Fig. 2
From: Tumor-initiating and metastasis-initiating cells of clear-cell renal cell carcinoma
Adapted from Turajlic et al. [41] and Mitchell et al. [51]
Genomic landscape of ccRCC tumor initiation and metastatic subclonal evolution. Two broadly defined scenarios can account for the initiation and progression of ccRCC. The RSPCs, expressing stem/progenitor cell markers such as Notch or Wnt signaling and CD133 or CD105, first acquire 3p loss (encompassing the VHL tumor suppressor gene), and begin a slow clonal expansion lasting 5–20 years before the appearance of TICs when the second allele of VHL is inactivated, which leads to expression of inflammatory markers such as KIM-1 and HIF targets such as CXCR4. The appearance of TICs initiates subclonal evolution that can last 10–30 years, giving rise to various genetically distinct benign subclones, before the emergence of MICs, which is often accompanied by the 9p21.3 loss. In rare cases, TICs, and hence MICs, can arise from VHL+ cells. These are not included in this general description. Early appearance (i.e., close to or on the phylogenetic stem) of the metastatic subclone characterizes low primary tumor heterogeneity and rapid progression of the disease (left), and late appearance (i.e., after multiple subclonal branching events) of metastatic subclone characterizes high primary tumor heterogeneity and slow progression of the disease (right). RSPC: renal stem/progenitor cell; RSTC*: pre-tumorigenic RSTC; TIC: tumor-initiating cell; P: heterogeneous primary tumor subclones; MIC: metastasis-initiating cell; and M: metastatic subclone.