Alterations in phenotypic biochemical markers in bladder epithelium during tumorigenesis.

Abstract

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...

Molecular Mechanisms and Pathways in Bladder Cancer Development and Progression

“…EGFR expression as detected by immunohistochemistry correlates with increased grade and stage and with poor prognosis. 61 Abnormal EGFR expression is also found in cystoscopically normal-appearing urothelium in patients with TCCs elsewhere in the bladder, 62 thus supporting the notions of the existence of an urothelial field defect 63 and that abnormal EGFR expression may be an early event in BC tumorigenesis. Additionally, because ligands that work through EGFRs not only induce mitogenesis but also cellular motility, stimulation of EGFRs in malignant urothelium may encourage transepithelial motility and tumor invasion as well as proliferation.…”

Biomarker analysis on breast ductal lavage cells in women with and without breast cancer

“…With additional genetic or epigenetic events, it might lead to the development of cancers in the cancerization field. 19 Abnormal G-actin level is an early marker for malignant transformation in number of epithelial tumors including cancer of bladder, 10,11,14 prostate, 12 lung 20 and breast. 16 More importantly, abnormal G-actin in the adjacent, non-cancerous epithelial cells often predicts the risk of tumor development in bladder, 13 prostate 12 and breast [unpublished data].…”

“…[9][10][11] Alternations of G-actin represent a malignancy-associated field defect that can be detected in morphologically ''normal'' epithelium adjacent to the cancer. 12,13 Abnormal G-actin level was detected in almost 50% of ''normal'' urothelium distant to areas with actual bladder cancer, 14 and, more importantly, it predicted the risk for bladder cancer recurrence after the original tumor was removed by transuretheral resection. 13 DNA5cER, the percentage of cells with a DNA content of more than 5c, is a marker of overall genetic instability.…”

Biochemical analysis of a bladder-cancer-associated mucin: structural features and epitope characterization

“…Immunohistochemical studies have shown no reactivity with fetal or adult normal human tissues [3,4] and variable reactivities with a few prostatic, colonic, breast and endometrial cancers [4]. Measurement of this antigen was shown to be useful for the diagnosis [5,6] and prognosis [7][8][9] of bladder cancer. Preliminary studies showed reactivity of the M series mAbs with a very-high-molecular-mass component and also with a 62 kDa component in about half of the positive samples [3].…”