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R.B. · 09-15-2008, 03:18 AM

Another mechanism by which Omega 6 linoleic acid induces tissue formation , migration and proliferation.

Oxidised Omega 6 linoleic acid induces rapid dose dependent upregulation of Syndecan-4

http://www.ncbi.nlm.nih.gov/pubmed/16636895

Breast Cancer Res Treat. 2006 Jul;98(1):91-8. Epub 2006 Apr 25.Click here to read Links
Syndecan-1 and syndecan-4 are overexpressed in an estrogen receptor-negative, highly proliferative breast carcinoma subtype.
Baba F, Swartz K, van Buren R, Eickhoff J, Zhang Y, Wolberg W, Friedl A.

Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53792, USA.

Members of the syndecan and glypican families of cell surface heparan sulfate proteoglycans (HSPGs) are modulators of growth factor signaling and cell adhesion. Both loss and gain in expression of syndecans and glypicans has been associated with malignant progression. The goal of this project was to investigate a possible relationship between expression of cell surface HSPGs (syndecan-1, syndecan-4 and glypican-1) and established prognostic factors or clinical outcome in breast carcinomas. Tissue arrays containing 207 human breast carcinoma samples in duplicate were immuno-labeled with antibodies to syndecan-1, syndecan-4, glypican-1, Ki67, E-cadherin, estrogen receptor (ER) and progesterone receptor (PR). Clinical follow-up information was available for up to 18.6 years (median follow-up 6.2 years). Syndecan-1 and syndecan-4 expression in carcinoma cells ranged from complete loss to high expression, but glypican-1 was detected only in a small subset of breast carcinomas. Expression of all three HSPGs was significantly associated with the Ki67 proliferation index (syndecan-1: p=0.0025; syndecan-4: p<0.0001; glypican-1 p=0.01). Syndecan-1 and syndecan-4 expression correlated with ER negativity, grade, and size of the primary tumors. Syndecan-1 expression (but not syndecan-4 nor glypican-1) predicted patient outcome (DFS: p=0.0054; OS: p=0.0086). However, multivariate analysis failed to identify syndecan-1 as an independent prognostic marker, which was due to its significant association with established prognostic factors. The strong association between cell surface HSPGs and the Ki67 proliferation marker would support a biologic role in carcinoma growth regulation. Furthermore, the close correlation between syndecan expression and negative ER status raises the possibility of hormonal regulation or more likely an association with an aggressive, ER-negative carcinoma phenotype.

http://www.asco.org/ASCO/Abstracts+&...tractID=202291

Specific Induction of Syndecan-4 in Vascular Endothelial Cells of Breast Cancer - Implications for FGF-2-Induced Angiogenesis.
Sub-category:

Proc Am Soc Clin Oncol 19: 2000 (abstr 2603)
Author(s):

Christoph Mundhenke, Sally Drew, Zhen Chang, Aung Choon, Andreas Friedl
Abstract:

Introduction: Fibroblast growth factor-2 (FGF-2) is a potent angiogenic stimulator. Binding of FGF-2 to its receptor tyrosine kinases (RTKs) and cellular signaling are modulated by heparan sulfate proteoglycans (HSPGs) via their heparin-like heparan sulfate (HS) side chains. HS can be specific positive or negative regulators of FGF signaling depending on their ability to bind to both FGF ligand and RTK. Aim: The goal of this study was to localize different cell surface HSPGs in breast cancer and normal breast tissue and to examine their roles in FGF signaling. Materials and Methods: HSPGs were detected immunohistochemically in paraffin embedded tissues using antibodies directed against the HSPG core proteins of glypican-1, syndecan-1 and syndecan-4. The ability of HSPGs to promote FGF-2 signaling complex assembly was tested by using FGF-2 ligand and soluble RTK fusion protein (FR1-AP) as binding probes (Chang et al. FASEB J., in press). Results: HSPGs are induced in the stroma of infiltrating carcinomas in a striking tissue compartment and cell type-specific fashion. Syndecan-4 is dramatically induced in activated endothelial cells within infiltrating carcinoma tissue, while endothelial cells in normal breast gland are syndecan-4 negative. Syndecan-1 is strongly up-regulated in fibroblasts within the desmoplastic stroma surrounding infiltrating cancer cells. Glypican-1 is found in stromal fibroblasts in the immediate vicinity of cancer cells. FGF-2 binds to HSPGs in all stromal compartments. FR1-AP binds to FGF-2 immobilized on stromal fibroblast and endothelial cell HSPGs, suggesting, that syndecan-1 on fibroblasts and syndecan-4 on endothelial cells promote FGF-2 signaling complex assembly. Summary: Syndecan-4 is induced in tumor vessel endothelial cells of infiltrating carcinomas of the breast, facilitating FGF-2 signaling and thereby likely promoting angiogenesis.

