoma: biochemical and therapeutic implications. Cancers 6(1):376–395

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim MS et al (2015a) Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer. Oncotarget 6(37):40158

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim J-M et al (2015b) BDNF promoter methylation associated with suicidal ideation in patients with breast cancer. Int J Psychiatry Med 49(1):75–94

    Article  PubMed  Google Scholar 

  • Kim MS, Lee WS, Jin W (2016) TrkB promotes breast cancer metastasis via suppression of Runx3 and Keap1 expression. Mol Cells 39(3):258

    Article  CAS  PubMed  Google Scholar 

  • Kimura S et al (2018) Expression of brain-derived neurotrophic factor and its receptor TrkB is associated with poor prognosis and a malignant phenotype in small cell lung cancer. Lung Cancer 120:98–107

    Article  PubMed  Google Scholar 

  • Kobayakawa M et al (2011) Serum brain-derived neurotrophic factor and antidepressant-naive major depression after lung cancer diagnosis. Jpn J Clin Oncol 41(10):1233–1237

    Article  PubMed  Google Scholar 

  • Kondo Y et al (2010) Expression and role of the BDNF receptor-TrkB in rat adrenal gland under acute immobilization stress. Acta Histochem Cytochem 43(6):139–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kopp F et al (2012) miR-200c sensitizes breast cancer cells to doxorubicin treatment by decreasing TrkB and Bmi1 expression. PLoS ONE 7(11):e50469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kowiański P et al (2018) BDNF: a key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol 38(3):579–593

    Article  PubMed  Google Scholar 

  • Kupferman ME et al (2009) Therapeutic suppression of constitutive and inducible JAK\STAT activation in head and neck squamous cell carcinoma. J Exp Therap Oncol 8(2):24

    Google Scholar 

  • Kupferman M et al (2010) TrkB induces EMT and has a key role in invasion of head and neck squamous cell carcinoma. Oncogene 29(14):2047–2059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lam C-T et al (2011) Brain-derived neurotrophic factor promotes tumorigenesis via induction of neovascularization: implication in hepatocellular carcinoma. Clin Cancer Res 17(10):3123–3133

    Article  CAS  PubMed  Google Scholar 

  • Lange AM, Lo H-W (2018) Inhibiting TRK proteins in clinical cancer therapy. Cancers 10(4):105

    Article  PubMed  PubMed Central  Google Scholar 

  • Li C, Zhou X (2013) The potential roles of neurotrophins in male reproduction. Reproduction 145(4):R89–R95

    Article  CAS  PubMed  Google Scholar 

  • Li C et al (2012) The expression and putative role of brain-derived neurotrophic factor and its receptor in bovine sperm. Theriogenology 77(3):636–643

    Article  CAS  PubMed  Google Scholar 

  • Li W et al (2018) Long noncoding RNA BDNF-AS is associated with clinical outcomes and has functional role in human prostate cancer. Biomed Pharmacother 102:1105–1110

    Article  CAS  PubMed  Google Scholar 

  • Li F, Wang X, Yang L (2020) MicroRNA-147 targets BDNF to inhibit cell proliferation, migration and invasion in non-small cell lung cancer. Oncol Lett 20(2):1931–1937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li T et al (2020) Activation of BDNF/TrkB pathway promotes prostate cancer progression via induction of epithelial-mesenchymal transition and anoikis resistance. FASEB J. https://doi.org/10.1096/fj.201802159RRR

    Article  PubMed  Google Scholar 

  • Lin C-Y et al (2014) Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells. Biochem Pharmacol 91(4):522–533

    Article  CAS  PubMed  Google Scholar 

  • Lin CY et al (2017) Brain-derived neurotrophic factor promotes VEGF-C-dependent lymphangiogenesis by suppressing miR-624-3p in human chondrosarcoma cells. Cell Death Dis 8(8):e2964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S et al (2019) miR-210 inhibits cell migration and invasion by targeting the brain-derived neurotrophic factor in glioblastoma. J Cell Biochem. https://doi.org/10.1002/jcb.28414

    Article  PubMed  PubMed Central  Google Scholar 

  • Lomen-Hoerth C, Shooter EM (1995) Widespread neurotrophin receptor expression in the immune system and other nonneuronal rat tissues. J Neurochem 64(4):1780–1789

    Article  CAS  PubMed  Google Scholar 

  • Long J et al (2016a) MicroRNA-15a-5p suppresses cancer proliferation and division in human hepatocellular carcinoma by targeting BDNF. Tumor Biol 37(5):5821–5828

