Tumor-initiating and metastasis-initiating cells of clear-cell renal cell carcinoma

Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of kidney malignancy. ccRCC is considered a major health concern worldwide because its numbers of incidences and deaths continue to rise and are predicted to continue rising in the foreseeable future. Therefore new strategy for early diagnosis and therapeutics for this disease is urgently needed. The discovery of cancer stem cells (CSCs) offers hope for early cancer detection and treatment. However, there has been no definitive identification of these cancer progenitors for ccRCC. A majority of ccRCC is characterized by the loss of the von Hippel-Lindau (VHL) tumor suppressor gene function. Recent advances in genome analyses of ccRCC indicate that in ccRCC, tumor-initiating cells (TICs) and metastasis-initiating cells (MICs) are two distinct groups of progenitors. MICs result from various genetic changes during subclonal evolution, while TICs reside in the stem of the ccRCC phylogenetic tree of clonal development. TICs likely originate from kidney tubule progenitor cells bearing VHL gene inactivation, including chromatin 3p loss. Recent studies also point to the importance of microenvironment reconstituted by the VHL-deficient kidney tubule cells in promoting ccRCC initiation and progression. These understandings should help define the progenitors of ccRCC and facilitate early detection and treatment of this disease.