It was almost 25 years ago that the first studies emerged describing TGF-β and its complex role in transformation and later in tumor suppression as well. This followed earlier studies which described hematopoietic stem cells and their response to their microenvironment. Over the ensuing time, we have seen an unrelenting quest to identify and understand stem cells, their markers, their ‘niches’, their plasticity in differentiating across cell types, as well as their role in normal, regenerative and cancerous cells. The role of the TGF-β/Smad signaling pathway in renewal and differentiation of stem cells/progenitor cells and tumorigenesis is still being elucidated through current molecular tools and gene knockout technologies. This issue of Oncogene is dedicated to reviews on the topic of ‘The role of TGF-β in stem cells and carcinogenesis’. Various chapters will describe the role of TGF-β and related family members in stem cell biology and others will describe the role of TGF-β signaling pathways involved in its suppression, as well as progression of tumorigenesis, thereby pointing to novel targets for cancer therapy. Contributors have attempted to provide an overview of the developing concepts and controversies in the area of TGF-β in stem cell biology of both normal and cancerous tissues. Specifically, the reviewers refer to the role of TGF-β and other family members in: (1) self-renewal of embryonic stem (ES) cells, as well as tissue specific stem cells; (2) generation of stem cells with reference to tumor development; (3) concepts of the role of TGF-β family members in stem cell assays; (4) mechanisms controlling pathogenesis and survival of tumor stem cells; (5) regulation of tissue/progenitor cell specification, maintenance and expansion; (6) identification and localization of solid tumor stem cells and (7) roles of Smad signaling in fetal and adult (hematopoietic or other systems) stem cell homeostasis. We have chosen to review multiple systems and tissues because of their involvement in extensive studies of TGF-β signaling, which could potentially become a model for other fields of research. We hope that Oncogene readers will find these articles applicable to their own investigations.
ES cells provide an essential model to understand the role of TGF-β signaling in lineage specification and differentiation. In this issue, Gabriella Minchiotti addresses the role of Nodal, a member of the TGF-β superfamily, in Cripto signaling in ES cell differentiation, while David Salomon extends these studies to the role of Cripto in stem cell maintenance and tumorigenesis. Jeff Wrana demonstrates a disparate role of the BMPs, also members of the TGF-β superfamily, in renewal and differentiation of mouse and human ES cells compared to neural crest stem cells. The review by Stefan Karlsson addresses the complex role of the TGF-β signaling pathway in hematopoietic progenitor and stem cells through regulation of BMPs and cross talk with other regulatory signals such as Erk, JNK and p38 MAPK kinases. Francis Ruscetti extends these studies to the role of TGF-β signaling in myeloid and erythroid leukemia, while John Letterio reviews the role of the pathway in T-cell regulation focusing on lymphoid and epithelial neoplasia. Pier Paolo Pandolfi addresses deregulated TGF-β signaling in cancer pathogenesis, particularly in promyelocytic leukemia. To date, the best studied mammalian stem cells are in the bone marrow, intestine, skin and brain. Lopa Mishra gives an overview of Smad signaling in gastrointestinal stem cells, development and cancers. Bibhuti Mishra and Nady Golestaneh review emerging data on the TGF-β pathway in a few specialized regions of the brain restricted to neuronal growth. TGF-β plays a Jekyll and Hyde role in cell transformation and in epithelial to mesenchymal transition that is associated with tumor invasiveness and metastases as well as other diseases including fibrosis. Erwin Bottinger reviews the complexity of TGF-β signaling networks in epithelial to mesenchymal transition in development, tumorigenesis and fibrosis, while cross-talk mechanisms between TGF-β signaling and MAP kinases in normal physiology and cancer pathogenesis are reviewed in detail by Alain Mauviel. Overall, these reviews point to an increasingly complex and coherent view of stem/progenitor cell signaling networks, including signaling from TGF-β and other members of the superfamily. Furthermore, identification of signaling pathways whereby TGF-β coordinates cell growth, proliferation, stress management and survival is helping to define mechanisms of malignant progression and shows promise for the development of new and improved cancer therapies.
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