Species- and cell type-specific requirements for cellular transformation

Recent evidence suggests that human cells require more genetic changes for neoplastic transformation than do their murine counterparts. However, a precise enumeration of these differences has never been undertaken. We have determined that perturbation of two signaling pathways—involving p53 and Raf—suffices for the tumorigenic conversion of normal murine fibroblasts, while perturbation of six pathways—involving p53, pRb, PP2A, telomerase, Raf, and Ral-GEFs—is needed for human fibroblasts. Cell type-specific differences also exist in the requirements for tumorigenic transformation: immortalized human fibroblasts require the activation of Raf and Ral-GEFs, human embryonic kidney cells require the activation of PI3K and Ral-GEFs, and human mammary epithelial cells require the activation of Raf, PI3K, and Ral-GEFs.