The long-term objective of this competing grant is to understand the biology of perlecan, a multifunctional heparan sulfate proteoglycan with wide tissue distribution and functional activities, and to discern its precise role in tumorigenesis. The central hypothesis is that the aberrant expression of perlecan contributes to tumor promotion and invasion, a working theory based on several key observations: [a] Perlecan expression is elevated in the pericellular matrix of human colon cancer and melanomas, [b] Abundant deposition of this gene product occurs in and around the newly-formed tumor blood vessels, [c] Transformed cells with a high proliferative index overproduce perlecan, [d] Perlecan is directly involved in the storing of angiogenic growth factors, [e] Perlecan protein core binds FGF7 and modulates its mitogenic activity, and [f] Perlecan protein core interacts with FGF- binding protein (FGF-BP), a protein that is also implicated in tumor formation and angiogenesis. The last two discoveries were made in the P.I.'s laboratory under the auspices of this grant and indicate that various modules of perlecan may act synergistically with biologically active proteins in modulating tumor growth. Over the next five years we plan to: (1) Investigate the role of perlecan in tumorigenesis by testing the behavior of cancer cells with abrogated or induced expression of perlecan in syngeneic hosts, (2) Investigate in depth the interaction between perlecan and FGF-BP, and (3) Identify cell surface proteins interacting with perlecan using expression cloning and the yeast two hybrid system. These concerted research lines will provide information, not only on the functional roles of mammalian perlecan in tumorigenesis, but will also identify novel biological partners that could directly affect perlecan's functions. The expected results could lead to future approaches of cancer prevention and treatment directed at hindering the expression of this proteoglycan thereby depriving the tumor cells of an essential macromolecule.
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