Urinary bladder cancer is the fifth most common cancer in men in Western society and its incidence in the U.S. is more than 45,000 cases each year. This cancer manifest as 2 types: superficial and invasive. The majority of them are of the first type and are characterized by a high rate of recurrence following surgical resection. The second type of tumors are deeply invasive and associated with a grave prognosis. The goal of the study is to determine the cause of the high rate of recurrence and to determine the mechanism(s) responsible for malignant conversion of superficial tumors. We propose the following hypotheses: 1. rat urinary bladder exposed to a low dose of N-methyl-N-nitrosourea (MNU) induces 2 types of low-grade neoplastic lesions; type 1 lesions elicit angiogenesis in response to urinary growth-stimulating factors [principally epidermal growth factor (EGF)], type 2 lesions are nonangiogenic and remain small because of their failure to respond to EGF (or other exogenous growth factors); 2. additional mutations of key oncogene(s) [or suppressor gene(s)] are involved in malignant conversion of low-grade superficial carcinomas. The following specific aims will be pursued to test these hypotheses: 1. to determine the biological properties of the 2 types of lesion induced by MNU by ascertaining that type 1 lesions grow because they respond to EGF with cell proliferation and angiogenesis; and type 2 lesions fail to grow because they do not respond to EGF; 2. to isolate and characterize genes involved in malignant conversion; i) tumorigenic convertants will be induced in the near-normal bladder epithelial cell line (MYP3) by brief exposure in vitro the MNU. Specific chromosomal loss if found will be tested for the involvement of suppressor gene(s) by cell fusion study; ii) we will attempt to identify gene(s) involved in the malignant conversion by searching for suppressor gene(s) by transfecting a highly malignant carcinoma cell line (MYU3L) with a eukaryotic expression cDNA library from MYP3, and for oncogenes by transfecting MYP3 cells with a eukaryotic expression cDNA library of MYU3L. Transfectants with altered in vitro characteristics will be isolated and transgenes involved will be characterized; and 3. to examine an immunotoxin TGF-alpha-PE40 (transforming growth factor alpha fused to pseudomonas exotoxin whose action is mediated by EGF receptors) for chemoprevention and chemotherapeutic effects on bladder neoplasia. These experiments will be conducted in the heterotopically transplanted rat bladder established in syngeneic rats and athymic nude mice. Angiogenic responses will be assessed by immunohistochemistry and endothelial cell migration assay, and a stable mammalian cell expression cloning system will be used. These investigations should enhance our basic knowledge on bladder cancer development and progression and help to establish strategies to intervene bladder neoplasia.
| Bookland, E A; Swaminathan, S; Oyasu, R et al. (1992) Tumorigenic transformation and neoplastic progression of human uroepithelial cells after exposure in vitro to 4-aminobiphenyl or its metabolites. Cancer Res 52:1606-14 |
