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12 - TGF-β signaling in stem cells and tumorigenesis
- from Part 2.1 - Molecular pathways underlying carcinogenesis: signal transduction
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- By Ying Li, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA, Ruth He, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA, Lopa Mishra, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA
- Edited by Edward P. Gelmann, Columbia University, New York, Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, New York, Frank J. Rauscher, III
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- Book:
- Molecular Oncology
- Published online:
- 05 February 2015
- Print publication:
- 19 December 2013, pp 119-134
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Summary
The transformation growth factor-β (TGF-β) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo, including cell growth, cell differentiation, apoptosis, cellular homeostasis, and other cellular functions, and deregulation of the pathway can result in tumor development. TGF-β signaling maintains tissue homeostasis and prevents tumorigenesis by regulating cellular proliferation, differentiation, survival, and micro-environment. Malignant cells can overcome the tumor-suppressive effects of TGF-β, usually through two different mechanisms. First, inactivation of core components of the pathway, demonstrated as frequent mutations of core proteins, results in loss of function in TGF-β signaling in many cancers. Second, downstream alterations that disable just the tumor-suppressor arm of the pathways, allow cancer cells to utilize the remainder of the TGF-β pathway for invasion and metastasis. Insight into the powerful TGF-β pathway in the context of type and stage of cancer, micro-environment, and alteration of other signaling transduction pathways within the cancer cells is crucial to decipher the role of TGF-β as tumor suppressor or promoter, followed by the development of anti-cancer therapeutics targeting TGF-β signaling.
Molecular mechanism of TGF-β signaling: ligands, receptors, and signaling molecules, the Smads
TGF-β represents a large family of pleiotrophic growth and differentiation factors that include activin/inhibins and bone morphogenetic proteins (BMPs) (1–3). These proteins mobilize a complex signaling network to control cell fate by regulating differentiation, proliferation, motility, adhesion, and apoptosis. TGF-β is represented by three isoforms, TGF-β1, -β2, and -β3, TGF-β is secreted as an inactive latent homodimeric polypeptide that is bound to other extra-cellular proteins (4–6). The mature, bioactive ligand is produced upon proteolytic cleavage of the latent complex. Binding of the active TGF-β dimer to the type I and II receptors results in the activation of type II (TβRII), which phosphorylates and activates type I (TβRI), then propagates the signals by phosphorylating Smad transcription factors (Figure 12.1). Smad proteins together comprise a unique signaling pathway with key roles in signal transduction by TGF-β. Currently, at least eight vertebrate Smads have been identified (1,7,8). They are characterized by homologous regions at their N- and C-termini known as Mad homology, MH-1 and MH-2 domains, respectively.
9 - TGF-β, Notch, and Wnt in normal and malignant stem cells: differentiating agents and epigenetic modulation
- from SECTION III - TARGETING CANCER STEM CELL PATHWAYS
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- By Stephen Byers, Michael Pishvaian, Lopa Mishra, Robert Glazer, Lombardi Comprehensive Cancer Center, Georgetown University
- Edited by William L. Farrar
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- Book:
- Cancer Stem Cells
- Published online:
- 15 December 2009
- Print publication:
- 24 August 2009, pp 139-162
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Summary
The notion that the growth and so-called aberrant differentiation of many tumors depend on the existence of a small population of cancer stem cells in much the same way that organogenesis and tissue replacement depend on normal stem cells is at the heart of contemporary investigations of neoplastic diseases. Not surprisingly, the same genetic and signaling pathways that are involved in normal stem cell renewal and specification are also important in tumorigenesis. These pathways include the Wnt/β-catenin, Notch, and TGF-β signaling systems, all of which have been reviewed recently. In this chapter, we will highlight areas that are either developing or have not been covered extensively in other reviews. For example, recent studies have highlighted a role for the RNA binding protein Musashi 1 (Msi1) in the regulation of normal and cancer stem cells through the Wnt and Notch pathways.
Notch and Wnt signaling also regulate and are regulated by asymmetric cell division, a defining stem cell characteristic that has received little attention in the cancer stem cell literature. Asymmetric cell division, which results in the segregation of damaged proteins into only one of the daughter cells, has also recently been linked to stem cell aging, a process that clearly differs between normal and cancer stem cells. The ability of carcinoma cells to take on characteristics typical of cells from quite different backgrounds is well established and almost certainly related to a pluripotent stem cell–like origin.