Autocrine growth stimulation in human bladder cancer

Abstract: Bladder cancer is one of the most common human cancers which, on a worldwide basis, represents 3-4 % of all malignancies. It is primarily occuring in people over 60 and males are about 2-3 times more likely to develop bladder cancer than are women. The formation of tumors is a multistep process in which the normal regulatory systems that govern cell proliferation and differentiation have been distorted or eliminated, which, in turn, leads to a selective growth advantage over the neighbouring normal cells. In vitro, this is reflected by that tumor cells are often less dependent on external growth factors to survive and proliferate than are their normal counterparts. This capacity to grow more or less autonomously has for several types of tumors been shown to depend on autocrine growth stimulation, i.e. the ability of cells to produce and respond to their own growth factors. In this thesis we have shown that this is a characteristic feature also of bladder tumors and we were able to identify the EGF-receptor and its ligands as being potentially responsible. This was demonstrated by the use of EGF-receptor-blocking antibodies as well as by neutralizing antibodies to the various ligands (EGF, TGFa, AR and HB-EGF) operating through this receptor. The observation supports and extends previous indications of this receptor/ligand system as being important for the development and progession of bladder tumors.During the course of the studies we could also demonstrate the production of a number of other cytokines by the tumor cells, several of which are known to be immunoregulatory (IL-1a/b, IL-6, IL-8, G-CSF, GM-CSF and TNFa/b). Although none of these appeared to affect tumor cell growth they could potentially act to modulate the natural or induced immune responses. To look at one potential mechanism behind the effective immunotherapy with BCG (Bacillus Calmette-Guerin) we analysed the effect on tumor cell growth of the three cytokines, IL-4, IL-10 and IFNg which all are likely to be induced in repsonse to the BCG-treatment. IL-4 and IL-10 were both inhibtory whereas IFNg either inhibited or stimulated growth depending on the cell line investigated. This shows that these factors may contribute to the positive effects of BCG treatment.The observations made in this study may contribute to a better understanding of the molecular background of bladder cancer as well as of the mechanism behind immunotherapy. This information will, hopefully, also have practical consequences for defining new or refined approaches to therapy and tumor diagnosis.