This project's goal is to investigate the role of epidermal growth factor (EGF) and its receptor (EGF-R) in the induction and maintenance of urothelial malignancy and normal urothelial homeostasis. This would be accomplished by: 1) examining EGF- Rs on normal and malignant transitional epithelium; 2) assessing selected effects of EGF on normal and malignant urothelium; 3) quantitating the amount of EGF and transforming growth factor alpha (TGF-alpha) excreted in urine and produced by transitional carcinoma (TCC). Studies in our laboratory indicate that this is promising direction of investigation since, in vitro, normal human urothelium is far more refractory to effects of EGF than TCC is. Most work in this application will be performed in situ using surgically obtained tissue. Immunoperoxidase staining of normal urothelium and TCC with antihuman EGF-R monoclonal antibodies will be used to study EGF-R distribution. Autoradiographic techniques will be used to quantitate differential EGF-R expression. In situ preservation methods will be employed along with the above techniques to study receptor function and target response, including stimulation of DNA synthesis and ornithine decarboxylase activity (detected by radio-bioassay). In vitro studies on TCC cell lines and normal urothelial cultures will further assess differences in EGF responsiveness vis a vis polyamine metabolism and susceptibility to polyamine synthesis blockade. Changes in polyamine levels will be measured by high pressure liquid chromatography. Urinary and tissue concentration of EGF and/or TGF-alpha will be determined by radioimmunassay. The bladder's epithelium is in the unique position of being perpetually bathed by EGF, a potent mitogen excreted in urine in very high concentrations in a biologically active form. In addition, other EGF-like molecules, particularly TGF-alpha, are also found in urine and tumor tissue. The continual exposure to these substances may lead to continued stimulation of susceptible targets and eventually to their unrestricted growth. Thus study of the GF/urothelial-TCC interaction could help elucidate processes which induce and maintain TCC. Clinical applications await the studies outlined above, but include clarification of TCC's variable malignant behavior, and new approaches to staging, treatment and prevention of TCC.
| Messing, E M (1990) Clinical implications of the expression of epidermal growth factor receptors in human transitional cell carcinoma. Cancer Res 50:2530-7 |
| Messing, E M; Hanson, P; Reznikoff, C A (1988) Normal and malignant human urothelium: in vitro response to blockade of polyamine synthesis and interconversion. Cancer Res 48:357-61 |
| Messing, E M; Hanson, P; Ulrich, P et al. (1987) Epidermal growth factor--interactions with normal and malignant urothelium: in vivo and in situ studies. J Urol 138:1329-35 |
