Development Of Renal Cell Tumors Research Articles

High risk of development of renal cell tumor in end-stage kidney disease: the role of microenvironment.

End-stage renal disease (ESRD) and acquired cystic renal disease (ACRD) are associated with high risk of development of renal cell tumors (RCT) displaying unusual phenotype and genotype. The underlying molecular mechanism is not yet known. To explore the molecular microenvironment, we have established the expression profile of ESRD/ACRD kidneys. RNA extracted from normal and ESRD/ACRD kidneys and distinct types of RCT was subjected to Affymetrix HG U133 micro array analysis. A gene expression signature indicated cancer-related biological processes in the remodeling of ESRD/ACRD kidneys. Quantitative RT-PCR studies confirmed a specific gene signature including a functional group of inflammatory cytokines and also cytokeratins associated with stem cell characteristics of epithelial cells. Several of the signature genes including the SCEL were expressed in ESRD/ACRD-associated papillary RCT as well. Immunohistological analysis confirmed the expression of CXCL8 and its receptor CXCR2 as well as the expression of SCEL in hyperplastic tubular, cystic, and papillary structures and RCTs in ESRD/ACRD kidney. Our data indicates that ESRD/ACRD is a novel disease and the inflammatory microenvironment altered plasticity, and stem cell characteristics of epithelial cells may be associated with the high risk of tumor development.

Promotion by sodium barbital induces early development but does not increase the multiplicity of hereditary renal tumors in Eker rats

Induced cell proliferation is important in the mode of action of many non-genotoxic renal carcinogens. Since Tsc2 mutant (Eker) rats are genetically predisposed to the development of renal cell tumors, they provide a useful animal model in which to study the action of renal carcinogens. Sodium barbital was used as a model non-genotoxic renal carcinogen to test whether a concentration that increased renal tubular proliferation without severe nephrotoxicity would enhance tumor induction in a hereditary tumor model. First, a subchronic concentration–response study was conducted in wild-type male Long-Evans rats to determine increased cell proliferation without severe nephrotoxicity. Rats were dosed with sodium barbital in the feed at 0, 50, 250, 500, 1000, 2000 or 4000 p.p.m. for 3 or 8 weeks. Cell proliferation within the cortex and nephrotoxicity were quantitated. Enhanced proliferation with minimal nephrotoxicity occurred at 500 p.p.m.. A second study was conducted in male Tsc2 mutant rats given sodium barbital in the feed at 0, 100 or 500 p.p.m. from 9 weeks of age to either 6 or 12 months of age. An additional group of rats was treated with sodium barbital for 6 months and then provided control feed until 12 months of age. Rats necropsied at 6 months of age had a concentration-dependent increase in preneoplastic and total renal lesions. Sodium barbital-treated rats necropsied at 12 months of age had numbers of lesions that were not different from controls. Total combined preneoplastic and neoplastic lesions in the 6 month, high dose group was the same as the 12 month control group. These data show that sodium barbital caused progression to the stage of spontaneous renal lesions in Tsc2 mutant rats but did not increase their overall number. These data suggest that enhanced cell proliferation without significant cytotoxicity exerted a promotional influence in this hereditary model.

Promotion by sodium barbital induces early development but does not increase the multiplicity of hereditary renal tumors in Eker rats

Induced cell proliferation is important in the mode of action of many non-genotoxic renal carcinogens. Since Tsc2 mutant (Eker) rats are genetically predisposed to the development of renal cell tumors, they provide a useful animal model in which to study the action of renal carcinogens. Sodium barbital was used as a model non-genotoxic renal carcinogen to test whether a concentration that increased renal tubular proliferation without severe nephrotoxicity would enhance tumor induction in a hereditary tumor model. First, a subchronic concentration-response study was conducted in wild-type male Long-Evans rats to determine increased cell proliferation without severe nephrotoxicity. Rats were dosed with sodium barbital in the feed at 0, 50, 250, 500, 1000, 2000 or 4000 p.p.m. for 3 or 8 weeks. Cell proliferation within the cortex and nephrotoxicity were quantitated. Enhanced proliferation with minimal nephrotoxicity occurred at 500 p.p.m. A second study was conducted in male Tsc2 mutant rats given sodium barbital in the feed at 0, 100 or 500 p.p.m. from 9 weeks of age to either 6 or 12 months of age. An additional group of rats was treated with sodium barbital for 6 months and then provided control feed until 12 months of age. Rats necropsied at 6 months of age had a concentration-dependent increase in preneoplastic and total renal lesions. Sodium barbital-treated rats necropsied at 12 months of age had numbers of lesions that were not different from controls. Total combined preneoplastic and neoplastic lesions in the 6 month, high dose group was the same as the 12 month control group. These data show that sodium barbital caused progression to the stage of spontaneous renal lesions in Tsc2 mutant rats but did not increase their overall number. These data suggest that enhanced cell proliferation without significant cytotoxicity exerted a promotional influence in this hereditary model.

