Figure 2
Frequent oncogenic pathways involved in the malignant transformation of PC stem/progenitor cells and their progenies during PC progression and metastases. The activation of the EGFR, sonic hedgehog SHH/PTCH/GLI, Wnt/β-catenin, HA/CD44, TGFβ/TGFβR, ECM component/β1-integrin and SDF-1/CXCR4 signaling pathways, which may contribute to the sustained growth, survival and migration of PC stem/progenitor cells and their progenies and possible interactions between these signaling cascades, are shown. The activation of the downstream signaling elements including PI3K/Akt, mitogen-activated protein kinases, NF-κB and focal adhesion kinase (FAK), which in turn contribute to the upregulation of the expression of different target genes involved in the malignant transformation of PC stem/progenitor cells and their progenies during the EMT process and treatment resistance, are indicated. More specifically, the inhibition of p21CIP1 and p27KIPI inhibitors of cyclin-dependent kinases induced through these growth factor cascades may cooperate to promote the cell cycle progression and growth of PC cells, while the enhanced expression of antiapoptotic factors such as Bcl-2, Bcl-xL and inhibitor of apoptosis protein (IAP) and phosphorylation of Bad may promote their survival. In addition, the potential stimulation of HIFs via the activation of mTOR and under hypoxic conditions, which may contribute to the enhanced glycolysis and acquisition of a more malignant behavior and chemoresistance of PC cells and tumor angiogenesis, is also illustrated.