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Investigating the role of TGF-β and BDNF in cancer-related depression: a primary cross-sectional study

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Abstract

Background

Cancer-related depression is a well-documented condition that significantly impacts long-term quality of life. Brain-derived neurotrophic factor (BDNF), a neurotrophin essential for neurogenesis and neuronal plasticity, has been implicated in various neuropsychological disorders including depression associated with cancer. Cytokines, on the other hand, play a crucial role in regulating depression, potentially by influencing BDNF expression. Transforming growth factor-β (TGF-β), a key immune regulator within the tumor microenvironment, has been found to elevate BDNF levels, establishing a link between peripheral immune responses and depression. The study aims to investigate the correlation of TGF-β and BDNF in cancer-related depression.

Methods

This study involved a cohort of 153 gynecological patients, including 61 patients with gynecological cancer and 92 patients without cancer. Depression levels were assessed using the subscale of Hospital Anxiety and Depression Scale (HADS-D), and TGF-β and BDNF plasma levels were measured using enzyme-linked immunosorbent assay (ELISA).

Results

The study revealed elevated plasma TGF-β levels in patients with cancer (32.24 ± 22.93 ng/ml) compared to those without cancer (25.24 ± 19.72 ng/ml) (P = 0.046). Additionally, reduced levels of BDNF were observed in patients presenting depression symptoms (44.96 ± 41.06 pg/ml) compared to those without depression (133.5 ± 176.7 pg/ml) (P = 0.036). Importantly, a significant correlation between TGF-β and BDNF was found in patients without cancer but with depression (correlation coefficient = 0.893, **P < 0.01). Interestingly, cancer appeared to influence the association between TGF-β and BDNF in patients with depression, as evidenced by a significant difference in the correlation of TGF-β and BDNF between cancer and non-cancer groups (P = 0.041).

Conclusions

These findings underscore the active involvement of TGF-β and BDNF crosstalk in the context of cancer-related depression.

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Data availability

The data that support the findings of this study are available from the Southern Medical University but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.

Abbreviations

BDNF:

Brain-derived neurotrophic factor

TGF-β:

Transforming growth factor-β

HADS:

Hospital Anxiety and Depression Scale

HADS-D:

Subscale of Hospital Anxiety and Depression Scale

ELISA:

Enzyme-linked immunosorbent assay

References 

  1. Honda K, Goodwin RD (2004) Cancer and mental disorders in a national community sample: findings from the National Comorbidity Survey. Psychother Psychosom 73(4):235–242

    Article  PubMed  Google Scholar 

  2. Harter M, Baumeister H, Reuter K, Jacobi F, Hofler M, Bengel J, Wittchen HU (2007) increased 12-month prevalence rates of mental disorders in patients with chronic somatic diseases. Psychother Psychosom 76(6):354–360

    Article  PubMed  Google Scholar 

  3. Dalton SO, Laursen TM, Ross L, Mortensen PB, Johansen C (2009) Risk for hospitalization with depression after a cancer diagnosis: a nationwide, population-based study of cancer patients in Denmark from 1973 to 2003. J Clin Oncol 27(9):1440–1445

    Article  PubMed  Google Scholar 

  4. Wang JL, Reimer MA, Metz LM, Patten SB (2000) Major depression and quality of life in individuals with multiple sclerosis. Int J Psychiat Med 30(4):309–317

    Article  CAS  Google Scholar 

  5. Eaton WW (2002) Epidemiologic evidence on the comorbidity of depression and diabetes. J Psychosom Res 53(4):903–906

    Article  PubMed  Google Scholar 

  6. Gagnon LM, Patten SB (2002) Major depression and its association with long-term medical conditions. Can J Psychiat 47(2):149–152

    Article  Google Scholar 

  7. Smith EM, Gomm SA, Dickens CM (2003) Assessing the independent contribution to quality of life from anxiety and depression in patients with advanced cancer. Palliative Med 17(6):509–513

    Article  CAS  Google Scholar 

  8. Mitchell AJ, Chan M, Bhatti H, Halton M, Grassi L, Johansen C, Meader N (2011) Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview-based studies. Lancet Oncol 12(2):160–174

    Article  PubMed  Google Scholar 

  9. Gabryelska A, Turkiewicz S, Ditmer M, Karuga FF, Strzelecki D, Bialasiewicz P (2022) Sochal M: BDNF and proBDNF serum protein levels in obstructive sleep apnea patients and their involvement in insomnia and depression symptoms. J Clin Med 11(23):7135

  10. Jehn CF, Becker B, Flath B, Nogai H, Vuong L, Schmid P, Lüftner D (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 

  11. Marshe V, Maciukiewicz M, Tiwari AK, Freeman N, Kennedy JL, Rotzinger S, Kennedy S, Muller D (2017) Investigating associations between Il-1beta, Il-2, Il-6, Tspo and Bdnf variants and response to duloxetine or placebo treatment in patients with major depression. Eur Neuropsychopharm 27:S187–S188

