Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Cellular and Molecular Biology

RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma

British Journal of Cancer volume 127, pages 408–421 (2022)Cite this article

Subjects

Abstract

Background

Testicular germ cell tumours (TGCTs) have a high sensitivity to chemotherapy and a high cure rate, although with serious adverse effects. In the search for tumour suppressive drugs, the RANKL inhibitor Denosumab, used to treat osteoporosis, came up as a candidate since RANKL signalling was recently identified in the testis.

Methods

Expression of RANKL, RANK and OPG, and the effects of RANKL inhibition were investigated in human TGCTs, TGCT-derived cell-lines, and TGCT-xenograft models. Serum RANKL was measured in TGCT-patients.

Results

RANKL, RANK, and OPG were expressed in germ cell neoplasia in situ (GCNIS), TGCTs, and TGCT-derived cell lines. RANKL-inhibition reduced proliferation of seminoma-derived TCam-2 cells, but had no effect on embryonal carcinoma-derived NTera2 cells. Pretreatment with Denosumab did not augment the effect of cisplatin in vitro. However, inhibition of RANKL in vivo reduced tumour growth exclusively in the TCam-2-xenograft model and Denosumab-treatment decreased proliferation in human GCNIS cultures. In TGCT-patients serum RANKL had no prognostic value.

Conclusions

This study shows that the RANKL signalling system is expressed in GCNIS and seminoma where RANKL inhibition suppresses tumour growth in vitro and in vivo. Future studies are needed to determine whether RANKL is important for the malignant transformation or transition from GCNIS to invasive tumours.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pathogenesis and classification of testicular germ cell tumours.
Fig. 2: Gene and protein expression of RANKL, RANK, and OPG in GCNIS and TGCTs.
Fig. 3: Expression of RANKL, RANK, and OPG in TGCT cell lines and the effect of RANKL inhibition in vitro.
Fig. 4: Effects of RANKL inhibition on TGCT cell lines in vivo.
Fig. 5: Effects of pretreatment with Denosumab on cisplatin sensitivity or resistance in TGCT cell lines.
Fig. 6: Effects of RANKL-inhibition on GCNIS cells cultured ex vivo.

Similar content being viewed by others

References

  1. Gurney JK, Florio AA, Znaor A, Ferlay J, Laversanne M, Sarfati D, et al. International Trends in the Incidence of Testicular Cancer: lessons from 35 years and 41 countries. Eur Urol. 2019;76:615–23. https://doi.org/10.1016/j.eururo.2019.07.002.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Feldman DR, Bosl GJ, Sheinfeld J, Motzer RJ. Medical treatment of advanced testicular cancer. JAMA. 2008;299:672–84.

  3. Pliarchopoulou K, Pectasides D. Late complications of chemotherapy in testicular cancer. Cancer Treat Rev. 2010;36:262–7.

  4. Bandak M, Jørgensen N, Juul A, Lauritsen J, Oturai PS, Mortensen J, et al. Leydig cell dysfunction, systemic inflammation and metabolic syndrome in long-term testicular cancer survivors. Eur J Cancer. 2017;84:9–17.

  5. Skakkebaek NE. Possible carcinoma-in-situ of the testis. Lancet. 1972;2:516–7.

  6. Skakkebaek NE, Berthelsen JG, Giwercman A, Müller J. Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int J Androl. 1987;10:19–28.

  7. Rajpert-De Meyts E. Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects. Hum Reprod Update. 2006;12:303–23.

    Article  CAS  PubMed  Google Scholar 

  8. Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. Eur Urol. 2016;70:93–105.

  9. Hoei-Hansen CE, Almstrup K, Nielsen JE, Brask Sonne S, Graem N, Skakkebaek NE, et al. Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours. Histopathology. 2005;47:48–56.

    Article  CAS  PubMed  Google Scholar 

  10. Rajpert-De Meyts E, Hanstein R, Jørgensen N, Græm N, Vogt PH, Skakkebæk NE. Developmental expression of POU5F1 (OCT-3/4) in normal and dysgenetic human gonads. Hum Reprod. 2004;19:1338–44.

    Article  CAS  PubMed  Google Scholar 

  11. Sonne SB, Almstrup K, Dalgaard M, Juncker AS, Edsgard D, Ruban L, et al. Analysis of gene expression profiles of microdissected cell populations indicates that testicular carcinoma in situ is an arrested gonocyte. Cancer Res. 2009;69:5241–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rajpert-De Meyts E, McGlynn KA, Okamoto K, Jewett MAS, Bokemeyer C. Testicular germ cell tumours. Lancet. 2016;387:1762–74.

