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Cellular and Molecular Biology

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

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.

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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.

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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.

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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.

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Correspondence to Martin Blomberg Jensen.

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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).

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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

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