    Article  CAS  Google Scholar 

  • Long J et al (2016b) MicroRNA-15a-5p suppresses cancer proliferation and division in human hepatocellular carcinoma by targeting BDNF. Tumour Biol 37(5):5821–5828

    Article  CAS  PubMed  Google Scholar 

  • Ma R et al (2019) miR-496 suppress tumorigenesis via targeting BDNF-mediated PI3K/Akt signaling pathway in non-small cell lung cancer. Biochem Biophys Res Commun 518(2):273–277

    Article  CAS  PubMed  Google Scholar 

  • Marchetti D et al (2004) p75 neurotrophin receptor functions as a survival receptor in brain-metastatic melanoma cells. J Cell Biochem 91(1):206–215

    Article  CAS  PubMed  Google Scholar 

  • Martinowich K et al (2003) DNA methylation-related chromatin remodeling in activity-dependent <em>Bdnf</em> gene regulation. Science 302(5646):890–893

    Article  CAS  PubMed  Google Scholar 

  • Massie MJ (2004) Prevalence of depression in patients with cancer. JNCI Monogr 2004(32):57–71

    Article  Google Scholar 

  • Meldolesi J (2017) Neurotrophin Trk receptors: new targets for cancer therapy. Reviews of physiology, biochemistry and pharmacology Vol. 174. Springer, pp 67–79

    Chapter  Google Scholar 

  • Meng L et al (2019) Targeting the BDNF/TrkB pathway for the treatment of tumors. Oncol Lett 17(2):2031–2039

    CAS  PubMed  Google Scholar 

  • Miknyoczki SJ et al (1999) Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior. Int J Cancer 81(3):417–427

    Article  CAS  PubMed  Google Scholar 

  • Mohammadi A, Amooeian VG, Rashidi E (2018) Dysfunction in brain-derived neurotrophic factor signaling pathway and susceptibility to schizophrenia, Parkinson’s and Alzheimer’s diseases. Curr Gene Ther 18(1):45–63

    Article  CAS  PubMed  Google Scholar 

  • Mojtabavi H et al (2020) Peripheral blood levels of brain-derived neurotrophic factor in patients with post-traumatic stress disorder (PTSD): a systematic review and meta-analysis. PLoS ONE 15(11):e0241928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moraes JKD et al (2019) Activation of BDNF/TrkB/Akt pathway is associated with aggressiveness and unfavorable survival in oral squamous cell carcinoma. Oral Dis 25(8):1925–1936

    Article  PubMed  Google Scholar 

  • Murer M et al (1999) An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult human brain, with particular reference to Alzheimer’s disease. Neuroscience 88(4):1015–1032

    Article  CAS  PubMed  Google Scholar 

  • Mutter D, Middendorff R, Davidoff MS (1999) Neurotrophic factors in the testis. Biomed Rev 10:25–30

    Article  Google Scholar 

  • Nakamura K et al (2006) Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1α in neuroblastoma cells. Can Res 66(8):4249–4255

    Article  CAS  Google Scholar 

  • Navé BT et al (1999) Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 344(2):427–431

    Article  PubMed  PubMed Central  Google Scholar 

  • Ng T et al (2017) Evaluation of plasma brain-derived neurotrophic factor levels and self-perceived cognitive impairment post-chemotherapy: a longitudinal study. BMC Cancer 17(1):867

    Article  PubMed  PubMed Central  Google Scholar 

  • Odate S et al (2013) TrkB/BDNF signaling pathway is a potential therapeutic target for pulmonary large cell neuroendocrine carcinoma. Lung Cancer 79(3):205–214

    Article  PubMed  Google Scholar 

  • Okugawa Y et al (2013) Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer. Br J Cancer 108(1):121–130

    Article  CAS  PubMed  Google Scholar 

  • Pacenta HL, Macy ME (2018) Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma. Drug Des Dev Ther 12:3549

    Article  CAS  Google Scholar 

  • Paredes A et al (2004) TrkB receptors are required for follicular growth and oocyte survival in the mammalian ovary. Dev Biol 267(2):430–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patani N, Jiang WG, Mokbel K (2011) Brain-derived neurotrophic factor expression predicts adverse pathological and clinical outcomes in human breast cancer. Cancer Cell Int 11(1):1–8

    Article  Google Scholar 

  • Pearse RN et al (2005) A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival. Blood 105(11):4429–4436

