Experimental Models for the Sequential Analysis of Chemically-Induced Renal Carcinogenesis

Abstract

In order to discriminate non-specific toxicity from the early precursor lesions of neoplasia, emphasis in these studies has been on the use of models requiring only a single administration of chemical. Our interests have focussed on three neoplastic entities in the kidney, renal mesenchymal neoplasia, renal cell carcinoma, and nephroblastoma. Dimethylnitrosamine administered as a single intraperitoneal injection to immature female Wistar rats, pre-conditioned for several days with a no-protein/sugar-only diet, has been used for investigating the complex morphological nature of renal mesenchymal tumors, their pathogenesis and the development of cell culture correlates. The near 100% tumor incidence and its facility for cell culture manipulation makes this a particularly potent model for studying chemical carcinogenesis and the evolution of cell transformation. Discovery that the rat kidney response to DMN was biphasic with respect to the time of treatment led to the subsequent development of a high incidence system for inducing renal adenocarcinoma, using older rats. Renal cell carcinomas could also be induced in mice by a single intravenous injection of streptozotocin. The tumor frequency in female CBA/H/T6J mice was almost 100%, providing a new model for the investigation of renal carcinogenesis in this species. Nephroblastoma has been a poorly comprehended neoplasm in both lower animals and man because of the lack of a high incidence model in conventional laboratory mammals. Recently, we have exploited an increased spontaneous predisposition of the Nb rat to nephroblastoma using a single intraperitoneal dose of N-ethylnitrosourea in pregnant females on day 18 of gestation, producing a frequency of 50% for this tumor type. More potent however, was a system which utilized the partially inbred IIIVO/J strain of rabbit using the same carcinogen and transplacental route of administration. The resultant incidence of nephroblastomas in the progeny was in excess of 90%, and like their counterparts in man, the neoplasms developed rapidly and had a potential for distant metastasis. Each one of these animal models is suitable for the sequential tracing of tumor pathogenesis, and in depth analysis of the biochemical and molecular mechanisms involved in the initiation and formation of different types of renal cancer.

Spontaneous Occurrence of a Distinctive Renal Tubule Tumor Phenotype in Rat Carcinogenicity Studies Conducted by the National Toxicology Program

“…In this survey, there was no relationship of the specific tumor type to the severity grade of CPN. In cases of chemically induced carcinogenesis, such as with N-nitrosodimethylamine (Hard, 1984(Hard, , 1986, fumonisin B1 (Hard et al, 2001), and ochratoxin A (Hard, 2000), basophilic carcinomas have a significant tendency to metastasize to the lungs when tumor dimensions approximate 2 cm or more. Although some of the AV tumors in this survey were considered to be carcinomas, some larger than 2 cm diameter, secondary deposits were not found when the lungs were examined.…”

Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

“…Chemically induced experimental models of renal carcinogenesis are not uncommon and include rabbits (24), hamsters (34), and monkeys (3) as well as rats (14,21,22,39,42). Within the rat models, the 2 factors that appear to most heavily influence the type of neoplasm produced are chemical entity (16,21,22) and time of exposure (16,20,21 (20)(21)(22) whereas N-ethyl-Nnitrosourea (ENU) appears to be the best-documented chemical for the induction of nephroblastomas (21,22 (14).…”

“…Within the rat models, the 2 factors that appear to most heavily influence the type of neoplasm produced are chemical entity (16,21,22) and time of exposure (16,20,21 (20)(21)(22) whereas N-ethyl-Nnitrosourea (ENU) appears to be the best-documented chemical for the induction of nephroblastomas (21,22 (14). With respect to time of exposure, most methylating agents are poor transplacental carcinogens (16), but they are much more potent in the immature rat kidney (20)(21)(22). DMN exposure prior to 1 month of age induces predominantly RMTs whereas later exposure results in predominantly renal adenomas/carcinomas (20 as an animal model of human nephroblastoma (21,22).…”

A dominant mutation in the Wilms tumor gene WT1 cooperates with the viral oncogene E1A in transformation of primary kidney cells.

“…Our initial studies of WTI developmental expression were performed in the mouse (7), but the rat may provide a more useful system to study neoplastic transformation, since BRK cells have generally lower backgrounds in transformation assays than similarly derived mouse cells (data not shown). In addition, rats, unlike mice, can be induced to develop Wilms tumor-like nephroblastomas (18), suggesting oncogenic pathways analogous to those of the human disease.…”