WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their ability to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heterogeneous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treatment with WNT inhibitors reduced both prostasphere size and self-renewal. In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear Β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are consistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector Β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen receptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit amplifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell characteristics and improve the therapeutic outcome.Peer reviewe

Extracorporeal shock wave lithotripsy in the treatment of renal pelvicalyceal stones in morbidly obese patients

INTRODUCTION: Management of urolithiasis in morbidly obese patients is usually associated with higher morbidity and mortality compared to non-obese patients. In morbidly obese patients, since the kidney and stone are at a considerable distance from the skin (compared to non-obese patients) difficulty may be found in positioning the patient so that the stone is situated at the focal point of the lithotripter. OBJECTIVE: To evaluate the outcomes and cost-efficiency of extracorporeal shock wave lithotripsy (ESWL) in the treatment of renal pelvicalyceal stones sized between 6 and 20 mm in morbidly obese patients. MATERIALS AND METHODS: Using various aids, such as mobile overtable module, extended shock pathway and abdominal compression 37 patients with body mass index more than 40 kg/m2 were treated using the Siemens Lithostar-plus third generation lithotripter. The size of renal pelvicalyceal stones was between 6 and 20 mm. Treatment costs for shock wave lithotripsy were calculated. RESULTS: The overall stone free rate at 3 months of 73% was achieved. The mean number of treatments per patient was 2.1. The post-lithotripsy secondary procedures rate was 5.4%. No complications, such as subcapsular haematoma or acute pyelonephritis were recorded. The most effective (87% success rate) and cost-efficient treatment was in the patients with pelvic stones. The treatment of the patients with low caliceal stones was effective in 60% only. The cost of the treatment of the patients with low calyceal stones was in 1.8 times higher than in the patients with pelvic stones. CONCLUSION: We conclude that ESWL with the Siemens Lithostar-plus is the most effective and cost-efficient in morbidly obese patients with pelvic stones sized between 6 and 20 mm. 87% success rate was achieved. The increased distance from the skin surface to the stone in those patients does not decrease the success rate provided the stone is positioned in the focal point or within 3 cm of it on the extended shock pathway. ESWL should not be considered as the first line of treatment in the morbidly obese patients with low caliceal stones where the stone was positioned more than 1 cm from the focal point on the extended shock pathway