    Article  CAS  PubMed  Google Scholar 

  • Piepmeier AT, Etnier JL (2015) Brain-derived neurotrophic factor (BDNF) as a potential mechanism of the effects of acute exercise on cognitive performance. J Sport Health Sci 4(1):14–23

    Article  Google Scholar 

  • Pinheiro KV et al (2017) Targeting tyrosine receptor kinase B in gliomas. Neuro Oncol 19(1):138–139

    Article  CAS  PubMed  Google Scholar 

  • Quartu M et al (2010) Brain-derived neurotrophic factor (BDNF) and polysialylated-neural cell adhesion molecule (PSA-NCAM): codistribution in the human brainstem precerebellar nuclei from prenatal to adult age. Brain Res 1363:49–62

    Article  CAS  PubMed  Google Scholar 

  • Rahmani F et al (2019) Plasma levels of brain-derived neurotrophic factor in patients with Parkinson disease: a systematic review and meta-analysis. Brain Res 1704:127–136

    Article  CAS  PubMed  Google Scholar 

  • Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Phil Trans R Soc B: Biol Sci 361(1473):1545–1564

    Article  CAS  Google Scholar 

  • Ren J et al (2014a) MicroRNA-206 suppresses gastric cancer cell growth and metastasis. Cell Biosci 4(1):26

    Article  PubMed  PubMed Central  Google Scholar 

  • Ren J et al (2014b) MicroRNA-206 suppresses gastric cancer cell growth and metastasis. Cell Biosci 4:26

    Article  PubMed  PubMed Central  Google Scholar 

  • Ricci A et al (2001) Neurotrophins and neurotrophin receptors in human lung cancer. Am J Respir Cell Mol Biol 25(4):439–446

    Article  CAS  PubMed  Google Scholar 

  • Saghazadeh A, Rezaei N (2017) Brain-derived neurotrophic factor levels in autism: a systematic review and meta-analysis. J Autism Dev Disord 47(4):1018–1029

    Article  PubMed  Google Scholar 

  • Saligan L et al (2016) Lower brain-derived neurotrophic factor levels associated with worsening fatigue in prostate cancer patients during repeated stress from radiation therapy. World J Biol Psychiatry 17(8):608–614

    CAS  PubMed  Google Scholar 

  • Scott LJ (2019) Larotrectinib: first global approval. Drugs 79(2):201–206

    Article  CAS  PubMed  Google Scholar 

  • Shang W et al (2018) Long noncoding RNA BDNF-AS is a potential biomarker and regulates cancer development in human retinoblastoma. Biochem Biophys Res Commun 497(4):1142–1148

    Article  CAS  PubMed  Google Scholar 

  • Shimizu E et al (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiat 54(1):70–75

    Article  CAS  PubMed  Google Scholar 

  • Shulman DS, DuBois SG (2020) The evolving diagnostic and treatment landscape of NTRK-fusion-driven pediatric cancers. Pediat Drugs 22:1–9

    Article  Google Scholar 

  • Simon M et al (2017) Genome-wide effects of MELK-inhibitor in triple-negative breast cancer cells indicate context-dependent response with p53 as a key determinant. PLoS ONE 12(2):e0172832–e0172832

    Article  PubMed  PubMed Central  Google Scholar 

  • Siu MK, Wong OG, Cheung AN (2009) TrkB as a therapeutic target for ovarian cancer. Expert Opin Ther Targets 13(10):1169–1178

    Article  CAS  PubMed  Google Scholar 

  • Smeele P et al (2018) Brain-derived neurotrophic factor, a new soluble biomarker for malignant pleural mesothelioma involved in angiogenesis. Mol Cancer 17(1):148

    Article  PubMed  PubMed Central  Google Scholar 

  • Smith MA et al (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15(3):1768–1777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9(1):59–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song D et al (2017) MicroRNA-382 inhibits cell proliferation and invasion of retinoblastoma by targeting BDNF-mediated PI3K/AKT signalling pathway. Mol Med Rep 16(5):6428–6436

    Article  CAS  PubMed  Google Scholar 

  • Song Y et al (2019) MicroRNA-584 prohibits hepatocellular carcinoma cell proliferation and invasion by directly targeting BDNF. Mol Med Rep 20(2):1994–2001

    CAS  PubMed  Google Scholar 

  • Sosonkina N, Starenki D, Park J-I (2014) The role of STAT3 in thyroid cancer. Cancers 6(1):526–544