The tcf17 gene at chromosome 5q is not involved in the development of conventional renal cell carcinoma.

The human Kid-1 homolog Tcf17 has been cloned and assigned to chromosome 5q35.3. Since the chromosome 5q22-qter region is duplicated in approximately 50% of conventional renal-cell carcinomas, it was suggested that Tcf17 is involved in the development of renal tumors. We have analyzed Tcf17 mRNA in normal kidneys and genetically distinct types of renal-cell tumor and found it expressed in nearly all normal kidney and tumor samples. There was no correlation between allelic duplication and expression of Tcf17. We did not find mutations within the coding sequences but did detect deletions within the zinc finger domain in a small proportion of RNA molecules in both normal and tumor tissues. We found ubiquitous expression of human Tcf17 as well as rat Kid-1 in different types of human and rat tissue, indicating that the putative transcription-regulating activity of this zinc finger gene, in contrast to the published data, is not restricted to the kidney. The results of expression and mutation analyses suggest that the Tcf17 gene is not involved in the development of renal-cell tumors.

Copper-nitrilotriacetate (Cu-NTA) is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen.

Earlier we have shown that ferric-nitrilotriacetate (Fe-NTA) is a hepatic as well as renal tumor promoter and acts by elaborating oxidative stress. In this study we show that copper-nitrilotriacetate (Cu-NTA) is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen. Similar to Fe-NTA, Cu-NTA has an ability to induce hepatic ornithine decarboxylase (ODC) activity dose-dependently. The maximum induction in hepatic ODC activity was observed 12 h after Cu-NTA treatment. However, renal ODC activity showed no significant changes at any time point and dose regimen studied. Similarly, hepatic and renal DNA synthesis which are measured as [3H]thymidine incorporation were increased dose-dependently in both the organs after Cu-NTA treatment. Unlike Fe-NTA, Cu-NTA administration had no significant effect on hepatic and renal glutathione, and on the activities of glutathione reductase, glutathione-S-transferase and catalase. In liver, saline-alone, DEN-alone, Cu-NTA-alone or DEN + Cu-NTA treated animals showed no hepatic tumors. Liver histology from only DEN-initiated and saline-treated control animals showed occasional appearance of a typical cell with large nucleus. Treatment of Cu-NTA to uninitiated and initiated animals showed more or less similar hepatic histology. Treatment of Cu-NTA to DEN-initiated animals resulted in the proliferative changes characterized by extensive hepatocellular hyperplasia. In case of kidney, the treatment of Cu-NTA to both the DEN-initiated and uninitiated animals led to the development of renal cell tumors. Treatment of Cu-NTA to the uninitiated animals produced renal cell tumors in about 18.7% animals. However, treatment of Cu-NTA to the DEN-initiated animals led to the development of renal cell tumors in 77.7% animals, of which most of the tumors were bilateral. However, DEN-initiated and saline-treated control animals showed no evidence of tumors. Our data indicate that Cu-NTA is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen.

Effect of polyphenon-60 on the development of renal cell tumors in rats treated with N-ethyl- N hydroxyethylnitrosamine

Green tea consumed as a beverage in Asia contains polyphenols, which contain about a 15% mixture of catechins. The present paper reports the effect of polyphenon-60 (60% pure catechin) on the development of renal cell neoplasms in Wistar rats pretreated with N-ethyl- N-hydroxyethylnitrosamine (EHEN): 0.1% polyphenon-60 in block diet was given over a period of 30 weeks while EHEN was given in drinking water for 2 weeks. The results appears to show a tendency for green tea catechins (GTC) to decrease the incidence of renal cell tumors greater than 3 mm in diameter in Wistar rats but not tumors that are less than 3 mm in diameter. Polyphenon-60 did not affect EHEN initiation in the kidneys of rats. It is postulated that free radicals induced by EHEN may be suppressed by GTC, resulting in a lowering of the tendency for tumor growth.

Estrogen treatment enhances hereditary renal tumor development in Eker rats.

Hormonal influences are known to affect the development of renal cell carcinoma in man and laboratory animal models. We tested the hypothesis that estrogen treatment or ovariectomy of rats modulates renal tumor development using tuberous sclerosis 2 (Tsc2) heterozygous mutant (Eker) rats in which a germline mutation predisposes the animals to renal cell tumor development. Two-month-old female wild-type and Eker rats were ovariectomized or sham-operated and treated with placebo or 5 mg 17beta-estradiol in s.c. pellets for 6 or 10 months. Rats were examined at 8 or 12 months of age, at which time the numbers of renal tumors and preneoplastic foci were quantitated and the severity of nephropathy was assessed. In contrast to what may have been expected, prolonged estrogen treatment enhanced the development of hereditary renal cell tumors, with a 2-fold greater number of preneoplastic and neoplastic renal lesions compared with untreated Eker rats. Ovariectomized Eker rats had 33% fewer renal lesions than the unmanipulated control group. No tumors or preneoplastic lesions were present in wild-type rats at either time point. Estrogen treatment increased the severity of nephropathy in both wild-type and Eker rats, whereas ovariectomy was protective against nephropathic changes. Although estrogen is not a rat renal carcinogen, it enhanced the development of hereditary renal cell tumors when administered to Eker rats. Eker rats heterozygous for a mutation in the Tsc2 locus provide a good model in which to study how genetic and hormonal factors contribute to the development of renal cell tumors and to understand the influence genetic susceptibility has on the development of renal cell carcinoma.

