Sensitivity Of Normal, Paramalignant, And Malignant Human Urothelial Cells To Inhibitors Of The Epidermal Growth Factor Receptor Signaling Pathway

Main Category: Urology / Nephrology
Also Included In: Cancer / Oncology
Article Date: 16 Mar 2008 - 0:00 PDT

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UroToday.com - Starting from a well-established cell culture system of normal human urothelial cells (1,2), the epithelial cells that line the bladder, we used retroviral transduction to generate "designer" cell lines with specific molecular alterations. These "paramalignant" human urothelial cell sub-lines were engineered with the loss of p53 and/or p16 tumour suppressor protein function (3), which are key events in the development and progression of early-stage bladder cancer. Our aim was to identify any changes in cell phenotype, malignant potential or response to chemotherapeutic agents attributable to inactivation of p53 or p16. This was achieved by comparing paramalignant human urothelial cells to their normal counterparts under various experimental conditions (3,4), including after exposure to inhibitors of the epidermal growth factor receptor (EGFR) signalling pathway (4). This is of particular importance as components of the EGFR signalling pathway are frequently over-expressed in cancer, including bladder cancer, and therefore represent targets for the development of anti-cancer agents.

Although cells with disabled p53 function showed reduced sensitivity to an EGFR tyrosine kinase inhibitor (4), malignant cell lines were most resistant to inhibitors of EGFR and downstream mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling pathways, suggesting that urothelial cells acquire insensitivity to such inhibitors as a result of malignant transformation (4). Our results therefore highlight the importance and necessity of carefully assessing EGFR pathway inhibitors for the treatment of bladder cancer. However, our work also indicates that the same inhibitors could provide protection for normal urothelial cells if used in combination with conventional chemotherapeutics that target proliferating cells (4). Indeed, an alternative use for EGFR pathway inhibitors could be to suppress the regenerative response of normal urothelial cells before exposing the bladder to chemotherapeutic compounds designed to target proliferating cells. Combination treatments of EGFR pathway inhibitors and chemotherapy or radiotherapy may therefore enable better selective targeting of malignant cells, and may represent a more realistic treatment option for bladder cancer patients.

1.Southgate, J., Hutton, K. A., Thomas, D. F., and Trejdosiewicz, L. K. (1994) Lab Invest 71(4), 583-594

2.Southgate, J., Masters, J. R. W., and Trejdosiewicz, L. K. (2002) Culture of Human Urothelium. In: Freshney, R. I., and Freshney, M. G. (eds). Culture of Epithelial Cells, Second edition Ed., John Wiley & Sons, Inc., New York

3. Shaw, N. J., Georgopoulos, N. T., Southgate, J., and Trejdosiewicz, L. K. (2005) Int J Cancer 116(4), 634-639

4.Maclaine, N. J., Wood, M. D., Holder, J. C., Rees, R. W., and Southgate, J. (2008) Mol Cancer Res 6(1), 53-63

Written by J. Southgate, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations, etc., of their research by referencing the published abstract.

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