    Article  PubMed  PubMed Central  Google Scholar 

  • Staniszewska I et al (2008) Integrin α9β1 is a receptor for nerve growth factor and other neurotrophins. J Cell Sci 121(4):504–513

    Article  CAS  PubMed  Google Scholar 

  • Street J et al (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci 99(15):9656–9661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Z et al (2019) Long non-coding RNA LINC00152 promotes cell growth and invasion of papillary thyroid carcinoma by regulating the miR-497/BDNF axis. J Cell Physiol 234(2):1336–1345

    Article  CAS  PubMed  Google Scholar 

  • Szekeres MR et al (2010) Angiotensin II-induced expression of brain-derived neurotrophic factor in human and rat adrenocortical cells. Endocrinology 151(4):1695–1703

    Article  CAS  PubMed  Google Scholar 

  • Tajbakhsh A et al (2017) Therapeutic potentials of BDNF/TrkB in breast cancer; current status and perspectives. J Cell Biochem 118(9):2502–2515

    Article  CAS  PubMed  Google Scholar 

  • Tang YP, Wade J (2013) Developmental changes in BDNF protein in the song control nuclei of zebra finches. Neuroscience 250:578–587

    Article  CAS  PubMed  Google Scholar 

  • Tokumine J et al (2003) Changes in spinal GDNF, BDNF, and NT-3 expression after transient spinal cord ischemia in the rat. J Neurosci Res 74(4):552–561

    Article  CAS  PubMed  Google Scholar 

  • Trisciuoglio D et al (2005) Involvement of PI3K and MAPK signaling in bcl-2-induced vascular endothelial growth factor expression in melanoma cells. Mol Biol Cell 16(9):4153–4162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsai Y-F et al (2017) Brain-derived neurotrophic factor (BDNF)-TrKB signaling modulates cancer-endothelial cells interaction and affects the outcomes of triple negative breast cancer. PLoS ONE 12(6):e0178173

    Article  PubMed  PubMed Central  Google Scholar 

  • Usui T et al (2014) Brain-derived neurotrophic factor promotes angiogenic tube formation through generation of oxidative stress in human vascular endothelial cells. Acta Physiol 211(2):385–394

    Article  CAS  Google Scholar 

  • Vaidya VA et al (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci 17(8):2785–2795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vanhecke E et al (2011) Brain-derived neurotrophic factor and neurotrophin-4/5 are expressed in breast cancer and can be targeted to inhibit tumor cell survival. Clin Cancer Res 17(7):1741–1752

    Article  CAS  PubMed  Google Scholar 

  • Walker J et al (2008) Better off dead: suicidal thoughts in cancer patients. J Clin Oncol 26(29):4725–4730

    Article  PubMed  Google Scholar 

  • Walzl G et al (2018) Tuberculosis: advances and challenges in development of new diagnostics and biomarkers. Lancet Infect Dis 18(7):e199–e210

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Calle M, Roubos EW (2005) Brain-derived neurotrophic factor in the hypothalamo-hypophyseal system of Xenopus laevis. Ann N Y Acad Sci 1040(1):512–514

    Article  CAS  PubMed  Google Scholar 

  • Wang P et al (2017) MicroRNA-497 inhibits thyroid cancer tumor growth and invasion by suppressing BDNF. Oncotarget 8(2):2825

    Article  PubMed  Google Scholar 

  • Wang L, Liu Y, Song J (2018) MicroRNA-103 suppresses glioma cell proliferation and invasion by targeting the brain-derived neurotrophic factor. Mol Med Rep 17(3):4083–4089

    CAS  PubMed  Google Scholar 

  • Wang Y et al (2020) Epidemiology of mental health problems among patients with cancer during COVID-19 pandemic. Transl Psychiatry 10(1):263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei J et al (2020) CircHIPK3 promotes cell proliferation and migration of gastric cancer by sponging mir-107 and regulating bdnf expression. Onco Targets Ther 13:1613–1624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia H, Li Y, Lv X (2016a) MicroRNA-107 inhibits tumor growth and metastasis by targeting the BDNF-mediated PI3K/AKT pathway in human non-small lung cancer. Int J Oncol 49(4):1325–1333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu AJ et al (2017a) MicroRNA-744 inhibits tumor cell proliferation and invasion of gastric cancer via targeting brain-derived neurotrophic factor. Mol Med Rep 16(4):5055–5061

