Cells of origin and cancer stem cells in cholangiocarcinoma

Many years of investigations and daily clinical practice suggest an alternative model of carcinogenesis where only a subset of cancer stem cells (CSCs) has the ability to proliferate extensively and form new tumours. Signalling pathways associated with oncogenesis, including the Notch, Sonic hedgehog and Wnt signalling play a major role in regulating stem cell self-renewal. Although the terms CSC and “cell-of-origin” have been used interchangeably, they are distinct concepts referring to cancer-initiating cells and cancer-propagating cells, respectively. The term “cell-of-origin” defines the normal cell that acquires the first cancer-promoting mutation(s); on the other side, the definition “cancer stem cell (CSC)” indicates the cellular subset within the tumour that uniquely sustains malignant growth. However, an unresolved question regarding liver cancers is which cell has to be considered as cell of origin. Recently, the study of the detailed immunohistochemical profile has revealed that a whole range of phenotypical traits of hepatocytes, cholangiocytes and progenitor cells can be seen in liver primitive tumors [hepatocarcinoma (HCC) and cholangiocarcinoma (CCA)] being consistent with an origin from the hepatic stem cell compartment within canals of Hering and the biliary tree stem cells located within peribiliary glands. In liver malignancies, a number of cell surface markers have proved useful for the isolation of subsets enriched for CSCs, including CD133 (Prominin-1), CD44, CD24, EpCAM, AFP, Thy-1 and ATP-binding cassette B5, as well as Hoechst33342 exclusion by the side population cells.