Michael Risk

A significant proportion of human prostate cancers carry a chromosomal rearrangement resulting in the overexpression of the ETS transcription factor, ERG; however, the functional significance of this event is poorly understood. We report here that up-regulation of ERG transcript is sufficient for the initiation of prostate neoplasia. In agreement with measurements of ERG transcripts, we found that ERG protein is expressed in neoplastic human prostate epithelium. Overexpression of ERG in prostate cell lines increased cell invasion. Moreover, targeted expression of this transcript in vivo in luminal prostate epithelial cells of transgenic mice results in initiation of prostate neoplasia observed as the development of focal precancerous prostatic intraepithelial neoplasia (PIN). Similar to human cancers, luminal epithelial cells in these PIN lesions displace diminishing in numbers basal epithelial cells and establish direct contact with the stromal cell compartment. Loss of basal cells is considered to be one of the critical hallmarks of human prostate cancer; however, the mechanisms responsible for this event were unknown. We propose that up-regulation of ERG in human prostate cancer activates cell invasion programs that subsequently displace basal cells by neoplastic epithelium. Our data demonstrate that ERG plays an important causal role in the transformation of prostate epithelium and should be considered as a target for prevention or early therapeutic intervention.

BACKGROUND: : Expression levels of mRNA and protein by cell types exhibit a range of correlations for different genes. In this study, we compared levels of mRNA abundance for several cluster designation (CD) genes determined by gene arrays using magnetic sorted and laser-capture microdissected human prostate cells with levels of expression of the respective CD proteins determined by immunohistochemical staining in the major cell types of the prostate - basal epithelial, luminal epithelial, stromal fibromuscular, and endothelial - and for prostate precursor/stem cells and prostate carcinoma cells. Immunohistochemical stains of prostate tissues from more than 50 patients were scored for informative CD antigen expression and compared with cell-type specific transcriptomes. RESULTS: : Concordance between gene and protein expression findings based on 'present' vs. 'absent' calls ranged from 46 to 68%. Correlation of expression levels was poor to moderate (Pearson correlations ranged from 0 to 0.63). Divergence between the two data types was most frequently seen for genes whose array signals exceeded background (> 50) but lacked immunoreactivity by immunostaining. This could be due to multiple factors, e.g. low levels of protein expression, technological sensitivities, sample processing, probe set definition or anatomical origin of tissue and actual biological differences between transcript and protein abundance. CONCLUSION: : Agreement between these two very different methodologies has great implications for their respective use in both molecular studies and clinical trials employing molecular biomarkers.

The identity of Na+/H+ exchanger (NHE) isoforms in the human small intestine and colon and their role in vectorial Na+ absorption are not known. The present studies were undertaken to examine the regional and vertical axis distribution of NHE-1, NHE-2, and NHE-3 mRNA in the human intestine. Ribonuclease protection assays were used to quantitate the levels of mRNA of these isoforms in various regions of the human intestine. In situ hybridization technique was used to localize NHE-2 and NHE-3 mRNA in the colon. The NHE-1 isoform message was present uniformly throughout the length of the human intestine. In contrast, mRNA levels for human NHE-2 and NHE-3 isoforms demonstrated significant regional differences. The NHE-3 abundance was found in decreasing order: ileum > jejunum > proximal colon = distal colon. The NHE-2 message level in the distal colon was significantly higher than in the proximal colon but was evenly distributed in the small intestine. In addition, NHE-2 mRNA was present in surface epithelial cells as well as in cells of the crypt region, suggesting the presence of NHE-2 message throughout the vertical axis of the colonic crypts. In contrast, NHE-3 mRNA was localized to surface colonocytes in the proximal colon. On the basis of this tissue-specific localization of NHE-2 and NHE-3 mRNA, it can be speculated that the relative contribution of NHE-2 and NHE-3 isoforms in Na+ absorption in the human intestine may be region specific, and these putative apical isoforms may be differentially regulated.

PURPOSE: Collecting duct renal cell carcinoma is a rare entity. Recent surgical series of the condition showed conflicting results. We used an American population based data set to compare the survival experience of patients with collecting duct vs clear cell renal cell carcinoma. MATERIALS AND METHODS: Cases of collecting duct and clear cell renal cell carcinoma were identified in the Surveillance, Epidemiology and End Results program (2001 to 2005). Demographic and pathological characteristics at diagnosis were compared. Differences in disease specific survival were compared with univariate and multivariate Cox regression analysis. RESULTS: A total of 160 collecting duct renal cell carcinoma cases were present in the database from 2001 to 2005. In that time 33,252 clear cell renal cell carcinoma cases were diagnosed. Collecting duct renal cell carcinoma was more common in black than in white patients (23% vs 9%, p <0.001). Collecting duct renal cell carcinoma was more commonly T3+ than T2/T1 (33% vs 18%, p <0.001) and metastatic than regional/local (28% vs 17%, p = 0.001). Nephrectomy rates were similar (84% and 78%, p = 0.06). The 3-year disease specific survival rate was 58% and 79% for collecting duct and clear cell renal cell carcinoma, respectively. On multivariate analysis there was an increased mortality risk in patients with collecting duct vs clear cell renal cell carcinoma (HR 2.42, 95% CI 1.72-3.39, p = 0.001). CONCLUSIONS: Compared to patients with clear cell renal cell carcinoma those with collecting duct renal cell carcinoma have higher stage and are more often black. Even after adjusting for demographic, surgical and pathological factors disease specific survival is significantly worse in patients with collecting duct rather than clear cell renal cell carcinoma. Further research into the biology of this rare tumor is required to explain these results.