Heparan sulfate proteoglycans in invasion and metastasis

doi:10.1006/scdb.2000.0241

Seminars in Cell & Developmental Biology

Volume 12, Issue 2, April 2001, Pages 89-98

https://doi.org/10.1006/scdb.2000.0241 Get rights and content

Abstract

Because heparan sulfate proteoglycans mediate cell adhesion and control the activities of numerous growth and motility factors, they play a critical role in regulating the metastatic behavior of tumor cells. Due to their utilitarian nature, heparan sulfate proteoglycans may at times act as inhibitors of cell invasion and at other times as promoters of cell invasion, with their function being determined by their location (cell surface or extracellular matrix), the heparin-binding molecules they associate with, the presence of modifying enzymes (proteases, heparanases) and the precise structural characteristics of the proteoglycan. Also, the tissue type and pathophysiological state of the tumor influence proteogylcan function. This review summarizes our current knowledge of the role heparan sulfate proteoglycans play in regulating tumor cell metastasis, proposes mechanisms of how these molecules function and examines the potential for discovery of new therapeutic approaches designed to block metastatic cancer.

References (92)

S Tumova et al.
Heparan sulfate proteoglycans on the cell surface: versatile coordinators of cellular functions
Int J Biochem Cell Biol
(2000)
CB Underhill et al.
A transformation-dependent difference in the heparan sulfate associated with the cell surface
Biochem Biophys Res Commun
(1975)
DJ Winterbourne et al.
Altered metabolism of heparan sulphate in simian virus 40 transformed cloned mouse cells
J Biol Chem
(1978)
G David et al.
Transformed mouse mammary epithelial cells synthesize undersulfated basement membrane proteoglycan
J Biol Chem
(1983)
F Redini et al.
Cell surface glycosaminoglycans of rat rhabdomyosarcoma lines with different metastatic potentials and of non-malignant rat myoblasts
Biochim Biophys Acta
(1986)
BF Liebersbach et al.
Expression of syndecan-1 inhibits cell invasion into type I collagen
J Biol Chem
(1994)
W Liu et al.
Heparan sulfate proteoglycans as adhesive and anti-invasive molecules: Syndecans and glypican have distinct functions
J Biol Chem
(1998)
TH van Kuppevelt et al.
Generation and application of type-specific anti-heparan sulfate antibodies using phage display technology. Further evidence for heparan sulfate heterogeneity in the kidney
J Biol Chem
(1998)
JK Langford et al.
Multiple heparan sulfate chains are required for optimal syndecan-1 function
J Biol Chem
(1998)
U Lindahl et al.
Regulated diversity of heparan sulfate
J Biol Chem
(1998)

D Schubert et al.

A role of secreted glycosaminoglycans in cell-substratum adhesion

J Biol Chem

(1980)

RD Sanderson et al.

Fine structure of heparan sulfate regulates syndecan-1 function and cell behavior

J Biol Chem

(1994)

J Kishibe et al.

Structural requirements of heparan sulfate for the binding to the tumor-derived adhesion factor/angiomodulin that induces cord-like structures to ECV-304 human carcinoma cells

J Biol Chem

(2000)

GC Jayson et al.

Heparan sulfate undergoes specific structural changes during the progression from human colon adenoma to carcinoma in vitro

J Biol Chem

(1998)

CL Merry et al.

Highly sensitive sequencing of the sulfated domains of heparan sulfate

J Biol Chem

(1999)

GL Nicolson et al.

Cancer cell heparanase activity associated with invasion and metastasis

Adv Enzyme Regul

(1998)

PH Kussie et al.

Cloning and functional expression of a human heparanase gene

Biochem Biophys Res Commun

(1999)

M Toyoshima et al.

Human heparanase. Purification, characterization, cloning, and expression

J Biol Chem

(1999)

JM Whitelock et al.

The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases

J Biol Chem

(1996)

CH Blood et al.

Tumor interactions with the vasculature: angiogenesis and tumor metastasis

Biochim Biophys Acta

(1990)

R Adatia et al.

Suppression of invasive behavior of melanoma cells by stable expression of anti-sense perlecan cDNA

Ann Oncol

(1997)

WH Yu et al.

Heparan sulfate proteoglycans as extracellular docking molecules for matrilysin (matrix metalloproteinase 7)

J Biol Chem

(2000)

R van der Voort et al.

