Department of Growth and Reproduction, Copenhagen University Hospital, Denmark.
J Pathol. 2013 Mar;229(4):588-98. doi: 10.1002/path.4154. Epub 2013 Feb 4.
Testicular germ cell tumours (TGCT) of young adults arise from the intratubular precursor, carcinoma in situ (CIS). CIS cells are thought to be developmentally arrested and transformed fetal germ cells that survive through childhood and gain invasive capacity after puberty. Given that germ cell neoplasms arise frequently in undervirilized and dysgenetic gonads and the striking physiological difference between meiotic entry in ovaries (fetal life) versus testes (at puberty), this study aimed to investigate whether errors in regulation of meiosis may be implicated in the pathogenesis of CIS or its invasive progression to TGCT. The main focus was on a key sex differentiation and meiosis regulator, DMRT1, which has also been linked to TGCT risk in recent genetic association studies. Expression patterns of DMRT1 and other meiosis regulators (SCP3, DMC1, STRA8, CYP26B1, NANOS2, NANOS3) were investigated in pre- and post-pubertal CIS samples and TGCT by quantitative RT-PCR and immunohistochemistry. The results demonstrated that meiosis markers and meiosis inhibitors were simultaneously expressed in CIS cells, in both pre- and post-pubertal testis samples. DMRT1 was present in a restricted subset of CIS cells, which was relatively greater in pre-pubertal (27%) compared to adult (2.6%) samples. In contrast to the majority of CIS cells, DMRT1-positive CIS cells in adult testes were not proliferating. DMRT1 and most of the other meiosis regulators were absent or expressed at low levels in invasive TGCT, except in spermatocytic seminoma (not derived from CIS). In conclusion, this study indicates that meiosis signalling is dysregulated in CIS cells and that a key regulator of the mitosis-meiosis switch, DMRT1, is expressed in 'early-stage' CIS cells but is down-regulated with further invasive transformation. Whether this mixed meiosis signalling in CIS cells is caused by insufficient virilization of the fetal somatic niche or a partial post-pubertal maturation remains uncertain and requires further study.
青年睾丸生殖细胞肿瘤 (TGCT) 起源于管内前体细胞，原位癌 (CIS)。CIS 细胞被认为是发育停滞和转化的胎儿生殖细胞，它们在儿童期存活，并在青春期后获得侵袭能力。鉴于生殖细胞肿瘤经常在未充分发育和发育不良的性腺中出现，以及减数分裂进入卵巢（胎儿期）与睾丸（青春期）之间的显著生理差异，本研究旨在探讨减数分裂调控中的错误是否可能与 CIS 的发病机制或其向 TGCT 的侵袭性进展有关。主要焦点是一个关键的性别分化和减数分裂调节剂，DMRT1，最近的遗传关联研究也将其与 TGCT 风险联系起来。通过定量 RT-PCR 和免疫组织化学，研究了 DMRT1 和其他减数分裂调节剂 (SCP3、DMC1、STRA8、CYP26B1、NANOS2、NANOS3) 在青春期前和青春期后 CIS 样本和 TGCT 中的表达模式。结果表明，减数分裂标记物和减数分裂抑制剂同时在 CIS 细胞中表达，无论是在青春期前还是青春期后睾丸样本中。DMRT1 存在于 CIS 细胞的一个受限亚群中，在青春期前样本中（27%）比成年样本中（2.6%）相对较多。与大多数 CIS 细胞不同，成年睾丸中 DMRT1 阳性的 CIS 细胞没有增殖。除精原细胞瘤外（不是源自 CIS），DMRT1 和大多数其他减数分裂调节剂在侵袭性 TGCT 中缺失或低表达。总之，本研究表明减数分裂信号在 CIS 细胞中失调，并且有丝分裂-减数分裂转换的关键调节剂 DMRT1 在“早期”CIS 细胞中表达，但随着进一步的侵袭性转化而下调。CIS 细胞中这种混合减数分裂信号是由于胎儿体腔的未充分雄性化还是部分青春期后成熟引起的尚不确定，需要进一步研究。
