Canonical WNT signaling activation leads to transcriptional up-regulation of FGF ligand, Notch ligand, noncanonical WNT ligand, WNT antagonist, TGFβ antagonist, and MYC. Non-canonical WNT signals inhibit canonical WNT signaling by using MAP3K7-NLK signaling cascade. Hedgehog up-regulates Notch ligand, WNT antagonist, BMP antagonists, and MYCN. TGFβ up-regulates non-canonical WNT ligand, CDK inhibitors, and NANOG, while BMP upregulates Hedgehog ligand. Based on these mutual regulations, WNT, FGF, Notch, Hedgehog, and TGFβ/BMP signaling cascades constitute the stem-cell signaling network, which plays a key role in the maintenance or homeostasis of pluripotent stem cells and cancer stem cells. Human embryonic stem cells (ESCs) are supported by FGF and TGFβ/Nodal/Activin signals, whereas mouse ESCs by LIF and canonical WNT signals. Combination of TGFβ inhibitor and canonical WNT activator alter the character of human induced pluripotent stem cells (iPSCs) from human ESC-like to mouse ESC-like. Fine-tuning of WNT, FGF, Notch, TGFβ/BMP, and Hedgehog signaling network by using small molecule compounds could open the door for regenerative medicine utilizing pluripotent stem cells without tumorigenic potential. Because FGF, Hedgehog, TGFβ, and non-canonical WNT signals synergistically induce EMT regulators, such as Snail (SNAI1), Slug (SNAI2), TWIST, and ZEB2 (SIP1), tumor-stromal interaction at the invasion front aids cancer stem cells to acquire more malignant phenotype. Cancer stem cells occur as mimetics of normal tissue stem cells based on germ-line variation, epigenetic change, and somatic mutation of stem-cell signaling components, and then acquire more malignant phenotype based on accumulation of additional epigenetic and genetic alterations, and tumor-stromal interaction at the invasion front.
Keywords: CXCR4, gastric cancer, GLI1, HES1, JAG2, pancreatic cancer, peritoneal dissemination, WNT2B, Pluripotent Stem Cells, Cancer Stem Cells, embryonic stem cells, TGF inhibitor, tumor-stromal interac-tion, fetal-tissue morphogenesis, adult-tissue, mammalian carcinogenesis, cysteine, single-trans-membrane-type, immunoglobulin-like domains, cytoplasmic tyrosine, serine, threonine, Patched (PTCH) recep-tors, Smoothened (SMO), endoplasmic reticulum, Porcupine, acyltransferase, palmitoleoylation, epidermal growth factor (EGF) repeats, Kringle domain, cytoplasmic tyrosine kinase domain, Secreted Frizzled-related protein, ligand-binding domain, Heparan sulfate proteoglycans (HSPGs), E-cadherin, phosphorylation, histone methyltransferase MLL, phosphol-ipase C (PLC), GTPase, Diaphanous-inhibitory domain, Formin-homology domain 1 (FH1), phosphatidylinositol diphosphate (PIP2), inositol triphosphate (IP3), Klotho-type co-receptors, non-mesoderm-derived hepatocytes, Notch signaling cascades, tissue-specific transcrip-tion factors, Noggin, NOG, Chordin (CHRD), Follistatin (FST), Gremlin (GREM1), HEDGEHOG SIGNALING CASCADES, Totipotent zygote