Syndecan is a heparan sulfate-rich integral membrane proteoglycan. On simple epithelia a high molecular mass (160 kDa) form of syndecan acts to bind cells to extracellular matrix and binds to basic fibroblast growth factor. Syndecan is required to maintain epithelial morphology and the available data suggest that the loss of syndecan from epithelia promotes tumor formation and dissemination. Syndecan is also expressed on B lymphocytes, but its function on these cells is unknown. Its molecular mass (85 kDa) on B lymphocytes is considerably smaller than that of syndecan from simple epithelia. B lymphocytes regulate syndecan expression during their differentiation. Syndecan is found on pre-B lymphocytes in the bone marrow, absent on circulating B lymphocytes and retial matrices. Thus, syndecan is expressed only when suggesting that B lymphocytes differentiating their stage-specific adhesion. The broad, long term objective of the proposed research is to define syndecan function on myeloma cells. The hypothesis is that syndecan functions as a myeloma adhesion molecule and that changes in syndecan amount or molecular structure promote myeloma cell dissemination.
The specific aims are to: (i) define the role of syndecan in myeloma cell adhesion, (ii) assess the effect of IL-6, a potent myeloma growth factor, on syndecan expression, structure and function, (iii) determine if syndecan mediates myeloma localization and dissemination in vivo, and (iv) investigate syndecan expression on cells from patients with multiple myeloma. Syndecan function in adhesion will be assessed by measuring affinity of myeloma syndecan for matrix ligands using the affinity co-electrophoresis technique and in vitro cell binding assay. Myeloma cells grown in the presence of IL-6 will be analyzed for syndecan function and compared to cells growing without IL-6. To investigate syndecan function in myeloma cell localization and dissemination, cells will be made deficient in syndecan by antisense transfection, marked with the lac Z reporter gene, and intravenously injected into syngeneic hosts. Syndecan expression on cells in flood and bone marrow aspirates taken from myeloma patients will be examined by flow cytometry and polymerase chain reaction.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA055879-03
Application #
2096969
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1992-02-01
Project End
1997-01-30
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Kaushal, G P; Xiong, X; Athota, A B et al. (1999) Syndecan-1 expression suppresses the level of myeloma matrix metalloproteinase-9. Br J Haematol 104:365-73
Liu, W; Litwack, E D; Stanley, M J et al. (1998) Heparan sulfate proteoglycans as adhesive and anti-invasive molecules. Syndecans and glypican have distinct functions. J Biol Chem 273:22825-32
Stanley, M J; Liebersbach, B F; Liu, W et al. (1995) Heparan sulfate-mediated cell aggregation. Syndecans-1 and -4 mediate intercellular adhesion following their transfection into human B lymphoid cells. J Biol Chem 270:5077-83
Sanderson, R D; Turnbull, J E; Gallagher, J T et al. (1994) Fine structure of heparan sulfate regulates syndecan-1 function and cell behavior. J Biol Chem 269:13100-6
San Antonio, J D; Karnovsky, M J; Gay, S et al. (1994) Interactions of syndecan-1 and heparin with human collagens. Glycobiology 4:327-32
Sneed, T B; Stanley, D J; Young, L A et al. (1994) Interleukin-6 regulates expression of the syndecan-1 proteoglycan on B lymphoid cells. Cell Immunol 153:456-67
Liebersbach, B F; Sanderson, R D (1994) Expression of syndecan-1 inhibits cell invasion into type I collagen. J Biol Chem 269:20013-9
Ridley, R C; Xiao, H; Hata, H et al. (1993) Expression of syndecan regulates human myeloma plasma cell adhesion to type I collagen. Blood 81:767-74
Sanderson, R D; Sneed, T B; Young, L A et al. (1992) Adhesion of B lymphoid (MPC-11) cells to type I collagen is mediated by integral membrane proteoglycan, syndecan. J Immunol 148:3902-11