RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma
RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma
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RANKL调节睾丸癌生长，Denosumab治疗对GCNIS和晚期睾丸癌具有抑制作用
DOI：
10.1038/s41416-022-01810-w
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发表时间：
2022-04-13
影响因子：
8.8
通讯作者：
Jensen, Martin Blomberg
中科院分区：
文献类型：
--
作者：
Andreassen, Christine Hjorth;Lorenzen, Mette;Jensen, Martin Blomberg
背景：睾丸生殖细胞肿瘤（tgct）对化疗具有高敏感性和高治愈率，但有严重的不良反应。在寻找肿瘤抑制药物的过程中，用于治疗骨质疏松症的RANKL抑制剂Denosumab成为候选药物，因为最近在睾丸中发现了RANKL信号。方法研究人tgct、tgct衍生细胞系和tgct异种移植模型中RANKL、RANK和OPG的表达及RANKL抑制作用。tgct患者血清RANKL测定。结果RANKL、RANK和OPG在生殖细胞原位瘤（GCNIS）、tgct和tgct衍生细胞系中均有表达。rankl抑制可降低精原细胞瘤来源的TCam-2细胞的增殖，但对胚胎癌来源的NTera2细胞没有影响。在体外，Denosumab预处理并没有增强顺铂的效果。然而，体内抑制RANKL仅在tcam -2异种移植模型中降低肿瘤生长，而denosumab治疗降低了人GCNIS培养物的增殖。tgct患者血清RANKL无预后价值。结论本研究表明RANKL信号系统在GCNIS和精原细胞瘤中表达，抑制RANKL在体外和体内抑制肿瘤生长。未来的研究需要确定RANKL是否在GCNIS恶性转化或向侵袭性肿瘤过渡中起重要作用。
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.