    Google Scholar 

  12. Hennings JM, Kohli MA, Uhr M, Holsboer F, Ising M, Lucae S (2019) Polymorphisms in the BDNF and BDNFOS genes are associated with hypothalamus-pituitary axis regulation in major depression. Prog Neuro-Psychoph 95:109686

  13. Ochi T, Vyalova NM, Losenkov IS, Levchuk LA, Loonen AJM, Bosker FJ, Simutkin GG, Bokhan NA, Wilffert B, Ivanova SA (2019) Investigating the potential role of BDNF and PRL genotypes on antidepressant response in depression patients: a prospective inception cohort study. Pharmacoepidem Dr S 28:132–132

    Google Scholar 

  14. Meshkat S, Alnefeesi Y, Jawad MY, Di Vincenzo JD, Rodrigues NB, Ceban F, Lui LMW, McIntyre RS, Rosenblat JD (2022) Brain-derived neurotrophic factor (BDNF) as a biomarker of treatment response in patients with treatment resistant depression (TRD): a systematic review & meta-analysis. Psychiat Res 317:114857

  15. Stielow C, Heinen D, Heinzel S, Schwefel M, Teran C, Kallies G, Fydrich T, Rapp M, Heissel A, Strohle A (2022) BDNF at rest and after acute aerobic exercise in women with depression. Med Sci Sport Exer 54(9):89–89

    Article  Google Scholar 

  16. Wang Y, Bai LP, Liu W, Zhu XD, Zhang XY (2022) Altered BDNF levels are associated with cognitive impairment in Parkinson?s disease patients with depression. Parkinsonism Relat D 103:122–128

    Article  CAS  Google Scholar 

  17. Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S 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 

  18. Sen S, Duman R, Sanacora G (2008) Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiat 64(6):527–532

    Article  CAS  PubMed  Google Scholar 

  19. Holubec L, Fiala O, Matejka VM, Podlipny J, Dreslerova J, Vrzalova J, Topolcan O, Finek J, Svoboda T (2012) The difference in the serum levels of Bdnf, Il-6, Il-8, Il-10 and Egf in oncology patients divided according to the presence of symptoms of depression. Ann Oncol 23:474–474

    Article  Google Scholar 

  20. Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, Knudsen GM, Aznar S (2011) Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychoph 14(3):347–353

    Article  CAS  Google Scholar 

  21. Dandekar MP, Saxena A, Scaini G, Shin JH, Migut A, Giridharan VV, Zhou YZ, Barichello T, Soares JC, Quevedo J et al (2019) Medial forebrain bundle deep brain stimulation reverses anhedonic-like behavior in a chronic model of depression: importance of BDNF and inflammatory cytokines. Mol Neurobiol 56(6):4364–4380

    Article  CAS  PubMed  Google Scholar 

  22. Liu BP, Zhang C, Zhang YP, Li KW, Song C (2022) The combination of chronic stress and smoke exacerbated depression-like changes and lung cancer factor expression in A/J mice: involve inflammation and BDNF dysfunction. Plos One 17(11):e0277945

  23. Arosio B, Guerini FR, Voshaar RCO, Aprahamian I (2021) Blood brain-derived neurotrophic factor (BDNF) and major depression: do we have a translational perspective? Front Behav Neurosci 15:626906

  24. Mosiolek A, Mosiolek J, Jakima S, Pieta A, Szulc A (2021) Effects of antidepressant treatment on neurotrophic factors (BDNF and IGF-1) in patients with major depressive disorder (MDD). J Clin Med 10(15):3377

  25. Felger JC, Lotrich FE (2013) Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229

    Article  CAS  PubMed  Google Scholar 

  26. Ayoub S, Berberi A, Fayyad-Kazan M (2020) Cytokines, masticatory muscle inflammation, and pain: an update. J Mol Neurosci 70(5):790–795

    Article  CAS  PubMed  Google Scholar 

  27. Muller HHO, Czwalinna K, Wang RH, Lucke C, Lam AP, Philipsen A, Gschossmann JM, Moeller S (2021) Occurence of post-traumatic stress symptoms, anxiety and depression in the acute phase of transient ischemic attack and stroke. Psychiat Quart 92(3):905–915

    Article  PubMed  Google Scholar 

  28. Himmerich H, Fulda S, Linseisen J, Seiler H, Wolfram G, Himmerich S, Gedrich K, Kloiber S, Lucae S, Ising M et al (2008) Depression, comorbidities and the TNF-alpha system. Eur Psychiat 23(6):421–429

