http://repub.eur.nl/res/aut/8130/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/13730/ 2005-03-01T00:00:00Z Prostate cancer development often includes a shift from androgen-dependent to androgen-independent growth. It is hypothesized that, during this transition, growth factors like the epidermal growth factor (EGF) gain importance as activators of tumour cell proliferation. To study this, androgen- and EGF-regulation of growth and gene-expression was analysed in the androgen-dependent human prostate cancer cell line LNCaP-FGC (FGC) and its androgen-independent derivative line LNCaP-LNO (LNO). It was observed that androgen-dependent FGC cells require exposure to either androgens or EGF to proliferate. This is in contrast to androgen-independent LNO cells that showed significant proliferation in medium depleted of androgens and growth factors. Gene expression data were obtained for the androgen-dependent FGC and androgen-independent LNO cells cultured in the presence or absence of androgens (synthetic R1881) or EGF for different time periods. Expression profiling showed that many cell cycle genes, including a number of androgen- and EGF-regulated genes, are constitutively activated in androgen-independent LNO cells. Furthermore, the overlap between changes in gene expression activated by androgen and EGF receptor signalling pathways was found to be very high (75%). These results partly explain why androgen-independent LNO cells can proliferate in the absence of androgenic stimulation. However, possibly other, so far unknown, signal transduction pathways that induce and maintain proliferation, have also been activated. http://repub.eur.nl/res/pub/7345/ 2004-10-21T00:00:00Z Prostate cancer has a high incidence in the western world. Early detection of the disease is crucial for successful management, since late stages of the disease cannot be cured. Unfortunately, however, conventional detection through rising PSA levels is already too late in one-third of the cases. These patients have metastatic disease, which can only be treated temporarily by androgen ablation therapy. The main problem of metastatic prostate cancer is a transition from initially androgen-dependent growth to androgen-independent growth. Androgen-independence of prostate cancer cells implies resistance to androgen ablation therapy, eventually leading to death of the patient. Next to androgens, many other growth and differentiation inducing factors play a role during development and homeostasis of the prostate and during progression of prostate cancer. Peptide growth factors like EGF, TGF-a, FGF, IGF, NGF, PDGF, VEGF, and TGF-ß have all been hypothesized to be involved in prostate cancer growth. The proposed mechanism of androgen-independent prostate cancer progression is through stimulation of proliferation via these factors as compensation for lack of proliferation stimulation through androgens. Furthermore, crosstalk between androgen signalling and growth factor signalling seems to play a role in prostate cancer growth. Growth factors are reported to activate androgen receptors and androgens to induce growth factor and growth factor receptor expression. In this thesis we focussed mainly on EGF signalling. First, because REPS2, a protein potentially involved in androgen-independent prostate cancer, acts through affecting EGF signalling, and second, because gene profiling indicated that EGF and androgen signalling seem to intertwine in androgen-independent prostate cancer.