Heparan sulfate-modified CD44 promotes hepatocyte growth factor/scatter factor-induced signal transduction through the receptor tyrosine kinase c-Met

J Biol Chem

(1999)

M Borset et al.

Syndecan-1 is targeted to the uropods of polarized myeloma cells where it sequesters heparin-binding proteins

Blood

(2000)

C Seidel et al.

Serum syndecan-1: a new independent prognostic marker in multiple myeloma

Blood

(2000)

ES Oh et al.

Syndecan-4 proteoglycan regulates the distribution and activity of protein kinase C

J Biol Chem

(1997)

AJ McFall et al.

Characterization of the high affinity cell-binding domain in the cell surface proteoglycan syndecan-4

J Biol Chem

(1998)

M Mongiat et al.

The protein core of the proteoglycan perlecan binds specifically to fibroblast growth factor-7

J Biol Chem

(2000)

G Pilia et al.

Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome

Nat Genet

(1996)

C McCormick et al.

The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate

Nat Genet

(1998)

CM Alexander et al.

Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice

Nat Genet

(2000)

P Inki et al.

The role of syndecan-1 in malignancies

Ann Med

(1996)

M Bernfield et al.

Functions of cell surface heparan sulfate proteoglycans

Annu Rev Biochem

(1999)

AD Lander et al.

The elusive functions of proteoglycans: in vivo veritas

J Cell Biol

(2000)

J Robinson et al.

Structure and properties of an undersulfated heparan sulfate proteoglycan synthesized by a rat hepatoma cell line

J Cell Biol

(1984)

S Kure et al.

Metastatic potential of murine B16 melanoma correlates with reduced surface heparan sulfate glycosaminoglycan

Jpn J Cancer Res

(1987)

M Moczar et al.

Accumulation of heparan sulfate in the culture of human melanoma cells with different metastatic ability

Clin Exp Metastasis

(1993)

J Timar et al.

Differential expression of proteoglycans on the surface of human melanoma cells characterized by altered experimental metastatic potential

Am J Pathol

(1992)

RM Day et al.

Changes in the expression of syndecan-1 in the colorectal adenoma-carcinoma sequence

Virchows Arch

(1999)

S Kumar-Singh et al.

Syndecan-1 expression in malignant mesothelioma: correlation with cell differentiation, WT1 expression, and clinical outcome

J Pathol

(1998)

K Nackaerts et al.

Heparan sulfate proteoglycan expression in human lung-cancer cells

Int J Cancer

(1997)

A Matsumoto et al.

Reduced expression of syndecan-1 in human hepatocellular carcinoma with high metastatic potential

Int J Cancer

(1997)

MJ Stanley et al.

Syndecan-1 expression is induced in the stroma of infiltrating breast carcinoma

Am J Clin Pathol

(1999)

P Inki et al.

Association between syndecan-1 expression and clinical outcome in squamous cell carcinoma of the head and neck

Br J Cancer

(1994)

S Leppa et al.

Steroid-induced epithelial-fibroblastic conversion associated with syndecan suppression in S115 mouse mammary tumor cells

Cell Regul

(1991)

Cited by (196)

