Network of WNT and other regulatory signaling cascades in pluripotent stem cells and cancer stem cells.
Canonical WNT signaling activation leads to transcriptional up-regulation of FGF ligand, Notch ligand, non-canonical 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 up-regulates 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.
Genetics and Cell Biology Section, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan. mkatoh-kkr@umin.ac.jp
Masaru
M
Katoh
D000818:Animals; D051157:Frizzled Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
D051157:Frizzled Receptors; D017468:Receptors, Fibroblast Growth Factor; D051880:Receptors, Notch; D051153:Wnt Proteins