http://ajpcell.physiology.org/cgi/co...ull/288/2/C458
ABSTRACT

Syndecan-4, a heparan sulfate proteoglycan that is widely expressed in the vascular wall and as a cell surface receptor, modulates events relevant to acute tissue repair, including cell migration and proliferation, cell-substrate interactions, and matrix remodeling. While syndecan-4 expression is regulated in response to acute vascular wall injury, its regulation under chronic proatherogenic conditions such as those characterized by prolonged exposure to oxidized lipids has not been defined. In this investigation, arterial smooth muscle cells were treated with 13-hydroperoxy-9,11-octadecadienoic acid (HPODE) and 13-hydroperoxy-10,12-octadecadienoic acid, oxidized products of linoleic acid, which is the major oxidizable fatty acid in LDL. Both oxidized fatty acids induced a dose-dependent, rapid upregulation of syndecan-4 mRNA expression that was not attenuated by cycloheximide. This response was inhibited by pretreatment with N-acetylcysteine, catalase, or MEK1/2 inhibitors, but not by curcumin or lactacystin, known inhibitors of NF-{kappa}B. These data suggest that oxidized linoleic acid induces syndecan-4 mRNA expression through the initial generation of intracellular hydrogen peroxide with subsequent activation of the extracellular signal-regulated kinase signaling pathway via MEK1/2. Notably, the HPODE-induced enhancement of syndecan-4 mRNA was accompanied by accelerated shedding of syndecan-4. In principle, alterations in both the cell surface expression and shedding of syndecan-4 may augment a variety of proatherogenic events that occur in response to oxidized lip