  13. Blomberg Jensen M, Jørgensen A, Nielsen JE, Steinmeyer A, Leffers H, Juul A, et al. Vitamin D metabolism and effects on pluripotency genes and cell differentiation in testicular germ cell tumors in vitro and in vivo. Neoplasia. 2012;14:952–63.

  14. Jacobsen C, Honecker F. Cisplatin resistance in germ cell tumours: models and mechanisms. Andrology. 2015;3:111–21.

    Article  CAS  PubMed  Google Scholar 

  15. Jørgensen A, Blomberg Jensen M, Nielsen JE, Juul A, Rajpert-De Meyts E. Influence of vitamin D on cisplatin sensitivity in testicular germ cell cancer-derived cell lines and in a NTera2 xenograft model. J Steroid Biochem Mol Biol. 2013;136:238–46. https://doi.org/10.1016/j.jsbmb.2012.10.008.

    Article  CAS  PubMed  Google Scholar 

  16. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29:155–92.

  17. Simonet W, Lacey D, Dunstan C, Kelley M, Chang M-S, Lüthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309–19.

    Article  CAS  PubMed  Google Scholar 

  18. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001;142:5050–5.

  19. Cummings SR, Martin JS, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756–65. https://doi.org/10.1056/NEJMoa0809493.

  20. Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017;5:513–23.

    Article  CAS  PubMed  Google Scholar 

  21. Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body J-J, et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol. 2007;25:4431–7. https://doi.org/10.1200/JCO.2007.11.8604.

  22. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone metastasis-free survival in men with castration-resistant prostate cancer: results of a global phase 3, randomised, placebo-controlled trial. Lancet. 2012;379:39–46.

    Article  CAS  PubMed  Google Scholar 

  23. Chamoux E, Houde N, L’Eriger K, Roux S. Osteoprotegerin decreases human osteoclast apoptosis by inhibiting the TRAIL pathway. J Cell Physiol. 2008;216:536–42.

    Article  CAS  PubMed  Google Scholar 

  24. McKee CM, Ye Y, Richburg JH. Testicular germ cell sensitivity to TRAIL-induced apoptosis is dependent upon p53 expression and is synergistically enhanced by DR5 agonistic antibody treatment. Apoptosis. 2006;11:2237–50.

  25. Ikeda T, Kasai M, Utsuyama M, Hirokawa K. Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus. Endocrinoloy. 2001;142:1419–26.

  26. Lum L, Wong BR, Josien R, Becherer JD, Erdjument-Bromage H, Schlöndorff J, et al. Evidence for a role of a tumor necrosis factor-α (TNF-α)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J Biol Chem. 1999;274:13613–8.

  27. Blomberg Jensen M, Andreassen CH, Jørgensen A, Nielsen JE, Juel Mortensen L, Boisen IM, et al. RANKL regulates male reproductive function. Nat Commun. 2021;12:1–15. https://doi.org/10.1038/s41467-021-22734-8.

    Article  CAS  Google Scholar 

  28. Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010;468:103–7.

  29. Li X, Liu Y, Wu B, Dong Z, Wang Y, Lu J, et al. Potential role of the OPG/RANK/RANKL axis in prostate cancer invasion and bone metastasis. Oncol Rep. 2014;32:2605–11.

    Article  CAS  PubMed  Google Scholar 

  30. Mikami S, Katsube KI, Oya M, Ishida M, Kosaka T, Mizuno R, et al. Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas. J Pathol. 2009;218:530–9.

    Article  CAS  PubMed  Google Scholar 

  31. Shang WQ, Li H, Liu LB, Chang KK, Yu JJ, Xie F, et al. RANKL/RANK interaction promotes the growth of cervical cancer cells by strengthening the dialogue between cervical cancer cells and regulation of IL-8 secretion. Oncol Rep. 2015;34:3007–16.

    Article  CAS  PubMed  Google Scholar 

  32. Juel Mortensen L, Lorenzen M, Jørgensen N, Andersson A-M, Nielsen JE, Petersen LI, et al. Possible link between FSH and RANKL release from adipocytes in men with impaired gonadal function including Klinefelter syndrome. Bone. 2019;123:103–14. https://doi.org/10.1016/j.bone.2019.03.022.

    Article  CAS  PubMed  Google Scholar 

  33. Jørgensen A, Nielsen JE, Almstrup K, Toft BG, Petersen BL, De Meyts ER. Dysregulation of the mitosis-meiosis switch in testicular carcinoma in situ. J Pathol. 2013;229:588–98.

