Cell cycle regulators in testicular cancer: Loss of p18(INK4C) marks progression from carcinoma in situ to invasive germ cell tumours

Cell cycle regulators govern cellular proliferation, modulate differentiati on and, when defective, contribute to oncogenesis. Here, we examined expres sion of cyclins A, B I and E, and cyclin-dependent kinase (CDK) inhibitors p18(INK4C) (p 18), p21(WAF1/Cip1) (p21) and p27(Kip1) (p27), in normal huma n adult testis (n = 5), and 53 testicular tumours, including 23 carcinomas in situ (CIS) and 30 germ cell tumours (GCTs). Immunohistochemical analysis revealed a correlation between proliferation and abundance of the cyclin p roteins, and abundant pig and the lack of p21 and p27 in normal spermatogen esis. Expression of p21 and/or p27 was induced in some differentiated struc tures seen in teratomas, and was recapitulated in cell culture, using human NTera2/D1 teratocarcinoma cells induced to differentiate into neurons. CIS lesions showed abundant p18, low cyclin E, and moderate p27, in contrast w ith most invasive seminomas and embryonal carcinomas with very low-to-negat ive p18, often elevated cyclin E, and, unexpectedly, sustained or increased p27. Our results suggest increased abundance of cyclin E, and particularly downmodulation or loss of p18(INK4C) as the features that correlate with p rogression from CIS to invasive germ cell tumours of the human testis. (C) 2000 Wiley-Liss, inc.