Fig. 1

An alternative model of the origin of ccRCC. Two mechanisms are proposed to explain the origin of CSCs: either they are mutated stem cells (left) or dedifferentiated mutant cells (right). The former suggests that CSCs originate from adult stem cells that accumulate mutations. In the latter theory, cellular changes and microenvironmental factors can transform differentiated cells into malignant, dedifferentiated cells. The development of ccRCC is likely a hybrid model (shaded pathway on the left), in which normal stem cells with 2 hits in the VHL gene, one of which involves chromosome 3p loss, become TICs. The TICs then undergo subclonal evolution to generate metastatic subclone, which constitutes MICs