The Wnt signal transduction pathway in stem cells and cancer cells: influence on cellular invasion.
The regulative network conducting adult stem cells in endogenous tissue repair is of prime interest for understanding organ regeneration as well as preventing degenerative and malignant diseases. One major signal transduction pathway which is involved in the control of these (patho)physiological processes is the Wnt pathway. Recent results obtained in our laboratories showed for the first time that canonical Wnt signaling is critically involved in the control of the migration/invasion behaviour of human mesenchymal stem cells (hMSC). In the first part of this review, we describe that the regenerative state is closely linked to the activation of the Wnt pathway. Central hallmarks of activated stem cells are recapitulated in a similar way also in cancer metastasis, where the acquisition of an invasive cancer stem cell phenotype is associated with the induction of Wnt-mediated epithelial to mesenchymal transition (EMT). In the second part, the influence of proinflammatory cytokines such as transforming growth factor (TGF-)beta1, interleukin (Il-)1beta, and tumor necrosis factor (TNF-)alpha is discussed with regard to the invasive characteristics of hMSC. In this context, special attention has been paid on the role of matrix metalloproteinases (MMPs), such as MMP-2, MMP-9 and membrane type 1 (MT1)-MMP, as well as on the tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2. Putative cross-talks between different signal transduction pathways that may amplify the invasive capacity of this stem cell population are also discussed. Finally, the consequences towards future drug-mediated therapeutical modifications of Wnt signaling in stem cells and tumor cells are highlighted.
Neth
Peter
P
Department of Clinical Chemistry and Clinical Biochemistry, Ludwig-Maximilians-University of Munich, Munich, Germany. Peter.Neth@med.uni-muenchen.de
Ries
Christian
C
Karow
Marisa
M
Egea
Virginia
V
Ilmer
Matthias
M
Jochum
Marianne
M
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D049109:Cell Proliferation; D006801:Humans; D020782:Matrix Metalloproteinases / Q000502:physiology; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000209:etiology* / Q000473:pathology*; D010447:Peptide Hydrolases / Q000235:genetics / Q000502:physiology; D012038:Regeneration / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D010447:Peptide Hydrolases; D020782:Matrix Metalloproteinases