Bartkova J, Rajpert-de Meyts E, Skakkebaek N E, Bartek J
Department of Cell Cycle and Cancer, Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark.
J Pathol. 1999 Apr;187(5):573-81. doi: 10.1002/(SICI)1096-9896(199904)187:5<573::AID-PATH289>3.0.CO;2-H.
D-type cyclins are proto-oncogenic components of the 'RB pathway', a G1/S regulatory mechanism centred around the retinoblastoma tumour suppressor (pRB) implicated in key cellular decisions that control cell proliferation, cell-cycle arrest, quiescence, and differentiation. This study focused on immunohistochemical and immunochemical analysis of human adult testis and 32 testicular tumours to examine the differential expression and abundance of cyclins D1, D2, and D3 in relation to cell type, proliferation, differentiation, and malignancy. In normal testis, the cell type-restricted expression patterns were dominated by high levels of cyclin D3 in quiescent Leydig cells and the lack of any D-type cyclin in the germ cells, the latter possibly representing the only example of normal mammalian cells proliferating in the absence of these cyclins. Most carcinoma-in-situ lesions appeared to gain expression of cyclin D2 but not D1 or D3, while the invasive testicular tumours showed variable positivity for cyclins D2 and D3, but rarely D1. An unexpected correlation with differentiation rather than proliferation was found particularly for cyclin D3 in teratomas, a conceptually significant observation confirmed by massive up-regulation of cyclin D3 in the human teratocarcinoma cell line NTera2/D1 induced to differentiate along the neuronal lineage. These results suggest a possible involvement of cyclin D2 in the early stages of testicular oncogenesis and the striking examples of proliferation-independent expression point to potential dual or multiple roles of the D-type cyclins, particularly of cyclin D3. These findings extend current concepts of the biology of the cyclin D subfamily, as well as of the biology and oncopathology of the human adult testis. Apart from practical implications for the assessment of proliferation and oncogenic aberrations in human tissues and tumours, this study may inspire further research into the emerging role of the cyclin D proteins in the establishment and/or maintenance of the differentiated phenotypes.
D型细胞周期蛋白是“RB通路”的原癌基因组成部分，“RB通路”是一种G1/S调节机制，以视网膜母细胞瘤肿瘤抑制因子（pRB）为中心，参与控制细胞增殖、细胞周期停滞、静止和分化的关键细胞决策。本研究聚焦于对成人睾丸和32例睾丸肿瘤进行免疫组织化学和免疫化学分析，以研究细胞周期蛋白D1、D2和D3在细胞类型、增殖、分化和恶性肿瘤方面的差异表达及丰度。在正常睾丸中，细胞类型特异性的表达模式表现为：静止的睾丸间质细胞中细胞周期蛋白D3水平较高，而生殖细胞中缺乏任何D型细胞周期蛋白，后者可能是正常哺乳动物细胞在缺乏这些细胞周期蛋白的情况下仍能增殖的唯一例子。大多数原位癌病变似乎获得了细胞周期蛋白D2的表达，但没有D1或D3的表达，而侵袭性睾丸肿瘤对细胞周期蛋白D2和D3显示出不同程度的阳性，但很少有D1阳性。尤其在畸胎瘤中发现细胞周期蛋白D3与分化而非增殖存在意外的相关性，这一在概念上具有重要意义的观察结果在人畸胎癌细胞系NTera2/D1沿神经谱系诱导分化时细胞周期蛋白D3大量上调得到证实。这些结果表明细胞周期蛋白D2可能参与睾丸肿瘤发生的早期阶段，而增殖非依赖性表达的显著例子表明D型细胞周期蛋白，特别是细胞周期蛋白D3可能具有潜在的双重或多重作用。这些发现扩展了目前关于细胞周期蛋白D亚家族生物学以及成人睾丸生物学和肿瘤病理学的概念。除了对评估人体组织和肿瘤中的增殖及致癌畸变具有实际意义外，本研究可能会激发对细胞周期蛋白D蛋白在分化表型的建立和/或维持中新兴作用的进一步研究。
