ANAHEIM, CA (UroToday.com) - This session focused on basic investigation on novel molecular components contributing to the pathophysiology of bladder cancer and genes or gene products which are incompletely understood but may have potential as novel tumor markers. Cohen and associates looked at the role of inflammation as it relates to the mechanism of survivan, an inhibitor of apoptosis [ABST 758]. In vitro work demonstrated that lipopolyscacharide from e.coli ( a major inflammatory regulator) increases proliferation and survivan levels in bladder cancer cell line T24. These levels were reduced by COX2 inhibitors and other inhibitors of inflammatory pathways. These data add to the potential role of inflammation in the carcinogenesis pathway by suggesting that inflammation increases survivan levels and proliferation. Therefore cells are protected from cell death for a longer period of time while in the proliferative state.

Matsuyama and collegues reported on the significance of centrosome amplification in relation to other genomic abnormalities in non-invasive bladder cancer by the use of various immunostaining techniques [ABST 760]. In a panel of non invasive lesions, increased centrosome number was noted in almost 60 per cent of tumors. 16% of lesions with amplification demonstrated tumor progression over time while none of the lesions with out amplification progressed. Progression occurred only if centrosome amplification was present irrespective of the other genomic aberrations, suggesting that centrosome amplification is an early event for progression.

Smith,Oxford and Theodorescu demonstrated the importance of the Ral GTPase pathway in the development of human bladder cancer [ABST 764]. Transformation of human tissues to cancer by RAS activiation depends on the activity of these downstream mediators yet they have not been explored to this point with regard to their expression status in human tumors. RalA, Ral B and their effectors Filamin A and RalBP1 were analyzed. At the mRNA level Ral A is over expressed yet this is not the case with RalB. On the protein level however both were strongly expressed on the protein level. Their down stream effector molecules were similar expressed in a pattern that suggested a role for tumor progression thought this pathway. These data are a unique report of RAS pathway components being overexpressed in cancer and suggests possible therapeutic targets for bladder cancer.

Cunningham Karnes and Tarter reported on c-kit expression in bladder cancer through a microarray meta-analysis and validated these observations experimentally[ABST 766]. A general finding of c-kit amplification was noticed un up to 72% of bladder tumors and with a log 2 fold change in muscle invasive lesions. Approximately 10% demonstrated high levels of expression suggesting that currently available agents to inhibit this pathway in GIST tumors may be applicable to a subset of bladder cancer patients.

Schmidt and associates described the evaluation of disseminated tumor cells(DTC) in peripheral blood of bladder cancer patients. [ABST 768]. 35% of TUBT patients and 33% of patients in the cystectomy group contained DTC. This reduced to about 22% after definitive surgical treatment. Additionally DTC were noted in a significant proportion of patients with advanced disease in a chemotherapy cohort.

Kim and associates presented data on the finding of nuclear EGF receptor (EGFR) activity and the regulatory function of its transcription function [ABST 777]. In pathologic conditions EGFR can accumulate in the nucleus and may carry out functions distinct from those it is associated with at the cell membrane level. Investigation of the kinetics of nuclear accumulation and assays to evaluate associated proteins demonstrated that PIKfyve plays a role in trafficking EGFR to the nucleus and cullin-2 may be a mediator of proteasomal degradation during trafficking. These data suggest a pleoitropic role for EGFR which is overexpressed in bladder cancer, and also noted two other potential targets for bladder cancer therapy

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Written by S.Bruce Malkowicz, MD, a Contributing Editor with UroToday.

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