PTEN deficiency is fully penetrant for prostate adenocarcinoma in C57BL/6 mice via mTOR-dependent growth.

The tumor suppressor phosphatase and tensin homolog (PTEN) is frequently involved in human prostate carcinoma. PTEN is therefore an attractive target for the development of preclinical animal models. Prostate intraepithelial neoplasia lesions develop in mice with Pten heterozygosity, but disease progression has been reported only in combination with either other tumor suppressor gene alterations or the conditional inactivation of both Pten alleles in prostate epithelial cells. We report that on a C57BL/6 background, in contrast to previous studies on mixed 129 genetic backgrounds, Pten locus heterozygosity is fully penetrant for the development of prostate adenocarcinoma. Grossly observable tumors were detected at 6 months of age, and, by 10 to 12 months, 100% of examined mice developed adenocarcinoma of the anterior prostate. Furthermore, double heterozygotes carrying both Pten and Tsc2-null alleles showed no increase relative to Pten(+/-) heterozygotes in either lesion development or progression. Lesions in both Pten(+/-); Tsc2(+/-), and Pten(+/-) mice exhibited loss of PTEN expression and activation of PI3K signaling. PI3K activation occurred early in prostate intraepithelial neoplasia lesion formation in these animals, consistent with loss of PTEN function, and contributed to the etiology of tumors that developed in Pten(+/-) mice. Furthermore, prostate lesion growth in Pten(+/-) mice was dependent on mTOR, as evidenced by a reduction in both phospho-S6 levels and proliferative index after rapamycin treatment.

Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats.

PURPOSE: Transforming growth factor beta (TGF-beta), which generally stimulates the growth of mesenchymally derived cells but inhibits the growth of epithelial cells, has been proposed as a possible target for cancer therapy. However, concerns have been raised that whereas inhibition of TGF-beta signaling could be efficacious for lesions in which TGF-beta promotes tumor development and/or progression, systemic pharmacologic blockade of this signaling pathway could also promote the growth of epithelial lesions. EXPERIMENTAL DESIGN: We examined the effect of a TGF-beta inhibitor on mesenchymal (leiomyoma) and epithelial (renal cell carcinoma) tumors in Eker rats, which are genetically predisposed to develop these tumors with a high frequency. RESULTS: Blockade of TGF-beta signaling with the ALK5/type I TGF-beta R kinase inhibitor, SB-525334, was efficacious for uterine leiomyoma; significantly decreasing tumor incidence and multiplicity, and reducing the size of these mesenchymal tumors. However, SB-525334 was also mitogenic and antiapoptotic for epithelial cells in the kidney and exacerbated the growth of epithelial lesions present in the kidneys of these animals. CONCLUSION: Although pharmacologic inhibition of TGF-beta signaling with SB-525334 may be efficacious for mesenchymal tumors, inhibition of this signaling pathway seems to promote the development of epithelial tumors.

Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in Vhl knockout mice.

The von Hippel-Lindau (VHL) tumor suppressor gene plays a prominent role in the development of renal cell carcinoma (RCC) in humans. VHL functions as a ubiquitin E3 ligase, controlling the stability of hypoxia inducible factor (HIF) and tumor angiogenesis. Alterations in this tumor suppressor gene are rarely observed in spontaneous or chemically induced RCC that arise in conventional strains of rodents and Vhl knockout mice (Vhl+/-) do not develop spontaneous RCC. We tested whether Vhl knockout mice exhibited increased susceptibility to renal carcinogenesis using the well-characterized renal carcinogen streptozotocin. No differences were observed between wild-type and Vhl+/- animals in the frequency or type of renal lesions induced by 50-200 mg/kg streptozotocin. Carcinogen-induced RCC that developed in Vhl heterozygotes and wild-type mice did not contain mutations in the wild-type Vhl, as determined by direct sequencing of the primary tumors. While Vhl+/- mice exhibited no increase in renal lesions in response to streptozotocin, heterozygous animals did develop vascular proliferative lesions of the liver, uterus, ovary, spleen and heart. These lesions, ranging from angiectasis to hemangiosarcoma, were most prominent in the livers of Vhl+/- mice, where they were found in high incidence and high multiplicity. Wild-type mice developed a low-frequency of liver angiectasis (7-15%) only at the highest doses of carcinogen used (150 and 200 mg/kg, respectively) while Vhl+/- mice exhibited angiectasis, hemangioma and hemangiosarcomas with a frequency ranging from 19 to 46% at 50-200 mg/kg streptozotocin. Untreated Vhl+/- mice had a spontaneous incidence of hepatic vascular lesions of 21%. Furthermore, vascular lesions of the uterus, ovary, spleen and heart were observed only in Vhl+/- mice, with an incidence of (5-28%). Taken together, the data indicate that heterozygosity at the Vhl locus predisposes mice to a vascular phenotype ranging from angiectasis to hemangiosarcoma, consistent with the ability of this tumor suppressor gene to control the stability of HIF and regulate key proteins that participate in angiogenesis.