Protein glycosylation in cancer
2023, Translational Glycobiology in Human Health and Disease
Cancer is a multifactorial disease resulting from somatic mutation and selection of a cell population that evades normal constraints on proliferation, invades tissues, and spreads to other organs. Changes in cellular glycosylation confer adaptive advantages to cells during tumor progression. Indeed, aberrant glycosylation mediates key pathophysiological events during the various steps of tumor progression such as cell proliferation, invasion, and metastasis. Inhibition of enzymes involved in the biosynthesis of cancer-associated aberrant glycans might have an effect on tumor progression. This chapter describes the biosynthesis and alterations in protein glycosylation, O-GlcNAcylation, N-linked glycosylation, mucin-type O-linked glycosylation, and proteoglycans involved in tumor progression and their importance in cancer diagnosis, vaccine development, and chemotherapy.
Enzymatic Digestion of Cell-surface Heparan Sulfate Alters the Radiation Response in Triple-negative Breast Cancer Cells
2022, Archives of Medical Research
Radiation resistance represents a major challenge in the treatment of breast cancer. As heparan sulfate (HS) chains are known to contribute to tumorigenesis, we aimed to investigate the interplay between HS degradation and radiation response in triple-negative breast cancer (TNBC) cells.
HS chains were degraded in vitro as TNBC cells MDA-MB-231 and HCC1806 were treated with heparinase I and III. Subsequently, radioresistance was determined via colony formation assay after doses of 2, 4 and 6 Gy. Cell cycle profile, stem cell characteristics, expression of HS, activation of beta integrins, and apoptosis were determined by flow cytometry. Additionally, cell motility was analyzed via wound-healing assays, and expression and activation of FAK, CDK-6, Src, and Erk1/2 were quantified by western blot pre- and post-irradiation. Finally, the expression of cytokines was analyzed using a cytokine array.
Radiation promoted cell cycle changes, while heparinase treatment induced apoptosis in both cell lines. Colony formation assays showed significantly increased radio-resistance for both cell lines after degradation of HS. Cell migration was similarly upregulated after degradation of HS compared to controls. This effect was even more prominent after irradiation. Interestingly, FAK, a marker of radioresistance, was significantly activated in the heparinase-treated group. Additionally, we found Src to be dysregulated in MDA-MB-231 cells. Finally, we observed differential secretion of GRO, CXCL1, IGFBP1, IL8, Angiogenin, and Osteoprotegerin after HS degradation and radiotherapy.
Our results suggest an influence of HS chains on the development of radioresistance in TNBC.
Chemokines and the extracellular matrix: Set of targets for tumor development and treatment
2021, Cytokine
Citation Excerpt :
Heparan sulfate proteoglycans are involved in the modulation of cancer cells and, thus, tumor growth, invasion, and metastasis[52]. Different cancers with lower quantities of heparan sulfate have been shown to demonstrate more aggressive and invasive profiles than those with adequate or high levels of heparan sulfate[53]. The overexpression of enzymes capable of cleaving heparan sulfate, such as heparinase-1, promote tumor growth and angiogenesis, while expression of heparinase-2, has the potential of suppressing tumor growth[54].
The extracellular matrix (ECM) consists of various molecules that support tissue cells, including proteins, fibronectin, laminin, collagen IV, and glycosaminoglycans. In addition to interactions between the ECM and cells, the ECM also interacts with chemokines, and growth factors, and these interactions ensure cell survival, development, differentiation, and migration of both immune system cells and tumor cells. This review provides an overview of the mechanisms of interaction between the ECM and chemokines, focusing on the tumor microenvironment and the modulation of these elements as a target for therapies in several types of cancer.
Strategies in Synthesis of Heparin/Heparan Sulfate Oligosaccharides: 2000–Present
2021, Advances in Carbohydrate Chemistry and Biochemistry
Heparin and heparan sulfate are members of the glycosaminoglycan family that are involved in a multitude of biological processes. The great interests in the anticoagulant properties of heparin have stimulated major advances in synthetic strategies toward clinically effective analogues, as demonstrated importantly by the approval of the fully synthetic pentasaccharide fragment, termed fondaparinux (Arixtra®), of the heparin macromolecule for treatment of deep-vein thrombosis. Given the highly complex nature of heparin and heparan sulfate, the chemical synthesis of their components is a challenging endeavor. In the past decade, multiple approaches have been developed to improve the overall synthetic efficiency. New strategies have emerged that can generate libraries of oligosaccharide components of heparin and heparan sulfate. This article discusses recent developments in the assembly of heparin and heparan sulfate oligosaccharides and the associated challenges in their synthesis.
Sulfated glycolipid PG545 induces endoplasmic reticulum stress and augments autophagic flux by enhancing anticancer chemotherapy efficacy in endometrial cancer
2020, Biochemical Pharmacology
The sulfated glycolipid PG545 shows promising antitumor activity in various cancers. This study was conducted to explore the effects and the mechanism of PG545 action in endometrial cancer (EC). PG545 exhibited strong synergy as assessed by the Chou-Talalay-Method in vitro when combined with cisplatin, or paclitaxel in both type I (Hec1B) and type II (ARK2) EC cell lines. While PG545 showed antitumor activity as monotherapy, a combination of PG545 with paclitaxel and cisplatin was highly effective in reducing the tumor burden and significantly prolonged survival of both Hec1B and ARK2 xenograft bearing mice. Mechanistically, PG545 elicits ER stress as an early response with resultant induction of autophagy. Our data demonstrated an increase in pERK, Bip/Grp78, IRE1α, Calnexin and CHOP/GADD153 within 6–24 hrs of PG545 treatment in EC cells. In parallel, PG545 also blocked FGF2 and HB-EGF mediated signaling in EC cells. Moreover, melatonin-mediated ER stress inhibition reduced PG545-mediated autophagy and PG545 in combination with cisplatin further heightened this stress response. Collectively these data indicate that PG545 exhibits strong synergistic effects with chemotherapeutics in vitro and showed promising antitumor activity in vivo. Our preclinical data indicates that in future studies PG545 can be a useful adjunct to chemotherapy in endometrial cancer.
Proteoglycans as miscommunication biomarkers for cancer diagnosis
2019, Progress in Molecular Biology and Translational Science
Cancer cells reside in a microenvironment comprising of fibroblasts, endothelial cells, pericytes, macrophages, and other immune cells. All these cells coevolve with the cancer cells into a clinically manifested tumor. The immune system of the host should eliminate the tumor but fails to do so until it develops into a deadly disease. Based on these facts, cancer is a system disorder caused by miscommunications among cancer cells, its microenvironment, and host immune system. Therefore, identifying communication-related biomarkers will be important for cancer diagnosis and treatment. Proteoglycans are important communication molecules made by all types of mammalian cells and present both at cell surfaces and in extracellular matrix. Proteoglycans consist of a core protein to which one or more glycosaminoglycan (GAG) chains are covalently attached. GAGs are long linear anionic polysaccharides. They interact with hundreds of growth factors, chemokines, cytokines, proteases, protease inhibitors, and facilitate many signaling transduction pathways in a GAG composition and/or sequence-specific manner. When the GAG network goes awry, the problem cannot be defined by conventional genomic or proteomic approaches because GAGs are assembled without a genetic template. This review will summarize all GAG- and proteoglycan-related cancer biomarkers as well as GAG modification enzymes including sulfotransferase-, heparanase-, hyaluronidase-, and sulfatase-based biomarkers identified during the past 20 years. The published data demonstrate that the proteoglycan- and GAG-related cancer biomarkers are not produced by cancer cells alone, and they are indicators of a miscommunicated system during cancer development.

