Correlation between integrin alpha 5 expression and the malignant phenotype of transitional cell carcinoma

Abstract

Summary We examined the expression of al, a2, a3, a4, a5 and ,B1 integrin on 36 transitional cell cancers (TCCs) in the bladder by immunohistochemistry. Only a2, a3 and /31 were detected on normal transitional cell epithelium, but four TCCs (12.5%) revealed positive staining for al, seven (19.4%) for a4 and seven (20%) for a5. These altered expressions of integrin a chain were more frequent in histologically higher stage or grade of TCC, and a correlation was found between increased aS expression and histological stage. ae5 was positive in 6 (35.3%) of 17 invasive TCCs whereas only 1 (5.9%) of 17 superficial TCCs. Flow cytometric analysis on bladder cancer cell lines showed that T24 and HT1376, which are undifferentiated TCC cell lines, highly expressed aS and P1. Also, SCaBER, which is derived from urinary bladder squamous cell cancer and which is recognised as the most malignant phenotype after metaplasia of transitional epithelium, had aS and P1.However, RT4, which is derived from transitional cell papilloma, showed no expression of a5. Furthermore, reverse transcriptase-polymerase chain reaction (RT-PCR) showed the presence of mRNA of aS on T24, SCaBER and HT1376, but not on RT4. Taken together, it seems that the presence of axS integrin might be a more malignant phenotype in transitional cell carcinoma.Keywords: integrin; VLA-5; transitional cell cancer; immunohistochemistry; flow cytometry; reverse transcriptase-polymerase chain reactionIn the process of tumour invasion and metastasis, the interaction between tumour cells and extracellular matrix (ECM), such as laminin, fibronectin and collagens, has a crucial role (Nicolson and Winkelmake, 1975;Horn and Tang, 1992). This interaction is facilitated through adhesion receptors such as integrins. Integrins are a family of cellsurface proteins that mediate cell adhesion to ECM and signal transduction to the cell interior (Hynes, 1990;Albelda, 1993). They are composed of two subunits, a and ,B, each of which spans the plasma membrane. Distinct a-subunits combine with common or related fl-subunits to form functionally distinct receptors.Integrin distributions have been studied in a number of tissues, including malignant tumours. Recent studies showed that patterns of integrin expression on tumour cells were different compared with normal counterparts and suggested that altered integrin expression may contribute to the invasive or metastatic phenotype. For example, the loss of integrin expression was reported in epithelial neoplasms, such as carcinomas of the breast, colon, pancreas and skin (Pignatelli et al., 1990;Zutter et al., 1990;Hall et al., 1991;Stamp and Pignatelli, 1991). On the other hand, up-regulation of aV#3 was described in malignant melanoma and glioblastoma multiforme, and acquisition of a4#1 has been described in malignant melanoma and renal cell carcinoma (Cheresh et al., 1989;Gladson and Cheresh, 1991;Tomita et al., 1995). In transitional cell carcinoma (TCC), progressive loss of a2 integrin expression from normal urothelial cells through inv...

Overexpression of Betaig-h3 gene downregulates integrin α5β1 and suppresses tumorigenicity in radiation-induced tumorigenic human bronchial epithelial cells

“…In non-small lung carcinoma cells, higher levels of a5b1 expression represents a negative prognostic factor (Adachi et al, 2000). Similar results have also been shown with other human tissues that high levels of a5b1 integrin is associated with more malignant phenotype in melanoma, transitional and colon cell carcinomas (Saito et al, 1996;Gong et al, 1997;Beliveau et al, 2000). The a5b1 integrin favours cell survival and protects cells from apoptosis in vitro via upregulation of anti-apoptotic Bcl-2, whereas resistance to apoptosis is a feature of many malignant cells (Zhang et al, 1995).…”

“…There is evidence that osteosarcoma cells that overexpress integrin a5b1 show reduced invasive potential (Giancotti and Ruoslahti, 1990). In contrast, upregulation of a5b1 has been shown to correlate with invasive phenotype in colon cancer and transitional cell carcinoma (Saito et al, 1996;Gong et al, 1997). Similarly, recent data show that high levels of integrin a6 in breast cancer and avb3 in melanoma correlate with tumour progression (Mukhopadhyay et al, 1999;Hofmann et al, 2000).…”

Blocking integrin β1 decreases adhesion in chemoresistant urothelial cancer cell lines

“…It was reported that integrin α5 contributes to a more malignant phenotype in urothelial bladder cancer (22). In our study, this integrin subunit was overexpressed in most of the tested chemoresistant sublines what might underline the more malignant phenotype of the chemoresistant sublines (Fig.…”

Interaction of Fibronectin with Human Colon Adenocarcinoma Cells: Effect on the in vivo Tumorigenic Capacity

“…However, our results agree with those reported by other authors that have found comparable levels of α 5 and β 1 integrins in transformed human bronchial epithelial cells [34]and in different CT-26 colon carcinoma sublines showing different tumorigenic capacity [29]. In addition, it has been described that the expression of α 5 -integrin might be correlated with a more malignant phenotype [13, 14, 15, 35]. In our system, the cell surface levels of α 5 β 1 do not seem to be related with the tumorigenic potential.…”

“…Several reports have suggested that the expression levels of α 5 β 1 integrin inversely correlate with malignancy [9, 10, 11, 12]. However, a decrease in α 5 β 1 expression does not always parallel an increase in the malignant potential of carcinoma cells: (1) in transitional cell carcinoma, a direct correlation between α 5 β 1 integrin expression and a more malignant phenotype has been described [13]; (2) genetic studies in mice have shown that the loss of FN or α 5 β 1 integrin does not contribute to tumorigenesis [14]; (3) the overexpression of this integrin has been proposed as a significant predictive factor for a poor prognosis in node-negative patients with non-small-cell lung cancer [15]. In colon cancer cells, α 5 β 1 is either not expressed at all [16], or only poorly expressed compared to normal epithelial cells [7]; contradictory data regarding the expression of this integrin in HT 29 cells have been reported [10, 16].…”