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

Abstract

Cell cycle regulators govern cellular proliferation, modulate differentiation and, when defective, contribute to oncogenesis. Here, we examined expression of cyclins A, BI and E, and cyclin-dependent kinase (CDK) inhibitors p 18(INK4C) (p 18), p21(WAF1/Cipl (p2 I) and p27(Kipl) (p27), in normal human 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 proteins, and abundant p 18 and the lack of p21 and p27 in normal spermatogenesis. Expression of p21 and/or p27 was induced in some differentiated structures seen in teratomas, and was recapitulated in cell culture, using human NTera2/DI teratocarcinoma cells induced to differentiate into neurons. CIS lesions showed abundant p18, low cyclin E, and moderate p27, in contrast with most invasive seminomas and embryonal carcinomas with very low-to-negative p18, often elevated cyclin E, and, unexpectedly, sustained or increased p27. Our results suggest increased abundance of cyclin E, and particularly down-modulation or loss of pl8(INK4C) as the features that correlate with progression from CIS to invasive germ cell tumours of the human testis.