Transforming growth factor beta (TGF-β) and inflammation in cancer
Section snippets
TGF-β dependent regulation of epithelial cell populations
TGF-β was initially described as a ligand that had the ability to promote or suppress cellular proliferation depending on the cell type and context of stimulation. In non-transformed or carcinoma-associated epithelial cells, TGF-β is well known for its ability to inhibit cell proliferation and promote an epithelial to mesenchymal transition (EMT) that has been associated with increased motility and invasiveness [56], [57]. In the years since discovery of TGF-β, an enormous volume of data has
Immature bone marrow derived cells promote invasion and metastasis
In many of the early studies, it was suggested that the loss of TGF-β signaling in carcinoma cells could lead to enhanced growth of primary tumors and metastases. However, it had also been suggested that TGF-β signaling was necessary for promoting an epithelial to mesenchymal transition that was thought to be essential for metastatic dissemination. This latter point was difficult to reconcile with data demonstrating that increased TGF-β signaling or complete abrogation of TGF-β signaling in
T-cells are significantly regulated by TGF-β
The impact of TGF-β signaling in the immune system is well documented. Importantly, TGF-β is present in the carcinoma extra-cellular matrix regardless of the carcinoma cell specific ability to bind the activated ligand. Further, in tumors where the carcinoma cells were unable to respond to TGF-β, recent results suggest that stromal TGF-β was more abundant [76]. Thus, in carcinomas where the carcinoma cell specific response to TGF-β is attenuated or ablated there remains an abundant supply of
TGF-β attenuates NK-cell associated tumor rejection
TGF-β inhibits NK cell and neutrophil effector functions and thereby contributes to a permissive microenvironment for tumor progression (Fig. 5B). In early studies, it was shown that TGF-β stimulation resulted in suppression of natural killer (NK) cell activity. in vivo, it was shown that growth of MDA-MB-231 mammary carcinomas and derivative metastases could be significantly reduced when systemic TGF-β inhibition was performed [107]. This effect was not observed in beige nude mice that were NK
TGF-β regulates monocyte and macrophage activity
Monocytes and macrophages have been studied in great detail with regard to their contribution to tumor progression. In general, the recruitment of monocytes and macrophages to the tumor microenvironment has been associated with enhanced tumor progression. TGF-β promotes recruitment of monocytes and it has been suggested that TGF-β can promote monocyte to macrophage differentiation [119], [120] (Fig. 5B). Early work suggested that in the case of macrophages that have the potential to be
Summary
The loss of TGF-β signaling in many common human carcinomas has been well documented [16]. Abundant literature dedicated to the impact of TGF-β signaling in non-transformed and carcinoma associated epithelium has focused primarily on the regulation of carcinoma cell behavior. Clearly the regulation of carcinoma cell survival, proliferation and epithelial to mesenchymal transition are significant factors that contribute to TGF-β mediated regulation of tumor progression. The current literature
Brian Bierie, Ph.D. performed his undergraduate work at Colorado State University in his home town of Fort Collins, Colorado. After finishing his undergraduate work he spent time working in the area of analytical chemistry for a large pesticide production plant. During this time he realized that some of the mutagens were so abundant in the soil and waste water produced by the production facilities that he began to think about dedicating his time to studies that could help people rather than
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Brian Bierie, Ph.D. performed his undergraduate work at Colorado State University in his home town of Fort Collins, Colorado. After finishing his undergraduate work he spent time working in the area of analytical chemistry for a large pesticide production plant. During this time he realized that some of the mutagens were so abundant in the soil and waste water produced by the production facilities that he began to think about dedicating his time to studies that could help people rather than contributing to the production of industrial mutagenic compounds. As a result, he switched to the study mammary gland biology and neoplasia mentored by Dr. Lothar Hennighausen, Ph.D. at the NIH in Bethesda, Maryland. After a three year tour at NIH he initiated his Ph.D. studies mentored by Dr. Harold L. Moses, M.D. at Vanderbilt University in Nashville, Tennessee. He received his Ph.D. in Cancer Biology and is now working as a postdoc mentored by Dr. Robert Weinberg, Ph.D. at the Whitehead Institute for Biomedical Research in Boston, Massachusetts.
Harold L. Moses, M.D. is the Hortense B. Ingram Professor of Molecular Oncology and Professor of Cancer Biology, Medicine and Pathology at Vanderbilt University School of Medicine. He was the founding director of the Vanderbilt-Ingram Cancer Center, which he led for twelve years; he is now director emeritus. Trained as a pathologist, he has devoted much of his career to basic research on growth factors and tumor suppressor genes, particularly in the TGF-β pathway, and has received many awards for his research. He has served as president of the American Association for Cancer Research, president of the Association of American Cancer Institutes, chair of the NIH Chemical Pathology Study Section, chair of the Molecular Oncogenesis Study Section, and chair of the National Cancer Institute Cancer Centers review panel. He is a member of the Institute of Medicine of the National Academies and currently chairs the National Cancer Policy Forum of the Institute of Medicine. He also currently co-chairs the Program Steering Committee for the NCI's Tumor Microenvironment Network.