BDNF and Its Signaling in Cancer

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2022 Sep 29

PMID 36173463

Authors

Mohammad Malekan

Sasan Salehi Nezamabadi

Elham Samami

Mehdi Mohebalizadeh

Amene Saghazadeh

Nima Rezaei

Affiliations

Soon will be listed here.

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.

Citing Articles

BDNF is a prognostic biomarker involved in the immune infiltration of lung adenocarcinoma and associated with programmed cell death.

Xia J, Zhuo W, Deng L, Yin S, Tang S, Yi L Oncol Lett. 2025; 29(4):191.

PMID: 40041412 PMC: 11877015. DOI: 10.3892/ol.2025.14937.

Decoding the Role of Neurotrophins in Glycogen Synthase Kinase 3-Beta Regulation in Alzheimer's Disease.

Rahmatkar S, Singh D Mol Neurobiol. 2025; .

PMID: 40014269 DOI: 10.1007/s12035-025-04776-x.

Impact and Mechanisms of Action of BDNF on Neurological Disorders, Cancer, and Cardiovascular Diseases.

Lei M, Liu Q, Nie J, Huang R, Mei Y, Pan D CNS Neurosci Ther. 2024; 30(12):e70138.

PMID: 39648800 PMC: 11626086. DOI: 10.1111/cns.70138.

Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor-Associated Macrophage.

Sun X, Zhang J, Dong B, Xiong Q, Wang X, Gu Y Adv Sci (Weinh). 2024; 12(1):e2400367.

PMID: 39499724 PMC: 11714161. DOI: 10.1002/advs.202400367.

Effects of short- and long-term exercise training on cancer cells in vitro: Insights into the mechanistic associations.

Bettariga F, Taaffe D, Galvao D, Newton R J Sport Health Sci. 2024; 14:100994.

PMID: 39370102 PMC: 11863286. DOI: 10.1016/j.jshs.2024.100994.

References

Aili A, Chen Y, Zhang H . MicroRNA‑10b suppresses the migration and invasion of chondrosarcoma cells by targeting brain‑derived neurotrophic factor. Mol Med Rep. 2015; 13(1):441-6. DOI: 10.3892/mmr.2015.4506. View

Aloe L, Alleva E, Bohm A, Levi-Montalcini R . Aggressive behavior induces release of nerve growth factor from mouse salivary gland into the bloodstream. Proc Natl Acad Sci U S A. 1986; 83(16):6184-7. PMC: 386464. DOI: 10.1073/pnas.83.16.6184. View

Aoki M, Blazek E, Vogt P . A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc Natl Acad Sci U S A. 2001; 98(1):136-41. PMC: 14557. DOI: 10.1073/pnas.98.1.136. View

Au C, Siu M, Liao X, Wong E, Ngan H, Tam K . Tyrosine kinase B receptor and BDNF expression in ovarian cancers - Effect on cell migration, angiogenesis and clinical outcome. Cancer Lett. 2009; 281(2):151-61. DOI: 10.1016/j.canlet.2009.02.025. View

Autry A, Monteggia L . Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev. 2012; 64(2):238-58. PMC: 3310485. DOI: 10.1124/pr.111.005108. View

Bailey J, Jaworski C, Tung D, Wangler C, Wangler B, Schirrmacher R . Tropomyosin receptor kinase inhibitors: an updated patent review for 2016-2019. Expert Opin Ther Pat. 2020; 30(5):325-339. DOI: 10.1080/13543776.2020.1737011. View

Banerjee K, Resat H . Constitutive activation of STAT3 in breast cancer cells: A review. Int J Cancer. 2015; 138(11):2570-8. PMC: 4801660. DOI: 10.1002/ijc.29923. View

Bao W, Wang H, Tian F, He X, Qiu M, Wang J . A TrkB-STAT3-miR-204-5p regulatory circuitry controls proliferation and invasion of endometrial carcinoma cells. Mol Cancer. 2013; 12:155. PMC: 3879200. DOI: 10.1186/1476-4598-12-155. View

Bao Y, Hou W, Liu R, Gao Y, Kong X, Yang L . PAR2-mediated upregulation of BDNF contributes to central sensitization in bone cancer pain. Mol Pain. 2014; 10:28. PMC: 4027994. DOI: 10.1186/1744-8069-10-28. View

10.

Barde Y, Edgar D, Thoenen H . Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1982; 1(5):549-53. PMC: 553086. DOI: 10.1002/j.1460-2075.1982.tb01207.x. View

11.

Berridge M, Irvine R . Inositol phosphates and cell signalling. Nature. 1989; 341(6239):197-205. DOI: 10.1038/341197a0. View

12.

Binder D, Scharfman H . Brain-derived neurotrophic factor. Growth Factors. 2004; 22(3):123-31. PMC: 2504526. DOI: 10.1080/08977190410001723308. View

13.

Bishop J, Thaper D, Zoubeidi A . The Multifaceted Roles of STAT3 Signaling in the Progression of Prostate Cancer. Cancers (Basel). 2014; 6(2):829-59. PMC: 4074806. DOI: 10.3390/cancers6020829. View

14.

Burak K, Lamoureux L, Boese A, Majer A, Saba R, Niu Y . MicroRNA-16 targets mRNA involved in neurite extension and branching in hippocampal neurons during presymptomatic prion disease. Neurobiol Dis. 2017; 112:1-13. DOI: 10.1016/j.nbd.2017.12.011. View

15.

Burbach G, Hellweg R, Haas C, Del Turco D, Deicke U, Abramowski D . Induction of brain-derived neurotrophic factor in plaque-associated glial cells of aged APP23 transgenic mice. J Neurosci. 2004; 24(10):2421-30. PMC: 6729483. DOI: 10.1523/JNEUROSCI.5599-03.2004. View

16.

Butler D, Marlein C, Walker H, Frame F, Mann V, Simms M . Inhibition of the PI3K/AKT/mTOR pathway activates autophagy and compensatory Ras/Raf/MEK/ERK signalling in prostate cancer. Oncotarget. 2017; 8(34):56698-56713. PMC: 5593594. DOI: 10.18632/oncotarget.18082. View

17.

Cacialli P, Gueguen M, Coumailleau P, DAngelo L, Kah O, Lucini C . BDNF Expression in Larval and Adult Zebrafish Brain: Distribution and Cell Identification. PLoS One. 2016; 11(6):e0158057. PMC: 4918975. DOI: 10.1371/journal.pone.0158057. View

18.

Ceccanti M, De Nicolo S, Mancinelli R, Chaldakov G, Carito V, Ceccanti M . 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. 2013; 49(4):383-90. DOI: 10.4415/ANN_13_04_11. View

19.

Chao M, Bothwell M . Neurotrophins: to cleave or not to cleave. Neuron. 2002; 33(1):9-12. DOI: 10.1016/s0896-6273(01)00573-6. View

20.

Chen B, Liang Y, He Z, An Y, Zhao W, Wu J . 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. 2016; 6:30404. PMC: 4960652. DOI: 10.1038/srep30404. View