    Article  PubMed  Google Scholar 

  34. Fenske AE, Glaesener S, Bokemeyer C, Thomale J, Dahm-Daphi J, Honecker F, et al. Cisplatin resistance induced in germ cell tumour cells is due to reduced susceptibility towards cell death but not to altered DNA damage induction or repair. Cancer Lett. 2012;324:171–8. https://doi.org/10.1016/j.canlet.2012.05.009.

    Article  CAS  PubMed  Google Scholar 

  35. Andrews PW, Gönczöl E, Plotkin SA, Dignazio M, Oosterhuis JW. Differentiation of TERA-2 human embryonal carcinoma cells into neurons and HCMV permissive cells: Induction by agents other than retinoic acid. Differentiation 1986;31:119–26.

    Article  CAS  PubMed  Google Scholar 

  36. Mizuno Y, Gotoh A, Kamidono S, Kitazawa S. Establishment and characterization of a new human testicular germ cell tumor cell line (TCam-2). Nihon Hinyōkika Gakkai zasshi. 1993;84:1211–8.

    CAS  PubMed  Google Scholar 

  37. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: Ultrafast universal RNA-seq aligner. Bioinformatics 2013;29:15–21.

    Article  CAS  PubMed  Google Scholar 

  38. Howe KL, Achuthan P, Allen J, Allen J, Alvarez-Jarreta J, Ridwan Amode M, et al. Ensembl 2021. Nucleic Acids Res. 2021;49:D884–91.

    Article  CAS  PubMed  Google Scholar 

  39. Liao Y, Smyth GK, Shi W. The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 2013;41:e108.

  40. Robinson M, McCarthy D, Smyth G edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26. https://doi.org/10.1093/bioinformatics/btp616.

  41. Law CW, Chen Y, Shi W, Smyth GK. Voom: Precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 2014;15:1–17.

    Article  Google Scholar 

  42. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wu D, Smyth GK. Camera: A competitive gene set test accounting for inter-gene correlation. Nucleic Acids Res. 2012;40:1–12.

    Article  Google Scholar 

  44. Wickham H. ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag New York; 2016.

  45. Harpelunde Poulsen K, Nielsen JE, Grønkær Toft B, Joensen UN, Rasmussen LJ, Blomberg Jensen M, et al. Influence of Nodal signalling on pluripotency factor expression, tumour cell proliferation and cisplatin-sensitivity in testicular germ cell tumours. BMC Cancer. 2020;20:349.

  46. Lorenzen M, Nielsen JE, Andreassen CH, Juul A, Toft BG, De Meyts ER, et al. Luteinizing hormone receptor is expressed in testicular germ cell tumors: Possible implications for tumor growth and prognosis. Cancers (Basel) 2020;12:1–15.

    Article  Google Scholar 

  47. Jørgensen A, Young J, Nielsen JE, Joensen UN, Toft BG, Rajpert-De Meyts E, et al. Hanging drop cultures of human testis and testis cancer samples: a model used to investigate activin treatment effects in a preserved niche. Br J Cancer. 2014;110:2604-14.

  48. Swarnkar G, Chen THP, Arra M, Nasir AM, Mbalaviele G, Abu-Amer Y. NUMBL interacts with TAK1, TRAF6 and NEMO to negatively regulate NF-κB signaling during osteoclastogenesis. Sci Rep. 2017;7:1–10. https://doi.org/10.1038/s41598-017-12707-7.

    Article  CAS  Google Scholar 

  49. Liang J, Nagahashi M, Kim EY, Harikumar KB, Yamada A, Huang W, et al. Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell. 2013;23:107–20.

  50. Jiang Y, Li J, Li G, Liu S, Lin X, He Y, et al. Osteoprotegerin interacts with syndecan-1 to promote human endometrial stromal decidualization by decreasing Akt phosphorylation. Hum Reprod. 2020;35:2439–53.

    Article  CAS  PubMed  Google Scholar 

  51. Armstrong L, Hughes O, Yung S, Hyslop L, Stewart R, Wappler I, et al. The role of PI3K/AKT, MAPK/ERK and NFkappabeta signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Hum Mol Genet. 2006;15:1894–913.

  52. Lee J, Kim HK, Rho JY, Han YM, Kim J. The human OCT-4 isoforms differ in their ability to confer self-renewal. J Biol Chem. 2006;281:33554–65.