09-15-2008, 03:18 AM	#264
R.B. Senior Member Join Date: Mar 2006 Posts: 1,843	Another mechanism by which Omega 6 linoleic acid induces tissue formation , migration and proliferation. Oxidised Omega 6 linoleic acid induces rapid dose dependent upregulation of Syndecan-4 http://www.ncbi.nlm.nih.gov/pubmed/16636895 Breast Cancer Res Treat. 2006 Jul;98(1):91-8. Epub 2006 Apr 25.Click here to read Links Syndecan-1 and syndecan-4 are overexpressed in an estrogen receptor-negative, highly proliferative breast carcinoma subtype. Baba F, Swartz K, van Buren R, Eickhoff J, Zhang Y, Wolberg W, Friedl A. Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53792, USA. Members of the syndecan and glypican families of cell surface heparan sulfate proteoglycans (HSPGs) are modulators of growth factor signaling and cell adhesion. Both loss and gain in expression of syndecans and glypicans has been associated with malignant progression. The goal of this project was to investigate a possible relationship between expression of cell surface HSPGs (syndecan-1, syndecan-4 and glypican-1) and established prognostic factors or clinical outcome in breast carcinomas. Tissue arrays containing 207 human breast carcinoma samples in duplicate were immuno-labeled with antibodies to syndecan-1, syndecan-4, glypican-1, Ki67, E-cadherin, estrogen receptor (ER) and progesterone receptor (PR). Clinical follow-up information was available for up to 18.6 years (median follow-up 6.2 years). Syndecan-1 and syndecan-4 expression in carcinoma cells ranged from complete loss to high expression, but glypican-1 was detected only in a small subset of breast carcinomas. Expression of all three HSPGs was significantly associated with the Ki67 proliferation index (syndecan-1: p=0.0025; syndecan-4: p<0.0001; glypican-1 p=0.01). Syndecan-1 and syndecan-4 expression correlated with ER negativity, grade, and size of the primary tumors. Syndecan-1 expression (but not syndecan-4 nor glypican-1) predicted patient outcome (DFS: p=0.0054; OS: p=0.0086). However, multivariate analysis failed to identify syndecan-1 as an independent prognostic marker, which was due to its significant association with established prognostic factors. The strong association between cell surface HSPGs and the Ki67 proliferation marker would support a biologic role in carcinoma growth regulation. Furthermore, the close correlation between syndecan expression and negative ER status raises the possibility of hormonal regulation or more likely an association with an aggressive, ER-negative carcinoma phenotype. http://www.asco.org/ASCO/Abstracts+&...tractID=202291 Specific Induction of Syndecan-4 in Vascular Endothelial Cells of Breast Cancer - Implications for FGF-2-Induced Angiogenesis. Sub-category: Proc Am Soc Clin Oncol 19: 2000 (abstr 2603) Author(s): Christoph Mundhenke, Sally Drew, Zhen Chang, Aung Choon, Andreas Friedl Abstract: Introduction: Fibroblast growth factor-2 (FGF-2) is a potent angiogenic stimulator. Binding of FGF-2 to its receptor tyrosine kinases (RTKs) and cellular signaling are modulated by heparan sulfate proteoglycans (HSPGs) via their heparin-like heparan sulfate (HS) side chains. HS can be specific positive or negative regulators of FGF signaling depending on their ability to bind to both FGF ligand and RTK. Aim: The goal of this study was to localize different cell surface HSPGs in breast cancer and normal breast tissue and to examine their roles in FGF signaling. Materials and Methods: HSPGs were detected immunohistochemically in paraffin embedded tissues using antibodies directed against the HSPG core proteins of glypican-1, syndecan-1 and syndecan-4. The ability of HSPGs to promote FGF-2 signaling complex assembly was tested by using FGF-2 ligand and soluble RTK fusion protein (FR1-AP) as binding probes (Chang et al. FASEB J., in press). Results: HSPGs are induced in the stroma of infiltrating carcinomas in a striking tissue compartment and cell type-specific fashion. Syndecan-4 is dramatically induced in activated endothelial cells within infiltrating carcinoma tissue, while endothelial cells in normal breast gland are syndecan-4 negative. Syndecan-1 is strongly up-regulated in fibroblasts within the desmoplastic stroma surrounding infiltrating cancer cells. Glypican-1 is found in stromal fibroblasts in the immediate vicinity of cancer cells. FGF-2 binds to HSPGs in all stromal compartments. FR1-AP binds to FGF-2 immobilized on stromal fibroblast and endothelial cell HSPGs, suggesting, that syndecan-1 on fibroblasts and syndecan-4 on endothelial cells promote FGF-2 signaling complex assembly. Summary: Syndecan-4 is induced in tumor vessel endothelial cells of infiltrating carcinomas of the breast, facilitating FGF-2 signaling and thereby likely promoting angiogenesis. http://ajpcell.physiology.org/cgi/co...ull/288/2/C458 ABSTRACT Syndecan-4, a heparan sulfate proteoglycan that is widely expressed in the vascular wall and as a cell surface receptor, modulates events relevant to acute tissue repair, including cell migration and proliferation, cell-substrate interactions, and matrix remodeling. While syndecan-4 expression is regulated in response to acute vascular wall injury, its regulation under chronic proatherogenic conditions such as those characterized by prolonged exposure to oxidized lipids has not been defined. In this investigation, arterial smooth muscle cells were treated with 13-hydroperoxy-9,11-octadecadienoic acid (HPODE) and 13-hydroperoxy-10,12-octadecadienoic acid, oxidized products of linoleic acid, which is the major oxidizable fatty acid in LDL. Both oxidized fatty acids induced a dose-dependent, rapid upregulation of syndecan-4 mRNA expression that was not attenuated by cycloheximide. This response was inhibited by pretreatment with N-acetylcysteine, catalase, or MEK1/2 inhibitors, but not by curcumin or lactacystin, known inhibitors of NF-{kappa}B. These data suggest that oxidized linoleic acid induces syndecan-4 mRNA expression through the initial generation of intracellular hydrogen peroxide with subsequent activation of the extracellular signal-regulated kinase signaling pathway via MEK1/2. Notably, the HPODE-induced enhancement of syndecan-4 mRNA was accompanied by accelerated shedding of syndecan-4. In principle, alterations in both the cell surface expression and shedding of syndecan-4 may augment a variety of proatherogenic events that occur in response to oxidized lip Last edited by R.B.; 09-15-2008 at 04:39 AM..