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

Christine Hjorth Andreassen, Mette Lorenzen, John E Nielsen, Sam Kafai Yahyavi, Birgitte Grønkær Toft, Lars R Ingerslev, Christoffer Clemmensen, Lene Juel Rasmussen, Carsten Bokemeyer, Anders Juul, Anne Jørgensen, Martin Blomberg Jensen*

*Corresponding author for this work


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.

Original languageEnglish
JournalBritish Journal of Cancer
Issue number3
Pages (from-to)408-421
Number of pages14
Publication statusPublished - Aug 2022


  • Denosumab/pharmacology
  • Humans
  • Male
  • Neoplasms, Germ Cell and Embryonal/drug therapy
  • Seminoma/drug therapy
  • Testicular Neoplasms/pathology


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