The mechanism by which CSC develop remains unclear[1]. Several studies have explored the role of dysregulation of the Wnt/β-catenin, transformation growth factor-beta (TGF-β) and hedhog pathways in generation of CSC[7-9]. In this review, we discuss the various molecular abnormalities that may be related to formation of CSC Paclitaxel structure in gastrointestinal malignancies, strategies to identify CSC and therapeutic strategies that are based on these concepts. MOLECULAR PATHWAYS

ASSOCIATED WITH CSCS IN GASTROINTESTINAL MALIGNANCIES Notch signaling pathway The Notch signaling pathway plays an important role in embryogenesis, cellular homeostasis-, differentiation and apoptosis[10-12]. While Notch mediates a number of biological processes through the “canonical “Notch signaling pathway, it also mediates a ligand- or transcription independent function known as the “non-canonical” pathway[12,13]. The canonical Notch pathway includes at least four Notch receptors (Notch 1-4) and five Notch ligands Delta-like 1,3 and 4 and Jagged 1 and 2[14]. When Notch ligand binds to a Notch

receptor, Notch will be cleaved through a series of proteolytic cleavages by multiple enzymes leading to release of the active Notch fragment and activation of Notch target genes[15]. Notch target genes include Akt, mTOR (mammalian target of rapamycin, NF-κB, c-Myc and VEGF (vascular endothelial growth factor) and cyclin D1[16,17]. Activation of the Notch pathway can have tumor suppressor function in HCC but may play on oncogenic role in colon and pancreatic cancers[14]. Notch signaling has been found to play a pivotal role in CSC. Overexpression of Notch-1 and -2 was observed in pancreatic CSC and was associated with increased expression of CSC surface markers such as CD44 and EpCAM[15,17-19]. This observation

suggests that Notch signaling may be involved in pancreatic CSC self-renewal but will need further confirmation. WNT/β-catenin pathway Notch signaling also perform a “non-canonical role” through antagonizing Wnt/β-catenin signaling[12,13]. Disrupted Wnt signaling is observed in a variety of gastrointestinal cancers which underscores its importance in carcinogenesis[20]. The Wnt pathway plays a crucial role in embryogenesis with signaling effects that regulate proliferation and apoptosis in developing cells[21]. Wnt pathway activation plays a fundamental role in maintenance of SC compartment and regulation of cellular differentiation[22]. The “canonical” Wnt pathway plays Batimastat a crucial role in modulating the balance between self-renewal and differentiation in several adult CSC[21]. The “canonical” Wnt pathway describes a sequence of events beginning with the translocation of β-catenin from the cell membrane into the nuclear, where β-catenin then acts as a co-activator of the TCF/LEF family of transcription factors[23,24]. The signaling cascade is typically initiated when Wnt ligand binds to Frizzled (FZD), a transmembrane receptor[23].