Fibronectin plays an important role in the extracellular matrix; it allows cells to attach to the matrix and it also influences both the growth and migration of cells. Normal fibroblasts in tissue culture secrete fibronectin and assemble it into a matrix that is essential to cell adhesion and growth. While many tumorigenic cells continue to produce fibronectin, they do not assemble the fibronectin into a matrix, and this lack of matrix assembly is thought to contribute to the invasive properties of malignant cells. Thus, one important stage in the progression of cancer may be the transition from assembly to nonassembly of the extracellular matrix, making it important to understand the mechanisms of fibronectin matrix assembly. Recent results from our laboratory and elsewhere suggest that integrin-induced fibronectin self- assembly is the key to matrix deposition. We have now found a fibronectin peptide that, when added to a fibronectin solution or to cell cultures, induces the formation of a fibrillar fibronectin matrix. The fibrillar fibronectin promotes cell attachment much more efficiently and in a qualitatively different manner than insolublized dimeric fibronectin; unlike dimeric fibronectin, it inhibits cell migration. The fibrillar fibronectin induced in vitro resembles the natural fibronectin matrix biochemically, and its biological properties may reflect those of tissue fibronectin matrices. The work proposed in this application builds on these observations and aims at the elucidation of the mechanisms of fibronectin matrix formation, analysis of the structure of the resulting fibronectin fibrils, and identification of the cell surface receptors that bind to fibrillar but not dimeric fibronectin. Finally, the role of fibronectin matrix in controlling the growth, migration, invasiveness and tumorigenicity of matrix-deficient tumorigenic cells will be assessed by modulating matrix deposition with matrix deposition-enhancing peptides. This work will lead to understanding of matrix assembly and its role as a determinant of the tumorigenic phenotype. It may also offer new possibilities for controlling tumor invasion and metastasis through manipulation of matrix deposition.
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