RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma
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RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma. / Andreassen, Christine Hjorth; Lorenzen, Mette; Nielsen, John E.; Kafai Yahyavi, Sam; Toft, Birgitte Grønkær; Ingerslev, Lars R.; Clemmensen, Christoffer; Rasmussen, Lene Juel; Bokemeyer, Carsten; Juul, Anders; Jørgensen, Anne; Jensen, Martin Blomberg.
I: British Journal of Cancer, Bind 127, 2022, s. 408-421.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma
AU - Andreassen, Christine Hjorth
AU - Lorenzen, Mette
AU - Nielsen, John E.
AU - Kafai Yahyavi, Sam
AU - Toft, Birgitte Grønkær
AU - Ingerslev, Lars R.
AU - Clemmensen, Christoffer
AU - Rasmussen, Lene Juel
AU - Bokemeyer, Carsten
AU - Juul, Anders
AU - Jørgensen, Anne
AU - Jensen, Martin Blomberg
N1 - Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1038/s41416-022-01810-w
DO - 10.1038/s41416-022-01810-w
M3 - Journal article
C2 - 35418213
AN - SCOPUS:85128104591
VL - 127
SP - 408
EP - 421
JO - The British journal of cancer. Supplement
JF - The British journal of cancer. Supplement
SN - 0007-0920
ER -
ID: 305688628