    Article  CAS  PubMed  Google Scholar 

  53. Luo J, Yang Z, Ma Y, Yue Z, Lin H, Qu G, et al. LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat Med. 2016;22:539–46. https://doi.org/10.1038/nm.4076.

    Article  CAS  PubMed  Google Scholar 

  54. Yi J, Xiong W, Gong X, Bellister S, Ellis LM, Liu Q. Analysis of LGR4 receptor distribution in human and mouse tissues. PLoS ONE. 2013;8:e78144.

  55. Yu C-Y, Liang G-B, Du P, Liu Y-H. Lgr4 promotes glioma cell proliferation through activation of Wnt signaling. Asian Pac J Cancer Prev. 2013;14:4907–11.

    Article  PubMed  Google Scholar 

  56. Zhu YB, Xu L, Chen M, Ma HN, Lou F. GPR48 promotes multiple cancer cell proliferation via activation of Wnt signaling. Asian Pac J Cancer Prev 2013;14:4775–8.

    Article  PubMed  Google Scholar 

  57. Ikebuchi Y, Aoki S, Honma M, Hayashi M, Sugamori Y, Khan M, et al. Coupling of bone resorption and formation by RANKL reverse signalling. Nature. 2018; http://www.nature.com/articles/s41586-018-0482-7.

  58. Steven A, Leisz S, Fussek S, Nowroozizadeh B, Huang J, Branstetter D, et al. Receptor activator of NF-κB (RANK)-mediated induction of metastatic spread and association with poor prognosis in renal cell carcinoma. Urol Oncol. 2018;0:1–10.

  59. Chen L-M, Kuo C-H, Lai T-Y, Lin Y-M, Su C-C, Hsu H-H, et al. RANKL increases migration of human lung cancer cells through intercellular adhesion molecule-1 up-regulation. J Cell Biochem. 2011;112:933–41.

    Article  CAS  PubMed  Google Scholar 

  60. Armstrong AP, Miller RE, Jones JC, Zhang J, Keller ET, Dougall WC. RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate. 2008;68:92–104.

    Article  CAS  PubMed  Google Scholar 

  61. Blomberg Jensen M, Leffers H, Petersen JH, Daugaard G, Skakkebaek NE, Rajpert-De Meyts E. Association of the polymorphism of the CAG repeat in the mitochondrial DNA polymerase gamma gene (POLG) with testicular germ-cell cancer. Ann Oncol. 2008;19:1910–4.

  62. Taylor-Weiner A, Zack T, O’Donnell E, Guerriero JL, Bernard B, Reddy A, et al. Genomic evolution and chemoresistance in germ-cell tumours. Nat [Internet]. 2016;540:114–8. https://doi.org/10.1038/nature20596.

    Article  CAS  Google Scholar 

  63. Sinha Hikim AP, Lue Y, Yamamoto CM, Vera Y, Rodriguez S, Yen PH, et al. Key apoptotic pathways for heat-induced programmed germ cell death in the testis. Endocrinology 2003;144:3167–75.

    Article  Google Scholar 

  64. Hase T, Yoshimura R, Matsuyama M, Kawahito Y, Wada S, Tsuchida K, et al. Cyclooxygenase-1 and -2 in human testicular tumours. Eur J Cancer. 2003;39:2043–9.

    Article  CAS  PubMed  Google Scholar 

  65. Jostes S, Nettersheim D, Fellermeyer M, Schneider S, Hafezi F, Honecker F, et al. The bromodomain inhibitor JQ1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo. J Cell Mol Med. 2017;21:1300–14.

    Article  CAS  PubMed  Google Scholar 

  66. Skakkebak NE Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001;16:972–8. https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/16.5.972.

  67. Paduch DA, Hilz S, Grimson A, Schlegel PN, Jedlicka AE, Wright WW. Aberrant gene expression by Sertoli cells in infertile men with Sertoli cell-only syndrome. PLoS ONE. 2019;14:1–27.

    Article  Google Scholar 

  68. Faget J, Contat C, Zangger N, Peters S, Meylan E. RANKL signaling sustains primary tumor growth in genetically engineered mouse models of lung adenocarcinoma. J Thorac Oncol. 2017;13:287–98.

  69. Yoldi G, Pellegrini P, Trinidad EM, Cordero A, Gomez-Miragaya J, Serra-Musach J, et al. RANK Signaling blockade reduces breast cancer recurrence by inducing tumor cell differentiation. Cancer Res. 2016;76:5857–69.

