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Phenotypic biochemical markers of oncogenesis and differentiation were mapped in bladder biopsies to investigate changes that occur in bladder tumorigenesis and to identify markers for increased bladder cancer risk. Touch preparations from biopsy specimens from 30 patients were obtained from tumors, the adjacent bladder epithelium, and random distant bladder epithelium. Markers, including DNA ploidy, epidermal growth factor receptor (EGFR), and oncoproteins, were quantified in individual cells by using quantitative fluorescence image analysis. Cluster analysis revealed the markers fell into three independent groups: (0) G-actin and EGFR; (it) ploidy, cytology, and p185 (HER-2/neu oncoprotein) (ERBB2); and (iil) p300, a low-grade tumor antigen. Each marker displayed a gradient of abnormality from distant field to adjacent field to tumor. Different patterns for each marker suggested a developmental sequence of bladder cancer oncogenesis; G-actin was altered in 58% of distant biopsies (vs. 0/6 normals, P < 0.001), ploidy and cytology were altered in <20% of distant fields and =80% of tumors, and the other markers were intermediate. Patterns of EGFR and p185 suggest lowand high-grade tracks diverge early (P < 0.05 by MannWhitney U test for EGFR and ANOVA for p185). In conclusion, this study shows that a sequence of phenotypic changes accompanies development and progression of bladder cancers. Biochemical alterations in cells of the bladder field are often detectable before abnormal pathology, and markers previously thought to be limited to tumors were found in the field. The hierarchy of expression may be useful in identifying high-risk patients, assessing completeness of response to therapy, and monitoring and predicting recurrence.Decreasing future deaths from bladder cancer will require a strategy of prevention, based in part upon identification of individuals at risk for invasive metastatic disease well before it becomes symptomatic. Recognition that clinical cancer is the end-point of the underlying disease of carcinogenesis (1) suggests that appropriate intervention with individuals determined to be at risk could prevent development of lifethreatening disease.The concept of "field cancerization" or "field disease," introduced in 1953 (2), suggests that the whole field of tissue is exposed to carcinogen and is at increased risk for developing cancers, even though individual lesions are of clonal origin. The field disease theory as applied to bladder cancer has provided a central organizing theory for understanding these multifocal, frequently recurrent tumors (3-5). The normal bladder, or any other solid organ, represents a complex ecosystem ofinteracting epithelial and stromal cells, and years are required for the progressive subversion of growth and differentiation controls (6-8) to result in eventual emergence of cells capable of at least partial autonomousThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" i...

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Loss of PTEN expression has been associated with advanced stages of tumor. Tumor angiogenesis is involved in tumor progression. In breast cancer, a high frequency of mutations of the PTEN locus has been reported. However, the prognostic importance of PTEN expression and its correlation with angiogenesis in breast cancer have not been well established. Formalin-fixed, paraffin-embedded tissues from 99 women with a primary diagnosis of invasive ductal carcinoma were evaluated for PTEN expression by immunohistochemical methods. The microvessel density (MVD) was also studied by immunohistochemical labeling of endothelial cells with CD34 antibody. Computerized image analysis was used to evaluate MVD. Reduced PTEN expression was seen in 27.3% of invasive ductal carcinoma. The MVD ranged from 22.0 to 197.0, with a median value of 58.5 (65.4 +/- 27.9). Reduced PTEN expression correlated with lymph node status (P < 0.01), tumor grade (P < 0.05), and tumor-node-metastasis (TNM) stage (P < 0.05). There was a statistically significant correlation between reduced PTEN expression and increased MVD (P < 0.05). The mean MVD was higher in reduced PTEN-expressive tumors, irrespective of stage, compared with normal PTEN-expressive tumors with the same stage. On multivariate analysis, only TNM stage and reduced PTEN expression correlated with survival. Our results suggest that reduced PTEN expression may be an independent prognostic indicator in patients with invasive ductal carcinoma. PTEN loss may be associated with increased tumor angiogenesis.