Tsc2+/– mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background

Abstract

Tuberous sclerosis (TSC) is an autosomal dominant genetic disorder in which benign hamartomas develop in multiple organs, caused by mutations in either TSC1 or TSC2. We developed a murine model of Tsc2 disease using a gene targeting approach. Tsc2-null embryos die at embryonic days 9.5-12.5 from hepatic hypoplasia. Tsc2 heterozygotes display 100% incidence of multiple bilateral renal cystadenomas, 50% incidence of liver hemangiomas, and 32% incidence of lung adenomas by 15 months of age. Progression to renal carcinoma, fatal bleeding from the liver hemangiomas, and extremity angiosarcomas all occur at a rate of less than 10%. The renal cystadenomas develop from intercalated cells of the cortical collecting duct and uniformly express gelsolin at high levels, enabling detection of early neoplastic lesions. The tumor expression pattern of the mice is influenced by genetic background, with fewer large renal cystadenomas in the outbred Black Swiss background and more angiosarcomas in 129/SvJae chimeric mice. The slow growth of the tumors in the heterozygote mice matches the limited growth potential of the great majority of TSC hamartomas, and the influence of genetic background on phenotype correlates with the marked variability in expression of TSC seen in patients.

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

“…The Eker rat, which carries a germline mutation in the rat TSC2 homologue, develops renal cysts and carcinomas with an autosomal-dominant pattern of inheritance (27,28). Two groups have developed mice with targeted inactivation of TSC2 (29,30). Both mouse models develop renal carcinomas and cysts similar to those of the Eker rat.…”

Distribution of Tsc1 Protein Detected by Immunohistochemistry in Various Normal Rat Tissues and the Renal Carcinomas of Eker Rat: Detection of Limited Colocalization with Tsc1 and Tsc2 Gene Products In Vivo

“…In other organs such as the adrenals, brain, pituitary, small and large intestine, stomach, testis, and retina, the distributions of the two proteins overlapped, but were not identical. Tsc1 and Tsc2 are the genes responsible for human TSC and renal carcinogenesis in rodents (European chromosome 16 tuberous sclerosis consortium, 1993; Kobayashi et al, 1995Kobayashi et al, , 1999Onda et al, 1999;van Slegtenhorst et al, 1997), and binding between two proteins has been reported as the possible cooperative function (Plank et al, 1998;van Slegtenhorst et al, 1998). In terms of cell type specificity, the overlapped, but not identical expression profile between Tsc1 and Tsc2 suggest that Tsc1 protein does not always associate with Tsc2 in all organs and tissues.…”

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

“…While the hamartomas can grow in size to cause serious medical problems, they rarely become malignant; for example, only B2% of TSC patients develop malignant tumors, which tend to occur in the kidney (reviewed in Kwiatkowski, 2003). In mice, homozygous inactivation of either TSC1 or TSC2 results in embryonic lethality, while heterozygous inactivation predisposes the animals to tumorigenesis, consistent with these proteins providing tumor suppressor function in vivo (Onda et al, 1999;Kobayashi et al, 1999Kobayashi et al, , 2001; and reviewed in Kwiatkowski, 2003).…”