These data suggest an important but contradictory role for TGF-β signaling in LSC-driven hepatocarcinogenesis, potentially

due to the interaction with other signaling pathways. A NEW CONCEPT UNDERLYING THE LCSC LINEAGE: VASCULAR ENDOTHELIAL TRANSDIFFERENTIATION Interestingly, CSCs can potentially transdifferentiate into cell common compound library types other than the original type from which the tumor arose. Several recent studies have shown that CSCs also can transdifferentiate into functional vascular endothelial cells that line the tumor vasculature, mediating tumor growth and metastasis[144-146]. In 2010, Wang et al[147] and Ricci-Vitiani et al[148] provided strong evidence that a proportion of the endothelial cells that contribute to blood vessels

in glioblastoma originate from the tumor itself, having differentiated from tumor stem-like cells. Wang et al[147] also demonstrated that blocking VEGF (vascular endothelial growth factor) or silencing VEGFR2 (VEGF receptor 2) inhibits the maturation of tumor endothelial progenitors into endothelium but not the transdifferentiation of tumor stem-like cells into endothelial progenitors, whereas γ-secretase inhibition or Notch1 silencing blocks the transition into endothelial progenitors. Subsequently, multiple studies have confirmed the presence of tumor-derived endothelial cells in several other malignancies, such as renal[149,150], ovarian[151], and breast cancers[152,153], which suggests that this is a general phenomenon in CSCs. Similarly, Marfels et al[154] found that chemoresistant hepatoma cells show increased pluripotent capacities and the ability to transdifferentiate into functional endothelial like cells both in vitro and in vivo. These tumor-derived endothelial cells possess increased angiogenesis and drug resistance capability (including chemotherapeutics and angiogenesis inhibitors) compared with normal endothelial cells[155,156]. Taken together, these data may provide new perspectives

on the biology of CSCs and reveal new insights into the mechanisms of resistance to anti-angiogenesis therapy. CONCLUSION Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in PLC with pivotal implications in the therapeutic perspectives. Although dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation AV-951 of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of LCSCs in PLC could result in the degeneration of downstream cells, making them potential targets for liver cancer therapies. Therefore, LSCs could represent a new target for therapeutic approaches to PLC in the near future. However, though LSCs have a bright future, their efficient therapeutic applications will demand further scientific advances.