In the quest for markers of expression and progression for
prostate cancer (PCa), the majority of studies have focussed on molecular data exclusively from primary tumours. Although expression in
metastases is inferred, a lack of correlation with secondary tumours potentially limits their applicability diagnostically and therapeutically. Molecular targets were identified by examining expression profiles of prostate cell lines using
cDNA microarrays. Those genes identified were verified on PCa cell lines and tumour samples from both primary and secondary tumours using real-time RT-PCR, western blotting and immunohistochemistry.
Claudin-4, coding for an integral membrane cell-junction
protein, was the most significantly (P<0.00001) upregulated marker in both primary and metastatic tumour specimens compared with
benign prostatic hyperplasia at both
RNA and
protein levels. In primary tumours,
claudin-4 was more highly expressed in lower grade (Gleason 6) lesions than in higher grade (Gleason >or=7)
cancers. Expression was prominent throughout
metastases from a variety of secondary sites in fresh-frozen and
formalin-fixed specimens from both
androgen-intact and
androgen-suppressed patients. As a result of its prominent expression in both primary and secondary PCas, together with its established role as a receptor for
Clostridium perfringens enterotoxin,
claudin-4 may be useful as a potential marker and therapeutic target for PCa
metastases.