Altered expression of transforming growth factor-α: An early event in renal cell carcinoma development

Transforming growth factor-alpha (TGF-alpha) is a multifunctional cell regulatory protein with a wide range of effects on cell growth and differentiation and has been implicated in the neoplastic transformation of a variety of cell types. Altered expression of TGF-alpha and its cognate receptor (epidermal growth factor receptor) is enhanced in human and rat renal cell carcinomas. The objective of the study reported here was to determine whether altered TGF-alpha expression is an early or late event in renal tubular oncogenesis. The immunohistochemical expression of TGF-alpha was studied in preneoplastic renal tubular lesions in a rat model of hereditary renal cell carcinoma. Strong TGF-alpha immunoreactivity was present at all stages of renal cell tumor development, including the earliest detectable dysplasias. In contrast, the non-neoplastic regenerating tubular epithelium of rat degenerative nephropathy did not stain for TGF-alpha, although this tissue exhibited a proliferative capacity similar to that observed in the dysplastic and neoplastic lesions. This study indicated that altered TGF-alpha expression was detectable early in the development of renal cell tumors and may be an important feature of the transformed phenotype.

Inhibitory Effect of Potassium Citrate on Rat Renal Tumors Induced by N‐Ethyl‐N‐hydroxyethylnitrosamine Followed by Potassium Dibasic Phosphate

Potassium dibasic phosphate (PDP) was administered at a concentration of 10% by weight in basal diet to unilaterally nephrectomized Wistar rats previously given 1000 ppm N‐ethyl‐N‐hydroxyethyl‐nitrosamine (EHEN) in the diet for 2 weeks. To study the effect of alkalinization on renal mineralization, some animals concomitantly received 5% potassium citrate (PC). Feeding PDP alone promoted adenomatous hyperplasias, which were regarded as preneoplastic lesions, as well as renal cell tumors in EHEN‐initiated rats, whereas the addition of PC to PDP diets reduced the promoting effect. Histopathology, serum biochemistry and urinalysis indicated retardation of renal calcium crystallization by PC. Two other phosphate salts, sodium phosphate (SP) and calcium phosphate (CP), were also administered. SP showed a slight promoting effect on adenomatous hyperplasias and a 2‐fold increase in the yield of renal cell tumors, while CP induced a clear reduction of both lesions, over EHEN alone. The promoting effects of both PDP and SP and the inhibitory effect of PC were somewhat correlated to 5‐bromo‐2′‐deoxyuridine labeling indices, the degree of nephropathy, and mineralization in the kidney. Immunohistochemically, the nephropathy induced by phosphate salts was not linked to αzu‐globulin. A pathogenesis for renal carcinogenesis is suggested in which nephropathy associated with mineralization enhances the development of renal cell tumors.

Relationship between the duration of treatment and the incidence of renal cell tumors in male F344 rats administered potassium bromate.

In order to ascertain the minimum induction time, minimum treatment period and total dose required for development of renal cell tumors, KBrO3 at a concentration of 500 ppm was administered in the drinking water to a total of 232 male F344 rats divided into 14 experimental groups and the development of tumors was examined by two different approaches. In a continued-treatment study, administration of KBrO3 was stopped at week 13, 26, 39, 52 or 104 and rats were immediately sacrificed for comparison with controls given distilled water (DW) alone. Renal cell adenomas were found as early as after 26 weeks of treatment with KBrO3. The yields of dysplastic foci, adenomas and adenocarcinomas of the kidney, follicular cell tumors of the thyroid and mesotheliomas of the peritoneum increased with treatment, the final incidences all being statistically significant after administration of KBrO3 for 104 weeks. To examine the effect of discontinued treatment, on the other hand, the rats were given KBrO3 for the first 13, 26, 39 or 52 weeks and were subsequently maintained on DW alone until sacrifice at week 104. The incidences of tumors in these groups were compared with that of a group continuously administered KBrO3 for 104 weeks. The yields of renal dysplastic foci, adenomas and adenocarcinomas in all discontinued-treatment groups were approximately equal to or even higher than those in the group given KBrO3 continuously for 104 weeks. It is concluded that, under the conditions of this study: the minimum induction time for the development of renal adenomas was 26 weeks and the minimum treatment period and total dose for the induction of renal adenomas and adenocarcinomas were 13 weeks and 4 g/kg, respectively, when the rats were maintained thereafter on DW for 2 years.