Alterations in antigen expression in superficial bladder cancer

Abstract

Bladder cancer can be viewed as a prototype for carcinogen-induced neoplasia. This has been demonstrated experimentally in a variety of systems and in man through epidemiological studies of occupational exposure to putative carcinogens. The natural history of this neoplasm demonstrates recurrence in time and space, i.e., multifocal disease. This clinical scenario is precisely what would be expected if a target tissue, e.g., urothelium, was continuously exposed to a weak carcinogen. The detection of gross disease is clinically easy. However, the ability to intervene at early stages and monitor the success of this treatment requires the definition of early markers for bladder cancer.lntegrins are a family of cell surface proteins, many of which function as receptors for extracellular matrix components.Normal epithelial cells express the integrin a6P4 in association with an anchoring structure known as the hemidesmosome. Urothelium expresses a6P4 on the basal layer of cells similar to the distribution seen on other epithelial surfaces. Even early stages of bladder cancer demonstrate an alteration in the expression of this integrin. Low-stage bladdertumors express asp4 diffusely throughout the tumor as well as at the invading margin. Altered expression of a6P4 may be an early marker for bladder cancer which may contribute to an invasive phenotype. A second potential marker is detected by DD23, an lgGl murine monoclonal antibody triggered by the immunization of a BALBk mousewith afresh human bladdertumor specimen. The antigen detected by DD23 is not present on normal urothelial specimens. It is expressed on 81 %of bladder tumors tested and is present on both low-grade, non-invasive and high-grade, invasive tumors. Although no normal bladder or ureteral tissues were DD23-positive, two of five histologically normal bladder areas from patients who had radical cystectomies for bladder cancer expressed the DD23 antigen. The significance of this finding has not yet been completely evaluated; however, it may represent an early neoplastic change prior to obvious histologic abnormality.Antigens associated with bladder cancer may be helpful in the early detection of bladder cancer and in providing markers useful in future chemoprevention trials. o 1992 Wiley-Liss, Inc. including cytology, flow cytometry, cystoscopy, and a variety of imaging techniques. However, the detection of sub-clinical changes has proved t o be a significant challenge.Cancer is manifested as alterations in the morphology and behavior of normal cells. At a sub-microscopic level, these changes are associated with modifications in cellular proteins and lipids. Some of these abnormally expressed cellular constituents have been used as tumor markers. One example of this phenomenon is the altered blood group antigen expression associated with bladder cancer cells [3]. We have focused our efforts on evaluating alter- ations in antigen expression in bladder cancer to determine how these changes result in the malignant phenotype. Our laboratory has develope...

Extracellular matrix and integrin composition of the normal bladder wall

“…The monoclonal antibody BQ16, raised against UM-UC9, a human bladder cell line, reacts with the c~6 integrin subunit of c~6~34, which is localized in a well-defined narrow bond just below the basal layer of normal bladder and ureteral urothelium [9]. The staining pattern was similar to that of UM-A9 raised to human squamous-cell carcinoma, which reacts with integrin 94, with the reaction of both antibodies in bladder cancer [8]. The intense reaction with the basal layer of the urothelium reported in normals is similar to that found in the current study (Fig.…”

Clinical significance of the integrin α6β4 in human malignancies

“…The integrin β4 is highly expressed in the basal cell layer in many benign epithelial tissues. During carcinoma progression, localization of the integrin α6β4 is altered, as has been described in tumors of the breast, bladder, cervix, and pancreas (72, 89, 91, 94, 95). It is likely that altered localization of the α6β4 integrin and its concurrent release from hemidesmosomes are as important in carcinoma progression as overexpression, thus altered integrin α6β4 localization should be studied carefully in these malignancies.…”

“…An early study reported that in normal urothelium integrin α6β4 is expressed in the basal layer of urothelial cells where this expression is highly polarized and localized to the lamina propria junction. The authors then examined integrin α6β4 expression in ten low stage bladder cancers, where they found increased, non-polarized expression in 80% of tumors (91). A subsequent study by the same group examined integrin α6β4 expression in bladder tumors from 57 patients; each case was categorized as having negative, weak, or strong expression of integrin α6β4, where weak was defined as expression that most closely resembled that of normal urothelium (92).…”

Use of Markers in Defining Urothelial Premalignant and Malignant Conditions

“…The monoclonal antibody DD23 (UroCor, Inc., Oklahoma City, OK, USA) binds to a protein dimer expressed on bladder cancer cells (13). Quantitative fluorescence image analysis has demonstrated that an increase in the expression of this protein on exfoliated cells can precede the clinical occurrence of bladder cancer by 2-5 months (14).…”