The long-term objective of this work is to determine how heparan sulfate proteoglycans on the cell surface regulate tumor cell behavior and to use this knowledge for developing novel therapies for cancer. Myeloma cells have been used as a model to demonstrate that expression of syndecan-1 has a dramatic impact on tumor cell behavior by promoting cell-cell and cell-matrix adhesion, inhibiting cell invasion, suppressing cell growth and inducing apoptosis. Together, these data indicate that syndecan-1 acts as a powerful tumor suppressor. Three striking new discoveries made during the previous funding period support the hypothesis that syndecan-1 function on tumor cells is tightly regulated by interactions with other effector molecules. The immediate goal is to identify these molecules and to determine how they regulate syndecan-1 function. This will be accomplished through three specific aims.
Aim 1. Studies using mutated and chimeric proteoglycans expressed in tumor cells indicate that a region of the ectodomain core protein of syndecan-1 interacts with other cell surface molecules (co-anchors) to promote the inhibition of cell invasion and cell spreading. The region of the core protein mediating these interactions will be determined, the co-anchor molecules isolated and characterized, and their role in regulating syndecan-1 function explored.
Aim 2. Recent work demonstrates that syndecan-1 localizes specifically to the uropod (training edge) of polarized myeloma cells and that this targeting is dependent on the presence of both heparan sulfate chains and the cytoplasmic domain of syndecan-1. This model will be exploited to examine the molecular interactions that link syndecan-1 to the cytoskeleton and to determine how heparan sulfate located on the cell surface can regulate targeting.
Aim 3. In direct contrast to cell surface syndecan-1 which inhibits cell invasion, new studies show that soluble syndecan-1 promotes cell invasion. Thus, enzymatic remodeling of syndecan-1 may have a dramatic impact on tumor cell behavior by shifting syndecan-1 from an inhibitor of metastasis to a promoter of metastasis. Studies will characterize the effects on tumor cells resulting from proteolytic shedding of syndecan-1 and from the degradation of heparan sulfate chains by heparanase. Insight gained from these studies will be used to design new therapeutic strategies aimed at halting tumor growth and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068494-07
Application #
6512777
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1996-09-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
7
Fiscal Year
2002
Total Cost
$295,650
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
Reigle, Kristin L; Di Lullo, Gloria; Turner, Kevin R et al. (2008) Non-enzymatic glycation of type I collagen diminishes collagen-proteoglycan binding and weakens cell adhesion. J Cell Biochem 104:1684-98
Langford, J Kevin; Yang, Yang; Kieber-Emmons, Thomas et al. (2005) Identification of an invasion regulatory domain within the core protein of syndecan-1. J Biol Chem 280:3467-73
Sanderson, Ralph D; Yang, Yang; Kelly, Thomas et al. (2005) Enzymatic remodeling of heparan sulfate proteoglycans within the tumor microenvironment: growth regulation and the prospect of new cancer therapies. J Cell Biochem 96:897-905
Kelly, Thomas; Suva, Larry J; Huang, Yan et al. (2005) Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases. Cancer Res 65:5778-84
Dai, Yuemeng; Yang, Yang; MacLeod, Veronica et al. (2005) HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo. J Biol Chem 280:40066-73
Reiland, Jane; Sanderson, Ralph D; Waguespack, Marian et al. (2004) Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion. J Biol Chem 279:8047-55
Sanderson, Ralph D; Yang, Yang; Suva, Larry J et al. (2004) Heparan sulfate proteoglycans and heparanase--partners in osteolytic tumor growth and metastasis. Matrix Biol 23:341-52
Kelly, Thomas; Miao, Hua-Quan; Yang, Yang et al. (2003) High heparanase activity in multiple myeloma is associated with elevated microvessel density. Cancer Res 63:8749-56
Bayer-Garner, Ilene B; Joseph, Lija; Sanderson, Ralph D et al. (2003) Expression of syndecan-1 is a sensitive marker for cutaneous plasmacytoma. J Cutan Pathol 30:18-22
Wilkins-Port, Cynthia E; Sanderson, Ralph D; Tominna-Sebald, Eiman et al. (2003) Vitronectin's basic domain is a syndecan ligand which functions in trans to regulate vitronectin turnover. Cell Commun Adhes 10:85-103

Showing the most recent 10 out of 30 publications