Role of Mast Cells in Tumor Biology
Stephen Galli's group attempts to understand how the development of mast cells is regulated, how these cells express their function, and what specific roles these cells play in health and disease. A special focus has been the development of genetic and cell-transfer models that can provide definitive information about the roles of mast cells in complex biological responses, such as asthma, tissue remodeling, carcinogenesis and tumor biology.
Highlights of this work include:
- the demonstration that essentially pure populations of mast cells can be generated from hematopoietic cells in vitro;
- development of the "mast cell knock-in mouse": genetically mast cell-deficient c- kit mutant mice that have been selectively repaired of their mast cell deficiency by the adoptive transfer of in vitro -derived mast cells---such mice represent the best currently available approach for defining precisely the contributions of mast cells to biological responses in vivo;
- development of methods to generate large numbers of mast cells directly from embryonic stem (ES) cells, and the demonstration that such ES cell-derived mast cells can be used to analyze mast cell development and function in vitro or, after transfer into mast cell-deficient mice, in vivo; and
- identification of mast cells as a source of both the cytokine TNF- a and many other interleukins, chemokines, and growth factors, including VEGF/VPF--this work established a "new class" of mast cell-associated biologically active products (many of which have been implicated in tumor biology), and greatly expanded our knowledge of the range of potential mast cell functions in health and disease.
Mast Cells and Gene Expression Patterns
One of Dr. Galli's current projects is to use genetic and gene-microarray-based approaches to define how mast cell activation, and subsequent production of mediators, cytokines and growth factors, drives "mast cell-associated" patterns of gene expression during biological responses associated with tissue remodeling (including angiogenesis, fibrosis and epithelial hyperplasia).
Mast Cells and Tumorigenesis
Another is to define why, in some models of tumorigenesis, mast cells contribute to this process. For example, the group has just discovered a model of carcinogen-induced intestinal adenoma formation in mice that appears to be largely mast cell-dependent, although the mechanisms by which mast cells influence this process remain to be defined.
However, in other settings, mast cells appear to contribute significantly to host resistance to the development or progression of tumors. Because few groups are investigating the roles of mast cells in tumorigenesis, tumor progression or host resistance to tumors, this avenue of investigation may well yield both new insights into the regulation of these process as well as new therapeutic targets for modulating the host response to tumors.
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