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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068494-02
Application #
2443194
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1996-09-01
Project End
2000-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
2
Fiscal Year
1997
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
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
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
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
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