    Article  CAS  PubMed  Google Scholar 

  • Xu Y et al (2017b) MiR-101 inhibits ovarian carcinogenesis by repressing the expression of brain-derived neurotrophic factor. FEBS Open Bio 7(9):1258–1266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan H et al (2015) Up-regulation of miR-204 enhances anoikis sensitivity in epithelial ovarian cancer cell line via brain-derived neurotrophic factor pathway in vitro. Int J Gynecol Cancer 25(6):944–952

    Article  PubMed  Google Scholar 

  • Ye J et al (2020) MicroRNA-496 suppresses tumor cell proliferation by targeting BDNF in osteosarcoma. Exp Ther Med 19(2):1425–1431

    CAS  PubMed  Google Scholar 

  • Yuan Y, Ye HQ, Ren QC (2018) Proliferative role of BDNF/TrkB signaling is associated with anoikis resistance in cervical cancer. Oncol Rep 40(2):621–634

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yue X, Wang Z (2020) Long intergenic non-coding RNA LINC00922 aggravates the malignant phenotype of breast cancer by regulating the microRNA-424-5p/BDNF axis. Cancer Manag Res 12:7539–7552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhai L et al (2017) MicroRNA-10a-5p suppresses cancer proliferation and division in human cervical cancer by targeting BDNF. Exp Ther Med 14(6):6147–6151

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Z et al (2013) The release of glutamate from cortical neurons regulated by BDNF via the TrkB/Src/PLC-γ1 pathway. J Cell Biochem 114(1):144–151

    Article  CAS  PubMed  Google Scholar 

  • Zhang X et al (2018a) HOXA3 promotes tumor growth of human colon cancer through activating EGFR/Ras/Raf/MEK/ERK signaling pathway. J Cell Biochem 119(3):2864–2874

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Song N, Duan Z (2018b) Rs6265 polymorphism in brain-derived neurotrophic factor (Val/Val and Val/Met) promotes proliferation of bladder cancer cells by suppressing microRNA-205 and enhancing expression of cyclin J. J Cell Biochem. https://doi.org/10.1002/jcb.28004

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang HY et al (2019) Long noncoding RNA DLX6-AS1 promotes neuroblastoma progression by regulating miR-107/BDNF pathway. Cancer Cell Int. https://doi.org/10.1186/s12935-019-0968-x

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao H et al (2018) LncRNA BDNF-AS inhibits proliferation, migration, invasion and EMT in oesophageal cancer cells by targeting miR-214. J Cell Mol Med 22(8):3729–3739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng B, Chen T (2020) MiR-489-3p inhibits cell proliferation, migration, and invasion, and induces apoptosis, by targeting the BDNF-mediated PI3K/AKT pathway in glioblastoma. Open Life Sci 15(1):274–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng L et al (2011) Expression of brain-derived neurotrophic factor in mature spermatozoa from fertile and infertile men. Clin Chim Acta 412(1–2):44–47

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. Mohammad Malekan, Sasan Salehi Nezamabadi and Elham Samami have equally contributed to the project.

Authors and Affiliations

  1. Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Sari, Iran

    Mohammad Malekan

  2. Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Mohammad Malekan

  3. Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Sasan Salehi Nezamabadi, Elham Samami & Amene Saghazadeh

  4. School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Sasan Salehi Nezamabadi

  5. Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Elham Samami

  6. Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Urmia, Iran

    Mehdi Mohebalizadeh

  7. Student Research Center, Urmia University of Medical Sciences, Urmia, Iran

    Mehdi Mohebalizadeh

  8. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran

    Amene Saghazadeh & Nima Rezaei

  9. Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Nima Rezaei

  10. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei

Authors
  1. Mohammad Malekan
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  2. Sasan Salehi Nezamabadi
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  3. Elham Samami
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  4. Mehdi Mohebalizadeh
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  5. Amene Saghazadeh
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  6. Nima Rezaei
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Contributions

MM, SSN, ES, and MM conceptualized the study, contributed to the preparation of the initial draft of the manuscript, and designed the graphical abstract, figures, and tables. AS conceptualized the study, critically revised the manuscript, and administered the project. NR supervised the project. All authors have read and approved the submitted version.

Corresponding author

Correspondence to Nima Rezaei.

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Malekan, M., Nezamabadi, S.S., Samami, E. et al. BDNF and its signaling in cancer. J Cancer Res Clin Oncol 149, 2621–2636 (2023). https://doi.org/10.1007/s00432-022-04365-8

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