Leibniz Institute on Aging-Fritz Lipmann Institute, Jena, Germany.
Mol Carcinog. 2019 May;58(5):621-626. doi: 10.1002/mc.22961. Epub 2019 Jan 28.
Loss-of-function of RHAMM causes hypofertility and testicular atrophy in young mice, followed by germ cell neoplasia in situ (GCNIS) of the testis, cellular atypia, and development of the testicular germ cell tumor (TGCT) seminoma. These pathologies reflect the risk factors and phenotypes that precede seminoma development in humans and-given the high prevalence of RHAMM downregulation in human seminoma-link RHAMM dysfunction with the aetiology of male hypofertility and GCNIS-related TGCTs. The initiating event underlying these pathologies, in RHAMM mutant testis, is premature displacement of undifferentiated progenitors from the basal compartment. We hypothesized that cd44 (both cancer initiating cell- and oncogenic progression marker) will drive GCNIS development, induced by RHAMM-loss-of-function in the mouse. We report that cd44 is expressed in a specific subset of GCNIS testes. Its genetic deletion has no effect on GCNIS onset, but it ameliorates oncogenic progression. We conclude that cd44 expression, combined with RHAMM dysfunction, promotes oncogenic progression in the testis.
RHAMM 功能丧失导致年轻小鼠的生育力降低和睾丸萎缩，随后出现睾丸生殖细胞原位肿瘤（GCNIS）、细胞异型性和睾丸生殖细胞肿瘤（TGCT）精原细胞瘤的发展。这些病理反映了人类 TGCT 发生之前的风险因素和表型——鉴于 RHAMM 在人类精原细胞瘤中下调的高发生率——将 RHAMM 功能障碍与男性生育力降低和 GCNIS 相关 TGCT 的病因联系起来。在 RHAMM 突变的睾丸中，这些病变的起始事件是未分化祖细胞过早从基底隔室移位。我们假设 cd44（既是癌症起始细胞标志物，也是致癌进展标志物）将驱动由 RHAMM 功能丧失引起的 GCNIS 发展。我们报告说，cd44 在特定的 GCNIS 睾丸亚群中表达。其基因缺失对 GCNIS 的发生没有影响，但可改善致癌进展。我们得出结论，cd44 的表达与 RHAMM 功能障碍相结合，促进了睾丸中的致癌进展。
