Survival outcomes in metastatic renal carcinoma based on histological subtypes: SEER database analysis.

381 Background: Renal cell cancer (RCC) represents a heterogeneous group of tumors with distinct histopathologic, genetic, and clinical features. This study was conducted to evaluate the prognostic value of histology in RCCs. Methods: 3,062 patients with metastatic RCC from year 1998-2007 were identified from Surveillance Epidemiology and End Results (SEER) database. Data regarding their age, sex, race, treatment modality utilized and cancer specific survival was extracted and analyzed. Results: Clear cell, sarcomatoid, adenocarcinoma NOS, papillary, collecting duct, chromophobe and cyst associated renal carcinoma accounted for 2,166 (70%), 433 (14%), 216 (7%), 160 (52%), 47 (1.5%), 35 (1.14%), and 5 (0.01%) respectively. The mean age of presentation was 63.5 in clear cell RCC and 62.7 years in non-clear cell RCC. Surgery was performed in 57.23% of all clear cell cancers and 50.84% in non-clear cell-RCC group. 27.34% of all clear cell cancer patients received radiation in contrast to 34.53% in the other group. Both clear cell RCC (64.54%) and non-clear cell RCC (69.52%) occurred commonly in males. Incidence of clear cell RCC was 4.67% in Asians, 7.01% in Blacks, 88.32% in Whites. The incidence of non-clear cell RCC was 3.81% in Asians, 14.78% in Blacks, and 81.41% in Whites. Cancer-specific survival was calculated in all histologic subtypes. Median survival for clear cell RCC was 8 months, 3 months for adenocarcinoma NOS, 7 months for cyst associated renal carcinoma, 8 months for papillary carcinoma, 7 months for chromophobe type, 4 months for sarcomatoid and 4 months for collecting duct RCC. Median overall survival was significantly better for clear cell cancer as compared to non-clear cell RCCs (8 months vs. 4 months; p< 0.0001). Conclusions: Non-clear histology RCCs represent 30% of metastatic RCC and are associated with poor prognosis when compared to clear cell RCC.While development of novel targeted therapies has improved survival in clear cell RCC, it has not made a impact in survival of non-clear RCCs. An indepth understanding of the genetic and molecular changes associated with non-clear cell RCCs is important to improve their prognosis. No significant financial relationships to disclose.

Bradykinin induces formation of vesicle-like structures containing vinculin and PtdIns(4,5)P2 in renal papillary collecting duct cells

Focal adhesions (FAs) are structures of cell attachment to the extracellular matrix. We previously demonstrated that the intrarenal hormone bradykinin (BK) induces the restructuring of FAs in papillary collecting duct cells by dissipation of vinculin, but not talin, from FAs through a mechanism that involves PLCβ activation, and that it also induces actin cytoskeleton reorganization. In the present study we investigated the mechanism by which BK induces the dissipation of vinculin-stained FAs in collecting duct cells. We found that BK induces the internalization of vinculin by a noncaveolar and independent pinocytic pathway and that at least a fraction of this protein is delivered to the recycling endosomal compartment, where it colocalizes with the transferrin receptor. Regarding the reassembly of vinculin-stained FAs, we found that BK induces the formation of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]-enriched vinculin-containing vesicles, which, by following a polarized exocytic route, transport vinculin to the site of FA assembly, an action that depends on actin filaments. The present study, which was carried out with cells that were not genetically manipulated, shows for the first time that BK induces the formation of vesicle-like structures containing vinculin and PtdIns(4,5)P2, which transport vinculin to the site of FA assembly. Therefore, the modulation of the formation of these vesicle-like structures could be a physiological mechanism through which the cell can reuse the BK-induced internalized vinculin to be delivered for newly forming FAs in renal papillary collecting duct cells.

Bradykinin modulates focal adhesions and induces stress fiber remodeling in renal papillary collecting duct cells

Focal adhesions (FAs) are specialized regions of cell attachment to the extracellular matrix. Previous works have suggested that bradykinin (BK) can modulate cell-matrix interaction. In the present study, we used a physiological cellular model to evaluate the potential role of BK in modulating FAs and stress fibers. We performed a quantitative morphometric analysis of FAs in primary cultured rat renal papillary collecting duct cells, which included size, axial ratio (shape), and average length. After 1, 5, or 10 min of incubation with BK, cultured cells were immunostained and analyzed by confocal microscopy. Although the shape of FAs was not altered, BK induced a decrease in the number of vinculin-stained FAs per cell, and a decrease in both their size and their average length, but not in talin-containing FAs, thus suggesting that BK could be inducing a restructuring of FAs. BK also induced a remodeling of the actin filament assemblies rather than their dissipation. Since we have previously demonstrated that BK stimulates activation of PLCβ in rat renal papillae, we attempted to determine whether BK can modulate FA restructuring by this mechanism, by pretreating cultured cells with the PLCβ inhibitor U73122. The present study, performed under physiological conditions with cells that were not genetically manipulated, provides new experimental evidence supporting the notion that the intrarenal hormone BK modulates FAs and actin cytoskeleton organization through a mechanism that involves the activation of PLCβ. We propose this finding as a novel mechanism for BK modulation of tubular collecting duct function.