Microenvironment-Derived FGF-2 Stimulates Renal Cell Carcinoma Cell Proliferation through Modulation of p27Kip1: Implications for Spatial Niche Formation and Functional Intratumoral Heterogeneity.

BACKGROUND/OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is characterized by a high degree of functional intratumoral heterogeneity (ITH). This is highlighted by the finding that tumor cell proliferation and intracellular signaling occur preferentially in the tumor periphery. The driving forces for such a spatial organization are largely unknown. Herein, we investigate the role of the tumor microenvironment in the control of tumor cell proliferation and functional ITH. METHODS: Conditioned media (CM) derived from nonmalignant peritumoral kidney tissue were used to stimulate RCC cells in vitro. A neutralization assay was used to characterize the role of FGF-2 in the CM. The molecular mechanisms underlying the action of CM on RCC cells were investigated using immunoblotting, flow cytometry and immunofluorescence microscopy. Lastly, a series of ccRCCs were stained for Ki-67 and p27Kip1, and expression was analyzed in both tumor periphery and center. RESULTS: We show that CM derived from nonmalignant kidney cells adjacent to an RCC can downregulate the expression of the CDK inhibitor p27Kip1 through enhanced protein degradation in an FGF-2-dependent fashion. FGF-2 functions mainly through the PI3K/AKT pathway downstream of its receptors, and RCC cells with constitutively high AKT activity show not only an enhanced degradation of p27Kip1 through the Emi1-Skp2 axis, but also a subcellular mislocalization of p27Kip1 to the cytoplasmic compartment. Such a mislocalization was also detected in the tumor periphery in vivo suggesting that p27Kip1 plays an important role in shaping this spatial niche. CONCLUSIONS: Our results suggest that the tumor microenvironment is involved in shaping the tumor peripheral niche by stimulating the enhanced proliferation that is characteristic for this zone.

Diagnostic Accuracy of Transperineal MRI Fusion Biopsy in Comparison to Transrectal Biopsy with Regard to Incidental Histopathological Findings in Transurethral Resection of the Prostate.

OBJECTIVE: To investigate the diagnostic accuracy of transperineal MRI/transrectal ultrasound (TRUS) fusion prostate biopsy vs. transrectal prostate biopsy in transurethral resection (TUR) specimen of men undergoing TUR of the prostate (TURP) for symptomatic bladder outlet obstruction. MATERIAL AND METHODS: From a database of 3,509 men receiving prostate biopsy, all those undergoing TURP and negative prostate biopsy (n = 95; 45 transrectal, 50 transperineal fusion) were analysed. TURP specimens were compared with regard to incidental prostate cancer. RESULTS: Pre- and peri-interventional parameters in transrectal vs. fusion biopsy groups for age (65.2 ± 7.8 vs. 65.5 ± 7.3 years; p = 0.84), prostate specific antigen (10.7 ± 8.5 vs. 10.9 ± 8.7 ng/mL; p = 0.93), preoperative prostate volume (72.5 ± 26.1 vs. 71.8 ± 28.1 mL; p = 0.91) and resected weight (43.7 ± 21.9 vs. 41.4 ± 20.7 g; p = 0.61) showed no significant differences. Analysing the TURP specimen, 5 incidental T1a prostate cancers were found (3 Gleason 3 + 3 = 6; 2 Gleason 3 + 4 = 7, all in the transrectal biopsy group). Although, more biopsy cores were obtained in the MRI/TRUS fusion biopsy group (26 cores [interquartile range, IQR 24-28] vs. 14 cores [IQR 12-24], p < 0.01), there was no statistical impact of the obtained number of cores (p = 0.9) on diagnostic accuracy. Statistical analyses revealed significantly better diagnostic accuracy favoring image-guided fusion biopsy (p = 0.02). CONCLUSIONS: Our findings showed that a combination of MRI-targeted and systematic transperineal prostate biopsy improves patient safety. This is associated with a combination of transperineal biopsy technique and pre-interventional MRI.