View all citing articles on Scopus

¹: Corresponding author. Department of Pathology, Slot 517, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA. Email: [email protected]

View full text

Regular ArticleHeparan sulfate proteoglycans in invasion and metastasis

Abstract

Int J Biochem Cell Biol

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

Biochim Biophys Acta

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Adv Enzyme Regul

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

Biochim Biophys Acta

Ann Oncol

J Biol Chem

J Biol Chem

Blood

Blood

J Biol Chem

J Biol Chem

J Biol Chem

Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome

Nat Genet

The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate

Nat Genet

Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice

Nat Genet

The role of syndecan-1 in malignancies

Ann Med

Functions of cell surface heparan sulfate proteoglycans

Annu Rev Biochem

The elusive functions of proteoglycans: in vivo veritas

J Cell Biol

Structure and properties of an undersulfated heparan sulfate proteoglycan synthesized by a rat hepatoma cell line

J Cell Biol

Metastatic potential of murine B16 melanoma correlates with reduced surface heparan sulfate glycosaminoglycan

Jpn J Cancer Res

Accumulation of heparan sulfate in the culture of human melanoma cells with different metastatic ability

Clin Exp Metastasis

Differential expression of proteoglycans on the surface of human melanoma cells characterized by altered experimental metastatic potential

Am J Pathol

Changes in the expression of syndecan-1 in the colorectal adenoma-carcinoma sequence

Virchows Arch

Syndecan-1 expression in malignant mesothelioma: correlation with cell differentiation, WT1 expression, and clinical outcome

J Pathol

Heparan sulfate proteoglycan expression in human lung-cancer cells

Int J Cancer

Reduced expression of syndecan-1 in human hepatocellular carcinoma with high metastatic potential

Int J Cancer

Syndecan-1 expression is induced in the stroma of infiltrating breast carcinoma

Am J Clin Pathol

Association between syndecan-1 expression and clinical outcome in squamous cell carcinoma of the head and neck

Br J Cancer

Steroid-induced epithelial-fibroblastic conversion associated with syndecan suppression in S115 mouse mammary tumor cells

Cell Regul

Regular Article
Heparan sulfate proteoglycans in invasion and metastasis