Christine Hjorth Andreassen1, Mette Lorenzen1, John E Nielsen2, Sam Kafai Yahyavi1, Birgitte Grønkær Toft3, Lars R Ingerslev4, Christoffer Clemmensen4, Lene Juel Rasmussen5,6, Carsten Bokemeyer7, Anders Juul2,8, Anne Jørgensen2, Martin Blomberg Jensen9,10. 1. Group of Skeletal, Mineral, and Gonadal Endocrinology, Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark. 2. Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark. 3. Department of Pathology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark. 4. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 5. Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark. 6. Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark. 7. Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 8. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 9. Group of Skeletal, Mineral, and Gonadal Endocrinology, Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark. Blombergjensen@gmail.com. 10. Division of Bone and Mineral Research, HSDM/HMS Harvard University, Boston, MA, USA. Blombergjensen@gmail.com.
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.
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.
Authors: Jason K Gurney; Andrea A Florio; Ariana Znaor; Jacques Ferlay; Mathieu Laversanne; Diana Sarfati; Freddie Bray; Katherine A McGlynn Journal: Eur Urol Date: 2019-07-17 Impact factor: 20.096
Authors: K Harpelunde Poulsen; J E Nielsen; B Grønkær Toft; U N Joensen; L J Rasmussen; M Blomberg Jensen; R T Mitchell; A Juul; E Rajpert-De Meyts; A Jørgensen Journal: BMC Cancer Date: 2020-04-23 Impact factor: 4.430