β-Catenin and K-RAS Synergize to Form Primitive Renal Epithelial Tumors with Features of Epithelial Wilms' Tumors

Abstract

Wilms' tumor (WT) is the most common childhood renal cancer. Although mutations in known tumorassociated genes (WT1, WTX , and CATNB) occur only in a third of tumors, many tumors show evidence of activated ␤-catenin-dependent Wnt signaling, but the molecular mechanism by which this occurs is unknown. A key obstacle to understanding the pathogenesis of WT is the paucity of mouse models that recapitulate its features in humans. Herein, we describe a transgenic mouse model of primitive renal epithelial neoplasms that have high penetrance and mimic the epithelial component of human WT. Introduction of a stabilizing ␤-catenin mutation restricted to the kidney is sufficient to induce primitive renal epithelial tumors; however, when compounded with activation of K-RAS, the mice develop large, bilateral, Wilms' tumor (WT) is an embryonal tumor of the kidney that is the most common childhood renal cancer and the fourth most common childhood malignancy overall. 1,2Modern multimodal management can cure 95% of patients with WT with the most favorable risk profile 3-7 but at the cost of significant short-and long-term morbidity. -11In addition, there remains a persistent cohort of children who ultimately fail therapy and die.3 Consequently, the main research priorities for WT are to lower the toxicity while maintaining efficacy of existing therapy for lowerrisk patients and to develop novel therapeutics for higherrisk patients. Achieving these goals depends on understanding the mechanisms underlying WT oncogenesis and progression.WTs are triphasic, embryonic tumors that classically have varying amounts of blastemal elements, primitive mesenchymal stroma, and primitive epithelia. They are generally thought to arise from nephrogenic rests (ie, embryonic tissue) derived from the metanephric mesenchyme during renal development. The genetic aberrations underlying this process are known to be heterogeneous 12 and can include inactivating mutations of Wilms' tumor 1 gene (WT1), 13,14 Wilms' tumor gene found on chromosome X (WTX), [15][16][17] and stabilizing/activating mutations of ␤-catenin (CTNNB1). 18,19 The precise mechaSupported in part by NIH grants K08 CA113452 (P.E.C.), DK065123 (R.Z.), DK075594 (R.Z.), DK65123 (R.Z.), and P30 DK079341 (P.E.C. and R.Z.); an American Heart Association Established Investigator Award (R.Z.); and a Merit Award from the Department of Veterans Affairs (R.Z.).Accepted for publication August 10, 2011. CME Disclosure: None of the authors disclosed any relevant financial relationships.Address reprint requests to Peter E. Clark, M.D., Associate Professor Urologic Surgery, Vanderbilt University Medical Center, A-1302 Medical Center North, Nashville, TN 37232-2765. E-mail: peter.clark@ vanderbilt.edu.

Depletion of K-Ras promotes proteasome degradation of survivin

“…25 This study, coupled with our K-Ras depletion results, suggests that while mutant K-Ras and other genetic aberrations are required for increasing the levels of survivin, depletion of only K-Ras is able to decrease survivin. Therefore, K-Ras is necessary for the maintenance of survivin but not sufficient to increase survivin levels.…”

“…Consistent with our results, expression of mutant K-Ras in mouse kidneys in the Wilms tumor mouse model was not able to induce survivin. 25 Interestingly, in this model, expression of both mutant K-Ras and β-catenine levels was demonstrated in cancer cell lines from different tissue of origin. Therefore, our results suggest that the requirement of K-Ras expression for the maintenance of aberrantly high levels of survivin in human cancer cells depends on the mutation status of K-Ras but is not tissue-specific.…”

Hyperglycemia in the absence of cilia accelerates cystogenesis and induces renal damage

“…Primitive tubules are normally seen in the developing kidney or in pediatric diseases such as Wilms' tumors. There is evidence for the activation of ␤-catenin/Wnt signaling in Wilms' tumors (8), and it has been suggested that ␤-catenin/Wnt signaling is activated in PKD as well (22,32), although this is debatable, as it does not appear to be true in all models (26). In our studies we found increased EMT and Wnt signaling in hyperglycemic cilia Ϫ kidneys.…”

A Murine Model of K-RAS and β-Catenin Induced Renal Tumors Expresses High Levels of E2F1 and Resembles Human Wilms Tumor

“…All mice were bred and housed under an Institutional Animal Care and Use Committee approved protocol. Mice were crossed to obtain mice with genotypes γGT-Cre/Catnb +/lox(ex3) (referred to as Catnb Δex3 ), γGT-Cre/Kras +/G12D (referred to as Kras G12D ), γGT-Cre/Kras +/G12D /Catnb +/lox(ex3) (referred to as Kras G12D /Catnb Δex3 ) and litter-mate controls as previously described 11 . For the microarray experiment, mice were sacrificed at age 15–20 weeks and the kidneys flash frozen in liquid nitrogen.…”

“…We showed that constitutive restricted activation of the canonical Wnt/β-catenin pathway in murine renal tubular epithelial cells late in renal development is sufficient to induce small tumors with features of human WT 11 . Metastatic disease progression required the simultaneous addition of an activating mutation of the G-coupled protein/oncogene K-ras .…”