Self Renewal Pluripotency Source for tissue engineering and cell replacement therapies Similar to cancer cells; stem cells thought to be derived from cancer stem cells Understanding stem cells is important for understanding cancer Adapted from System Biosciences (systembio.com) Background: Stem Cells
Background: Signaling Pathways Abnormalities in pathways may give rise to cancer stem cells and tumors Understanding the signaling pathways and identifying important factors helps to understand cancer transformation as well stem cell differentiation for tissue engineering and regenerative medicine applications
Transforming Growth Factor β TGF-β proteins and TGF-β related bone morphogenetic proteins (BMPs) are important regulators of stem cell differentiation, maintenance, and self-renewal, as well as carcinogenesis suppression. Comprised of 30 related proteins in the SMAD pathway
SMAD Signaling Pathway OCT3 OCT4 Nanog Adapted from Blank et al. (2008)
Stem Cell Differentiation Overview Adapted from Watabe et al. (2009)
SMAD Signaling Examples Nodal and activin cooperate with the WNT pathway to maintain ES cells and keep them undifferentiated and pluripotent. Activin and TGF-β confers mesodermal differentiation depending on amount. BMP signaling results in mesodermal and ectodermal differentiation in human ES cells. Nodal signals are important for OCT3/4 expression and maintenance of ES cells. Activin is important for maintenance of pluripotency, which is possibly done through induction of Nanog and OCT-4
TGF-β in Neural Stem Cells BMP inhibits neural differentiation TGF-β promotes differentiation in committed progenitors Inactivation of TGF-β growth- inhibitory functions result in tumor progression Adapted from Mishra et al. (2005).
TGF-β in other Cell Types Hematopoietic Stem cells – Inhibits early progenitors, while enhances differentiation of committed stem cells Mesenchymal Stem Cells – Inhibits differentiation and maturation into myoblasts, osteoblasts, and adipocytes, while stimulating MSC proliferation – Basis for efficient wound repair in mesenchymal tissue Gastrointestinal Epithelial Stem Cells – Inactivation with one TGF-β component (Receptor, SMAD protein) is present in all gastrointestinal cancer
WNT Signaling Pathway Adapted from Katoh et al. (2007).
WNT Signaling Pathway Cell fate determination Transformation of cancer stem cells due to disregulation
Notch Signaling Pathway Adapted from Bray et al. (2009).
Notch Signaling Pathway Promotion of neural cell differentiation Involved in self-renewal of hematopoietic stem cells
Hedgehog Signaling Pathway Adapted from Altaba et al. (2002).
Hedgehog Signaling Pathway Induces differentiation of hematopoietic progenitors and neural stem cells Skin, muscle, and brain cancers develop when pathway is maintained improperly in stem cells
FGF Signaling Pathway Adapted from Katoh et al. (2006)
FGF Signaling Pathway EMT Cell survival Proliferation/differentiation Cross-talk is seen between WNT and FGF via down-regulation of GSK3β, resulting in tumors with more malignant phenotypes of mammary carcinogenesis
TGF-β1 /WNT Pathway Cross-talk SMAD and TCF/LEF associate to cooperatively regulate genes Series of experiment by Jian et. al. (2006) show that TGF-β1 addition results in rapid nuclear accumulation of β-catenin in MSCs in a new form of cross-talk. β-catenin nuclear accumulation is not due to phosphorylation as from canonical WNT pathway Mediated by SMAD3/GSK3β disruption through TGF-β mediated phosphorylation.
TGF-β1 /WNT Pathway Cross-talk
WNT/FGF/Notch/SMAD/Hedgehog Cross-talk Balance of all signaling pathways is important for homeostasis and prevention of cancer and congenital diseases Notch family receptor Hedgehog pathway induced SMAD pathway Notch family receptor Hedgehog pathway
Conclusions Many signaling pathways with cross talk involved in stem cell proliferation, maintenance, and differentiation Dependent on differentiation stage, type of cell, local environment, and the identity and amount of particular ligand Identification of key regulators has potential for generation of iPS cells and cell replacement therapies
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