ys the scaffold protein axin, a crucial component of the ??catenin destruction Bafetinib INNO-406 complex. Furthermore, antibody based thera peutic approaches targeting EpCAM are currently being developed. EpCAM directed thera pies will be efficacious in eradicating Ep CAM expressing CSCs. The Hedgehog pathway is another potentially druggable target for CSC eradication. Several small molecule modulators of Sonic hedgehog sig naling have been used to regulate the activity of this pathway in medulloblastoma, basal cell carcinoma, pancreatic cancer, prostate cancer and developmental disorders. In liver cells, suppression of the Sonic Hedgehog pathway by siRNA not only decreased HCC cell proliferation but also chemosensitized the cells to 5 fluorouracil and to the induction of cell apoptosis.
Furthermore, in hepatoblastoma, blocking Hh signaling with the antagonist cyclopa mine SKI-606 had a strong inhibitory effect on cell prolifera tion of hepatoblastoma cell lines. Thus, targeting intracellular pathways associated with self renewal of CSCs remains a viable approach to be extended in the near future. Anti Tumor growth and inducing tumor cell differentia tion PTEN plays a role in the expansion of the CD133 liver CSC population in liver specific PTEN deleted mice, which supports PTEN as a promising target in HCC therapy. In addition, TGF ??family proteins have also emerged as key players in promoting the growth of stem cells in their undifferentiated state. A recent investigation revealed normal hepatic stem cells committing to malignant transformation due to aberrant TGF ??and activated IL 6 signaling.
Therefore, inhibition of IL 6 signaling may be a potential therapeutic strategy in liver cancer treatment. CSC cells, which only make up a small propor tion in cancer, have the capability to sustain tumor growth and are more resistant to conventional chem otherapy than other differentiated cancer cells. One approach to treat malignancies is to induce differen tiation of the CSC cells. Differentiation therapy could force hepatoma cells to differentiate and lose their self renewal property. Hepatocyte nuclear factor 4?? a central regulator of differentiated hepatocyte phenotype, suppresses a tumorigenesis and tumor development by inducing HCC differenti ation, especially CSC cells. Interferon therapy is effective for eradicating hepatitis viruses and also preventing the development of HCC.
Interferon alpha treatment accelerated hepatocytic and biliary differ entiation in oval cell lines. Interferon could be applied to the treatment of HCC by targeting CSCs. In addition, oncostatin M, an interleukin 6 related cytokine known to induce differentiation of hepatoblasts into hepatocytes, could be used to effec tively induce differentiation and cell division of dormant EpCAM liver CSCs, and the combination of OSM and conventional chemotherapy with 5 FU effi ciently eliminates HCC by targeting both CSCs and non CSCs. These findings indicate that combi nation of differentiation therapy an