Hedgehog signalling in androgen independent prostate cancer.
OBJECTIVE
Androgen-deprivation therapy effectively shrinks hormone-naïve prostate cancer, both in the prostate and at sites of distant metastasis. However prolonged androgen deprivation generally results in relapse and androgen-independent tumour growth, which is inevitably fatal. The molecular events that enable prostate cancer cells to proliferate in reduced androgen conditions are poorly understood. Here we investigate the role of Hedgehog signalling in androgen-independent prostate cancer (AIPC).


METHODS
Activity of the Hedgehog signalling pathway was analysed in cultured prostate cancer cells, and circulating prostate tumour cells were isolated from blood samples of patients with AIPC.


RESULTS
AIPC cells were derived through prolonged culture in reduced androgen conditions, modelling hormone therapy in patients, and expressed increased levels of Hedgehog signalling proteins. Exposure of cultured AIPC cells to cyclopamine, which inhibits Hedgehog signalling, resulted in inhibition of cancer cell growth. The expression of the Hedgehog receptor PTCH and the highly prostate cancer-specific gene DD3(PCA3) was significantly higher in circulating prostate cancer cells isolated from patients with AIPC compared with samples prepared from normal individuals. There was an association between PTCH and DD3(PCA3) expression and the length of androgen-ablation therapy.


CONCLUSIONS
Our data are consistent with reports implicating overactivity of Hedgehog signalling in prostate cancer and suggest that Hedgehog signalling contributes to the androgen-independent growth of prostate cancer cells. As systemic anti-Hedgehog medicines are developed, the Hedgehog pathway will become a potential new therapeutic target in advanced prostate cancer.
Shaw
Greg
G
Institute of Cancer, Bart's and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
Price
Anna M
AM
Ktori
Elena
E
Bisson
Isabelle
I
Purkis
Patricia E
PE
McFaul
Siobhan
S
Oliver
R Tim D
RT
Prowse
David M
DM
D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000502:physiology; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000209:etiology*; D015398:Signal Transduction
D000728:Androgens; D053823:Hedgehog Proteins