Establishment of a versatile seminoma model indicates cellular plasticity of germ cell tumor cells
Establishment of a versatile seminoma model indicates cellular plasticity of germ cell tumor cells
复制标题
DOI：
10.1002/gcc.21958
复制
发表时间：
2012-07-01
影响因子：
3.7
通讯作者：
Schorle, Hubert
中科院分区：
文献类型：
--
作者：
Nettersheim, Daniel;Westernstroeer, Birgit;Schorle, Hubert
在西方国家，在1745岁之间的男性中诊断出的所有恶性肿瘤中有60%是生殖细胞肿瘤（GCT）。GCT起源于常见的原位癌前病变，平均在9年内转变为侵袭性II型GCT。精原细胞瘤被认为是原位癌细胞的默认发育途径，并且精原细胞瘤样细胞系TCam-2已被用于体外研究精原细胞瘤生物学。然而，动物模型的产生，这将允许在体内分析的肿瘤形成，仍然难以捉摸。我们应用TCam-2细胞转移到免疫缺陷小鼠的异位（皮肤，脑）和原位（睾丸）部位的移植方法。我们证明，移植到曲细精管的结果在原位癌/结肠癌的形成。相比之下，TCam-2细胞在移植到侧腹或纹状体时采用胚胎癌样命运，并显示出胚胎癌标志物SOX 17的下调和胚胎癌标志物SOX 2和CD 30的上调。移植的TCam-2细胞将AKT-、ERK-、EphA 3-和Tie 2/TEK-信号传导降低至与胚胎癌细胞相当的水平。因此，将TCam-2细胞移植到睾丸中产生了原位癌/结肠癌小鼠模型，这使得能够在体内解决这些肿瘤的生物学。TCam-2细胞以移植部位特异性方式产生原位癌/乳腺癌或胚胎癌的事实意味着原位癌/乳腺癌向胚胎癌的转化不需要额外的遗传畸变，而是依赖于来自肿瘤微环境的信号。(c)2012 Wiley Periodicals，Inc.
In western countries, 60% of all malignancies diagnosed in men between 1745 years of age are germ cell tumors (GCT). GCT arise from the common precursor lesion carcinoma in situ, which transforms within an average of 9 years into invasive Type-II GCTs. Seminomas are considered to be the default developmental pathway of carcinoma in situ cells and the seminoma-like cell line TCam-2 has been used to study seminoma biology in vitro. However, the generation of an animal model, which would allow for the in vivo analysis of seminoma formation, remained elusive. We applied transplantation approaches using TCam-2 cell transfer into ectopic (skin, brain) and orthopic (testis) sites of immunodeficient mice. We demonstrate that a transplantation into the seminiferous tubules results in formation of a carcinoma in situ/seminoma. In contrast, TCam-2 cells adopt an embryonal carcinoma-like fate when grafted to the flank or corpus striatum and display downregulation of the seminoma marker SOX17 and upregulation of the embryonal carcinoma markers SOX2 and CD30. Grafted TCam-2 cells reduce AKT-, ERK-, EphA3-, and Tie2/TEK-signaling to levels comparable to embryonal carcinoma cells. Hence, TCam-2 cell transplantation into the testis generated a carcinoma in situ/seminoma mouse model, which enables addressing the biology of these tumors in vivo. The fact that TCam-2 cells give rise to a carcinoma in situ/seminoma or embryonal carcinoma in a transplantation site specific manner implies that conversion of carcinoma in situ/seminoma to an embryonal carcinoma does not require additional genetic aberrations but relies on signals from the tumor-microenvironment. (c) 2012 Wiley Periodicals, Inc.