    Article  CAS  Google Scholar 

  29. Enzerink A, Vaheri A (2011) Fibroblast activation in vascular inflammation. J Thromb Haemost 9(4):619–626

    Article  CAS  PubMed  Google Scholar 

  30. Barbierato M, Facci L, Argentini C, Marinelli C, Skaper SD, Giusti P (2013) Astrocyte-microglia cooperation in the expression of a pro-inflammatory phenotype. Cns Neurol Disord-Dr 12(5):608–618

    Article  CAS  Google Scholar 

  31. Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25(2):181–213

    Article  CAS  PubMed  Google Scholar 

  32. Himmerich H, Patsalos O, Lichtblau N, Ibrahim MAA, Dalton B (2019) Cytokine research in depression: principles, challenges, and open questions. Front Psychiatry 10:30

  33. Miller AH, Maletic V, Raison CL (2009) Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiat 65(9):732–741

    Article  CAS  PubMed  Google Scholar 

  34. Haroon E, Raison CL, Miller AH (2012) Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacol 37(1):137–162

    Article  CAS  Google Scholar 

  35. Schmidt FM, Lichtblau N, Minkwitz J, Chittka T, Thormann J, Kirkby KC, Sander C, Mergl R, Fasshauer M, Stumvoll M et al (2014) Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity. J Psychiatr Res 55:29–34

    Article  PubMed  Google Scholar 

  36. Huang W, Gan W, Huang A, Fu YL, Shang YZ, Chen Y, Tian Z, Zhang Y, Fang G (2019) Efficacy of electroacupuncture combined with probiotics for depression and chronic diarrhea in patients and effect on serum inflammatory cytokines. NE and BDNF Exp Ther Med 18(5):3470–3474

    CAS  PubMed  Google Scholar 

  37. Yap NY, Toh YL, Tan CJ, Acharya MM, Chan A (2021) Relationship between cytokines and brain-derived neurotrophic factor (BDNF) in trajectories of cancer-related cognitive impairment. Cytokine 144:155556

  38. Li HY, Shi XH, Yang F, Zhang XR, Li F (2022) Blood inflammatory cytokines as predictors of depression in patients with glioma. Front Psychiatry 13:930985

  39. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, Gabrilovich DI, Ostrand-Rosenberg S, Hedrick CC et al (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24(5):541–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kartikasari AER, Huertas CS, Mitchell A, Plebanski M (2021) Tumor-induced inflammatory cytokines and the emerging diagnostic devices for cancer detection and prognosis. Front Oncol 11:692142

  41. David CJ, Massague J (2018) Contextual determinants of TGF beta action in development, immunity and cancer. Nat Rev Mol Cell Bio 19(7):419–435

    Article  CAS  Google Scholar 

  42. Kumari A, Shonibare Z, Monavarian M, Arend RC, Lee NY, Inman GJ, Mythreye K (2021) TGF beta signaling networks in ovarian cancer progression and plasticity. Clin Exp Metastas 38(2):139–161

    Article  Google Scholar 

  43. Luo FY, Huang Y, Li YL, Zhao XL, Xie Y, Zhang QW, Mei J, Liu XH (2021) A narrative review of the relationship between TGF-β signaling and gynecological malignant tumor. Ann Transl Med 9(20):1601

  44. Dobolyi A, Vincze C, Pál G, Lovas G (2012) The neuroprotective functions of transforming growth factor beta proteins. Int J Mol Sci 13(7):8219–8258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kim YK, Lee SW, Kim SH, Shim SH, Han SW, Choi SH, Lee BH (2008) Differences in cytokines between non-suicidal patients and suicidal patients in major depression. Prog Neuro-Psychoph 32(2):356–361

    Article  CAS  Google Scholar 

  46. Musil R, Schwarz MJ, Riedel M, Dehning S, Cerovecki A, Spellmann I, Arolt V, Muller N (2011) Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression - no influence of celecoxib treatment. J Affect Disorders 134(1–3):217–225

    Article  CAS  PubMed  Google Scholar 

  47. Caraci F, Spampinato SF, Morgese MG, Tascedda F, Salluzzo MG, Giambirtone MC, Caruso G, Munafò A, Torrisi SA, Leggio GM et al (2018) Neurobiological links between depression and AD: the role of TGF-β1 signaling as a new pharmacological target. Pharmacol Res 130:374–384

    Article  CAS  PubMed  Google Scholar 

  48. Sometani A, Kataoka H, Nitta AI, Fukumitsu H, Nomoto H, Furukawa S (2001) Transforming growth factor-beta 1 enhances expression of brain-derived neurotrophic factor and its receptor, TrkB, in neurons cultured from rat cerebral cortex. J Neurosci Res 66(3):369–376

