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Therapeutic value of glycosaminoglycans in cancer

George W. Yip,1 Martin Smollich,2 of alternating uronic acids and amino sugars (ref. 1;
and Martin Götte2 Fig. 1A). Four major classes of glycosaminoglycans have
been identified, all of which have relevance in cancer:
Department of Anatomy, National University of Singapore, heparan sulfate, chondroitin sulfate/dermatan sulfate,
Singapore, Singapore and 2Department of Obstetrics and keratan sulfate, and hyaluronan. Posttranslational modifi-
Gynecology, Münster University Hospital, Münster, Germany
cations such as epimerization and sulfation result in
structural diversity and formation of specific binding
Abstract motifs for many ligands (1, 2). Hyaluronan is the only
Glycosaminoglycans are unbranched polysaccharides com- glycosaminoglycan without sulfate groups. Physiologically,
posed of repeating units of alternating uronic acids and most glycosaminoglycans are covalently attached to core
amino sugars. Most glycosaminoglycans are covalently proteins to form proteoglycans. Proteoglycans are classified
attached to core proteins to form proteoglycans. Posttrans- based on the amino acid homology of their protein cores,
lational modifications result in specific motifs that bind to a their location [cell surface, basement membrane, or
large variety of ligands, thus regulating growth factor extracellular matrix (ECM)], and their glycosaminoglycan
signaling, cellular behavior, inflammation, angiogenesis, substitution (1, 2). However, some proteoglycans are
and the proteolytic environment. Dysregulated expression substituted with more than one glycosaminoglycan chain
of glycosaminoglycans is present in cancer and reported to type, such as syndecan-1 (heparan sulfate and chondroitin
correlate with clinical prognosis in several malignant neo- sulfate) and aggrecan (keratan sulfate and chondroitin
plasms. Recent knowledge on the biological roles of these sulfate; refs. 1, 2). In this review, the biological roles and
molecules in cancer biology, tumor angiogenesis, and therapeutic values of hyaluronan, together with selected
metastasis has promoted the development of drugs target- examples of cell-surface and matrix heparan sulfate and
ing them. Pharmaceutical approaches include the use of small leucine-rich proteoglycans, in cancer are discussed.
chemically modified heparins and glycosaminoglycans with In addition, cancer-related functions of glycosaminoglycan
defined structures, combination of inhibitors of glycosami- receptors and enzymes involved in glycosaminoglycan
noglycan biosynthesis and polyamine depletion, and biolog- synthesis and modification are presented.
ically active glycosaminoglycan-binding peptides. In
addition, glycosaminoglycans are used as tumor-specific
delivery and targeting vehicles for toxins and chemother- Roles of Glycosaminoglycans and
apeutics. Encouraging results in animal studies and clinical Proteoglycans in Cancer
trials show the clinical relevance of glycosaminoglycan- Glycosaminoglycans and proteoglycans both play major
based drugs and the use of glycosaminoglycans as thera- roles in multiple cancer-related processes. Changes in
peutic targets. [Mol Cancer Ther 2006;5(9):2139 – 48] expression of these molecules, as well as of enzymes
involved in their biosynthesis and degradation, contribute
An Introduction to Glycosaminoglycans and to the different steps of tumor progression. Due to space
Proteoglycans limitations, we will use selected examples to show the
diverse roles of glycosaminoglycans and proteoglycans in
Glycosaminoglycans are long, unbranched polysacchar-
cancer. The reader is referred to a number of recent reviews
ides composed of repeating disaccharide units consisting
for a more comprehensive view (3 – 7).
Cancer Cell Proliferation and Growth
Received 2/13/06; revised 6/12/06; accepted 6/29/06. Rapid cell proliferation is an important characteristic of
Grant support: Münster University Hospital grant ‘‘Innovative Medizinische malignant transformation. There is ample evidence for a role
Forschung’’ IMF GÖ 1 2 04 15 (M. Götte), Deutsche Forschungsgemein- of glycosaminoglycans and proteoglycans in controlling cell
schaft grant DFG GO 1392/1-1 (M. Götte), and the National Medical
Research Council, Singapore grants NMRC/0772/2003 and NMRC/CPG/
proliferation. Cell-surface heparan sulfate proteoglycans
004/2004 (G.W. Yip). serve as coreceptors for several growth factor tyrosine
Requests for reprints: Martin Götte, Department of Obstetrics and kinase receptors, which transduce signals on formation of
Gynecology, Münster University Hospital, Research Laboratory, a ternary complex of ligand, receptor, and heparan sulfate
Domagkstraße 11, D-48149 Münster, Germany.
Phone: 49-251-835-6117; Fax: 49-251-835-5928. proteoglycan (ref. 2; Fig. 1B). In some cases, heparan sulfate
E-mail: proteoglycan – bound growth factors are released by hepar-
Copyright C 2006 American Association for Cancer Research. anase, a h-endoglucuronidase that cleaves glycosidic bonds
doi:10.1158/1535-7163.MCT-06-0082 in heparan sulfate via hydrolysis, to achieve an activating

