REGULATION OF MYELOMA CELL GROWTH BY SYNDECAN 1

University Of Arkansas Med Scis Ltl Rock, Little Rock AR

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Abstract

DESCRIPTION: (Applicant's Description) The long-term goal of this work is to develop cytostatic therapies that regulate the growth and progression of MM. Syndecan-1, a heparan sulfate proteoglycan, has therapeutic potential because it acts as a tumor suppressor in myeloma - it mediates tight cell adhesion, inhibits cell invasion, induces apoptosis and inhibits tumor cell growth. We hypothesize that syndecan-1 forms part of a beneficial regulatory loop that inhibits myeloma growth in vivo. The immediate goal is to determine how syndecan-1 regulates myeloma cell behavior and to examine the effect of syndecan-1 on myeloma pathobiology in vivo. Aim 1 will characterize the molecular components of syndecan-1 that mediate apoptosis and determine how syndecan-1 promotes myeloma cell death. Mutated syndecan-1 molecules, as well as other heparan sulfate-bearing proteoglycans and proteoglycan mimics will be tested for their ability to induce myeloma cell apoptosis. The regulatory effect of syndecan-1 on other pathways of myeloma apoptosis and survival will be examined (e.g., IL-6, IGF-I, Fas). In Aim 2, SCID mice containing human bone segments will be used to determine the effect of syndecan-1 on regulating myeloma cell growth and behavior within human marrow. Myeloma cells expressing various levels of syndecan-1 will be assessed and the effect of exogenous syndecan-1 and proteoglycan mimics on the behavior of cell lines and primary myeloma patient cells will be studied. Aim 3 will use differential display and DNA array technology to identify alterations in specific gene expression that occur immediately following syndecan-1-mediated myeloma cell adhesion. Once identified, the function of these differentially expressed genes will be examined. Execution of these specific aims, facilitated through interactions with other investigators within the program project, will provide new insight into the regulatory function of syndecan-1 in myeloma. Although syndecan-1 exerts tumor suppressive effects, they are obviously not sufficient to overcome the growth promoting effects of other mediators (e.g., IL-6) that produce the malignant phenotype in myeloma patients. However, exposure of tumor cells to exogenous syndecan-1 or proteoglycan mimics or upregulation of syndecan-1 expression may be sufficient to avert the malignant phenotype, thereby halting disease progression.