    Article  CAS  PubMed  Google Scholar 

  49. Zigmond AS, Snaith RP (1983) The Hospital Anxiety and Depression Scale. Acta Psychiat Scand 67(6):361–370

    Article  CAS  PubMed  Google Scholar 

  50. Yang Y, Ding RJ, Hu D, Zhang F, Sheng L (2014) Reliability and validity of a Chinese version of the HADS for screening depression and anxiety in psycho-cardiological outpatients. Compr Psychiat 55(1):215–220

    Article  PubMed  Google Scholar 

  51. Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiat 54(7):597–606

    Article  CAS  PubMed  Google Scholar 

  52. Murawska-Cialowicz E, Wiatr M, Cialowicz M, de Assis GG, Borowicz W, Rocha-Rodrigues S, Paprocka-Borowicz M, Marques A (2021) BDNF impact on biological markers of depression-role of physical exercise and training. Int J Env Res Pub He 18(14):7553

  53. Park H, Poo MM (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14(1):7–23

    Article  CAS  PubMed  Google Scholar 

  54. Shen J, Yang L, Wei WS (2022) Dl-3-n-butylphthalide prevents chronic restraint stress-induced depression-like behaviors and cognitive impairment via regulating CaMKII/CREB/BDNF signaling pathway in hippocampus. NeuroReport 33(14):597–603

    Article  CAS  PubMed  Google Scholar 

  55. Wang Z, Wang S, Liu Y, Gao S, Yu YQ, Hu ZL (2021) Serum levels of BDNF in patients with adenoma and colorectal cancer. Dis Markers 2021:8867368

  56. Brierley GV, Priebe IK, Purins L, Fung KYC, Tabor B, Lockett T, Nice E, Gibbs P, Tie J, McMurrick P et al (2013) Serum concentrations of brain-derived neurotrophic factor (BDNF) are decreased in colorectal cancer patients. Cancer Biomark 13(2):67–73

    Article  CAS  PubMed  Google Scholar 

  57. Guzel T, Mech K, Iwanowska M, Wronski M, Slodkowski M (2021) Brain derived neurotrophic factor declines after complete curative resection in gastrointestinal cancer. Peerj 9:e11718

  58. Massague J (2008) TGF beta in cancer. Cell 134(2):215–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Khanehsar MA, Hoseinbeyki M, Taha MF, Javeri A (2020) Repression of TGF-beta signaling in breast cancer cells by miR-302/367 cluster. Cell J 21(4):444–450

    Google Scholar 

  60. Colak S, ten Dijke P (2017) Targeting TGF-β signaling in cancer. Trends Cancer 3(1):56–71

    Article  CAS  PubMed  Google Scholar 

  61. Sulaiman A, Chambers J, Chilumula SC, Vinod V, Kandunuri R, McGarry S, Kim S (2022) At the intersection of cardiology and oncology: TGFβ as a clinically translatable therapy for TNBC treatment and as a major regulator of post-chemotherapy cardiomyopathy. Cancers 14(6):1577

  62. Yi M, Li TY, Niu MK, Wu YZ, Zhao ZY, Wu KM (2022) TGF-β: a novel predictor and target for anti-PD-1/PD-L1 therapy. Front Immunol 13:1061394

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Acknowledgements

The authors would like to express their gratitude to the participants for their willingness to complete the questionnaires, which made this study possible.

Funding

The study was supported by the National Natural Science Foundation of China (grant number: 72004088).

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Author notes

  1. Lili Zhang and Yawei Liu contributed equally to this work.

Authors and Affiliations

  1. School of Nursing, Southern Medical University, Guangzhou, China

    Jingjing Lin, Lin Xiao, Yuanyuan Luo, Lili Zhang & Yawei Liu

  2. Health College, Zhejiang Industry Polytechnic College, Shaoxing, China

    Jingjing Lin

  3. Department of Biology, University of Copenhagen, Copenhagen, Denmark

    Xinchen Nie

  4. Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Zhijian Wang

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  1. Jingjing Lin
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Contributions

JJL: performing experiments, data collection, and data analysis, and contributing to writing. LX: methodology, supervision, funding acquisition. XCN: methodology, data analysis, and contributing to writing. ZJW: data collection. YYL: data collection. LLZ: conceptualization, supervision, funding acquisition. YWL: conceptualization, writing the manuscript, supervision, funding acquisition. All authors agree to be accountable for the content of the work.

Corresponding authors

Correspondence to Lili Zhang or Yawei Liu.

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Ethics approval and consent to participate

The study was approved by the Medical Ethics Committee of X Hospital of Southern Medical University (NFEC-2020–281). All methods were carried out in accordance with relevant guidelines and regulations. All patients had been provided informed consent before participating this study.

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The authors declare no competing interests.

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Lin, J., Xiao, L., Nie, X. et al. Investigating the role of TGF-β and BDNF in cancer-related depression: a primary cross-sectional study. Support Care Cancer 32, 365 (2024). https://doi.org/10.1007/s00520-024-08542-y

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