The long-term goal of this work is to define th role of cell surface proteoglycans in regulating the behavior of malignant cells. As a model for these studies, human myeloma cells are being used to test the hypothesis that expression of syndecan-1 inhibits tumor cell invasion and suppresses tumor cell growth. This hypothesis is supported by the following observation. The myeloma cell line ARCH-77 does not express syndecan-1 and these cells readily invade type I collagen matrices and have a high rate of tumor formation when injected into SCID mice. Following their transfection with a cDNA for syndecan 1, ARH-77 cell behavior is dramatically altered. The transfected cells that express syndecan 1, in contrast to their syndecan-1-negative counterparts, do not invade collagen matrices and do not form tumors readily when injected into SCID mice.
Aim 1 of the proposed research is to determine the molecular basis for the anti-invasive nature of syndecan-1. Mutated or chimeric syndecan-1 cDNAs will be transfected into invasive myeloma cells and cell behavior will be analyzed in adhesion and invasion assays. These studies will define which domains of th syndecan-1 core protein and which glycosaminoglycan attachment sites are required to promote the anti-invasive effect of syndecan-1. In addition, cells will be transfected with other syndecans, betaglycan, or glypican to determine if heparan sulfate proteoglycans other than syndecan-1 suppress the invasive phenotype.
Aim 2 will be to examine the tumorigenicity and metastatic potential of control and syndecan-1- expressing myeloma cells following their injection into SCID mice. Cells bearing mutated or chimeric syndecans, produced as part of aim 1, will be used to determine if the effects of syndecan-1 on cell behavior in vivo are mediated by its heparan sulfate chains and/or more protein. Cells bearing other syndecans, betaglycan or glypican will be tested to determine if the changes in behavior mediated by syndecan-1 are common to other cell surface heparan sulfate proteoglycans. Additionally, a panel of myeloma cell lines expressing different levels of syndecan-1 will be examined, as will melanoma cells, to determine if the initial finding that syndecan-1 is anti-tumorigenic is broadly applicable to different myeloma tumors and to tumors of distinct tissue origin. The proposed studies will provide insight into the regulatory roles of heparan sulfate proteoglycans and moreover, an understanding of how syndecan-1 controls tumor cell behavior may lead to new therapeutic strategies designed to prevent or halt the growth and metastatic spread of tumors.
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