  70. Peters S, Clézardin P, Márquez-Rodas I, Niepel D, Gedye C. The RANK-RANKL axis: an opportunity for drug repurposing in cancer? Clin Transl Oncol. 2019;21:977–91. http://link.springer.com/10.1007/s12094-018-02023-5.

  71. van Dam PA, Verhoeven Y, Jacobs J, Wouters A, Tjalma W, Lardon F, et al. RANK-RANKL Signaling in cancer of the uterine cervix: a review. Int J Mol Sci. 2019;20:1–15.

  72. Oechsle K, Bokemeyer C, Kollmannsberger C, Mayer F, Berger LA, Oing C, et al. Bone metastases in germ cell tumor patients. J Cancer Res Clin Oncol. 2012;138:947–52.

    Article  CAS  PubMed  Google Scholar 

  73. Johnson DE, Appelt G, Samuels ML, Luna M. Metastases from testicular carcinoma Study of 78 autopsied cases. Urology. 1976;8:234–9.

    Article  CAS  PubMed  Google Scholar 

  74. Mueller T, Mueller LP, Luetzkendorf J, Voigt W, Simon H, Schmoll HJ. Loss of Oct-3/4 expression in embryonal carcinoma cells is associated with induction of cisplatin resistance. Tumor Biol. 2006;27:71–83.

    Article  CAS  Google Scholar 

  75. Abada PB, Howell SB Cisplatin induces resistance by triggering differentiation of testicular embryonal carcinoma cells. PLoS ONE. 2014;9;e87444.

Download references

Acknowledgements

We acknowledge Mie Mechta and Lars Roed Ingerslev and The Single-Cell Omics platform at the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) for technical and computational expertise and support. We also wish to thank laboratory technicians Ana Ricci Guarnes-Nielsen and Brian Vendelbo Hansen for excellent technical assistance. We acknowledge the efforts by Carsten L. Buus from Pipeline Biotech, who performed the xenograft experiments.

Funding

Novo Nordisk Fonden (Novo Nordisk Foundation), The Danish Cancer Society, and Candys Foundation.

Author information

Authors and Affiliations

  1. Group of Skeletal, Mineral, and Gonadal Endocrinology, Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

    Christine Hjorth Andreassen, Mette Lorenzen, Sam Kafai Yahyavi & Martin Blomberg Jensen

  2. Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

    John E. Nielsen, Anders Juul & Anne Jørgensen

  3. Department of Pathology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

    Birgitte Grønkær Toft

  4. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Lars R. Ingerslev & Christoffer Clemmensen

  5. Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark

    Lene Juel Rasmussen

  6. Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

    Lene Juel Rasmussen

  7. Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Carsten Bokemeyer

  8. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Anders Juul

  9. Division of Bone and Mineral Research, HSDM/HMS Harvard University, Boston, MA, USA

    Martin Blomberg Jensen

Authors
  1. Christine Hjorth Andreassen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mette Lorenzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John E. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sam Kafai Yahyavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Birgitte Grønkær Toft
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lars R. Ingerslev
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christoffer Clemmensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lene Juel Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Carsten Bokemeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anders Juul
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anne Jørgensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martin Blomberg Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceived and designed the experiments: MBJ and CHA. Performed the experiments: CHA, JEN, and ML. Analysed the data: CHA, LRI, MBJ, and SKF. Contributed reagents/materials/analysis tools and expertise: BGT, AJØ, LJR, CC, CB, AJ, and SKF. Wrote the manuscript: CHA and MBJ. All authors revised and approved the manuscript.

Corresponding author

Correspondence to Martin Blomberg Jensen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Ethical approval was obtained for collection of human testis and serum samples from University Hospital of Copenhagen (Rigshospitalet), Copenhagen, Denmark (H-1-2012-007). Serum samples from infertile men, men with TGTs, men with Leydig cell tumour, and men Sertoli cell only pattern in testis biopsy were obtained after after approval from the regional ethical committee (H-4-2010-138, H-17004362, KF-01-2006-3472). Written and informed consent was obtained for the use of all tissues and serum samples included in the study. Animal experiments were approved prior to the beginning of the study and were conducted by Pipeline Biotech in compliance with the Danish Animal Experiments Inspectorate (license number 2011/561-1956).

Consent to publish

Not applicable.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Andreassen, C.H., Lorenzen, M., Nielsen, J.E. et al. RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma. Br J Cancer 127, 408–421 (2022). https://doi.org/10.1038/s41416-022-01810-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-022-01810-w

This article is cited by

Search

Advanced search

Quick links