VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail.

The product of the von Hippel-Lindau gene (VHL) acts as the substrate-recognition component of an E3 ubiquitin ligase complex that ubiquitylates the catalytic alpha subunit of hypoxia-inducible factor (HIF) for oxygen-dependent destruction. Although emerging evidence supports the notion that deregulated accumulation of HIF upon the loss of VHL is crucial for the development of clear-cell renal cell carcinoma (CC-RCC), the molecular events downstream of HIF governing renal oncogenesis remain unclear. Here, we show that the expression of a homophilic adhesion molecule, E-cadherin, a major constituent of epithelial cell junctions whose loss is associated with the progression of epithelial cancers, is significantly down-regulated in primary CC-RCC and CC-RCC cell lines devoid of VHL. Reintroduction of wild-type VHL in CC-RCC (VHL(-/-)) cells markedly reduced the expression of E2 box-dependent E-cadherin-specific transcriptional repressors Snail and SIP1 and concomitantly restored E-cadherin expression. RNA interference-mediated knockdown of HIFalpha in CC-RCC (VHL(-/-)) cells likewise increased E-cadherin expression, while functional hypoxia or expression of VHL mutants incapable of promoting HIFalpha degradation attenuated E-cadherin expression, correlating with the disengagement of RNA polymerase II from the endogenous E-cadherin promoter/gene. These findings reveal a critical HIF-dependent molecular pathway connecting VHL, an established "gatekeeper" of the renal epithelium, with a major epithelial tumor suppressor, E-cadherin.

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma.

The loss of functional von Hippel-Lindau (VHL) tumor suppressor gene is associated with the development of clear-cell renal cell carcinoma (CC-RCC). Recently, VHL was shown to promote the transcription of E-cadherin, an adhesion molecule whose expression is inversely correlated with the aggressive phenotype of numerous epithelial cancers. Here, we performed immunohistochemistry on CC-RCC tissue microarrays to determine the prognostic value of E-cadherin and VHL with respect to Fuhrman grade and clinical prognosis. Low Fuhrman grade and good prognosis associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumors associated with a lack of E-cadherin and lower frequency of VHL staining. A significant portion of CC-RCC with positive VHL immunostaining correlated with nuclear localization of C-terminally cleaved E-cadherin. DNA sequencing revealed in a majority of nuclear E-cadherin-positive CC-RCC, subtle point mutations, deletions and insertions in VHL. Furthermore, nuclear E-cadherin was not observed in chromophobe or papillary RCC, as well as matched normal kidney tissue. In addition, nuclear E-cadherin localization was recapitulated in CC-RCC xenografts devoid of functional VHL or reconstituted with synthetic mutant VHL grown in SCID mice. These findings provide the first evidence of aberrant nuclear localization of E-cadherin in CC-RCC harboring VHL mutations, and suggest potential prognostic value of VHL and E-cadherin in CC-RCC.

Effect of healthcare provider characteristics on nodal yield at radical cystectomy.

OBJECTIVES: Current evidence suggests that patient outcomes after radical cystectomy are dependent on nodal yield, even in cases of node-negative disease. We hypothesized that the final lymph node (LN) counts would be associated with the service provider (surgeon, pathologist) and the level of experience of the provider's assistant. METHODS: We reviewed a series of 89 consecutive patients who had undergone cystectomy from 2001 to 2005 for the effect of provider factors on LN counts. The effect of the surgeon was assessed on an individual basis and the effect of the pathologist was determined according to the uropathologic subspecialization. Provider assistant experience was classified according to the training level of the surgical assistant and the caseload volume of the pathology assistant. Multivariate linear regression analysis, controlling for patient factors, number of nodal packets, and margin status, was used to determine the provider factors associated with the final nodal counts. RESULTS: The median number of LNs harvested was 14 per patient. On univariate analyses, the individual surgeon and the number of nodal packets submitted were significantly associated with nodal yield (P <0.001 for both). Surgical margin status was also significant (P = 0.003), with fewer LNs collected from those with margin-positive disease. On multivariate linear regression analysis, only surgeon (P = 0.01) and number of packets (P < 0.001; with more LNs taken with more packets) remained statistically significant. CONCLUSIONS: The results of our study have shown that the nodal yield from radical cystectomy is dependent on surgeon-specific factors (the number of packets submitted and the operating surgeon). The patient or pathology service providers did not influence the ultimate LN counts.

Techniques, safety and accuracy of sampling of renal tumors by fine needle aspiration and core biopsy.

PURPOSE: The incidence of renal cell carcinoma is increasing worldwide and there are new treatments for localized as well as metastatic tumors. The traditional role for percutaneous biopsy of renal masses has been limited, and so there is little general experience. There have been concerns about safety and accuracy. This review provides an update on the current techniques, indications and accuracy of needle biopsy of renal tumors. MATERIALS AND METHODS: PubMed and MEDLINE were searched for English language reports of percutaneous needle core biopsy and fine needle aspiration of renal tumors that were published from 1977 to 2006. RESULTS: With the development of new biopsy techniques and wider experience with percutaneous probe ablation therapies the risk of tumor seeding appears negligible. Significant bleeding is unusual and almost always self-limiting. At centers with expertise needle core biopsy with or without fine needle aspiration appears to provide adequate specimens for an accurate diagnosis in more than 90% of renal masses. CONCLUSIONS: Percutaneous biopsy of renal masses appears to be safe and it carries minimal risk of tumor spread. Urologists should consider increasing the indications for renal biopsy of small renal masses that appear to be renal cell carcinoma, especially in elderly and unfit patients. With more experience and followup preoperative biopsy has the potential to decrease unnecessary treatment since up to a third of small renal masses are now reported to be benign at surgery. Percutaneous biopsy may also allow a better selection of renal tumors for active surveillance and minimally invasive ablative therapies. Finally, there is potential for stratifying initial therapy for metastatic renal cell carcinoma by histological subtype and in the future molecular characteristics.