Then, to mimic development of human ccRCC from Wnt- and Notch-dependent stem cells, we have generated genetic mutants in mice, i.e. Wnt-β-catenin-GOF together with Notch-GOF or with Vhl-LOF, using an adult kidney tubular epithelium-specific Cre to circumvent embryonic or postnatal kidney defects and non-renal confounding influences. Here, VHL is linked to nonpapillary renal cell carcinoma.