Mol Cancer Ther 2006;5(9). September 2006

breast cancer (11). September2006 .2140 Glycosaminoglycans as Cancer Therapeutics effect (2. thus controlling cell sulfate proteoglycans have also been shown to have a role as proliferation (9). whereas antisense-mediated suppression of hyalur- extracellular signal – regulated kinase activation (8). 3).5(9). and the onan synthase 2 inhibits tumorigenesis and progression of dermatan sulfate proteoglycan decorin modulates epider. Mol Cancer Ther 2006. Chondroitin sulfate proteoglycans/dermatan mal growth factor receptor signaling. Melanoma chondroitin increases ErbB2-dependent signaling in breast cancer cells sulfate proteoglycan enhances focal adhesion kinase and (10). Overexpression of hyaluronan synthase 2 modulators of signal transduction.

migration in primitive. and hyaluronidases (HYAL ). Glycosamino- has. Heparanase promotes invasion and metastasis chemotherapy. Molecular Cancer Therapeutics 2141 Invasion and Metastasis of Cancer Cells increased angiogenesis in syndecan-1-deficient mice (20) The ability of cancer cells to invade into surrounding and the formation of abnormally dilated blood vessels in tissues involves changes in expression of cell-surface syndecan-1-overexpressing mice (23). heparanase (HPSE ). 15). 3. leading to massive clonal expansion and lack of differentiation (right ). angiogenesis is a crucial fate proteoglycan in hematopoietic precursor cells (34. We recently showed largely resistant to mammary tumor formation (3). They have been to penetrate the basement membrane and ECM to invade identified in a range of cancers and are proposed to surrounding tissues (3. thus promoting cancer cell proliferation and angiogenesis. Loss of of progenitor cells. heparan sulfate proteoglycans act as coreceptors for growth factor receptor (GFR ) signaling. and syndecans. fibroblast growth factors. production is related to the metastatic potential of mouse Cancer Stem Cells mammary carcinoma cells (14). 27). wnt signaling may be promoted by presentation of heparan sulfate proteoglycan – bound wnt to its receptor or by increasing the concentration of wnt at the cell surface via heparan sulfate proteoglycan-wnt interactions. Omnipotent. Cancer cells also secrete Cancer stem cells have recently attracted considerable matrix metalloproteinases. Chondroitin sulfate versican. droitin sulfate proteoglycan marks a class of epidermal lial interactions (20). Mol Cancer Ther 2006. A. Moreover. led to decreased colon carcinoma growth and tumor Changes in expression of these molecules reduce cell angiogenesis. 12. Although the mode of glypican action is not fully understood. chondroitin sulfate. N -acetyl-h-D-galactosamine-D-glucuronic acid. the chondroitin sulfate proteoglycan NG2 of cancer cells to blood and lymphatic vessel endothelium marks oligodendrocyte progenitors (31). progenitor cell proliferation is no longer restricted. B. decorin with integrins (2). active DNA repair capacity. a process involving heparan sulfate (HS ) proteoglycans and chondroitin sulfate proteoglycans via direct interactions with and modulation of chemokine signaling. 1D). CD44/hyaluronan. produced by prostate cancer cells. Fig.’’ This has been shown for For a cancer to grow beyond a diameter of 2 mm. glycosaminoglycan disaccharide units. Malignant cells need to loosen cell-cell and cell-matrix contact to invade the surrounding tissues and need to regain adhesiveness on escape from the circulation. 4. acting in concert thelial monocyte migration (28). The wnt signaling pathway. For example. 35). and hyaluronan. Fig. 4. Hyaluronan cancer cells (24). heparanase. heparin displays a higher degree of sulfation and iduronic acid content compared with heparan sulfate. Glycosaminoglycans and proteoglycans by degrading heparan sulfate chains in cell-surface and have been identified as part of specific marker signatures matrix heparan sulfate proteoglycans (16 – 19). B). slow cycling stem cells generate a pool of rapidly cycling pluripotent committed progenitor cells. Keratan sulfate: N -acetyl-h-D-glucosamine-h-D-galactose. which is modulated by glypican family of heparan sulfate proteoglycan (middle). contribute to increased cancer cell motility through of vascular endothelial growth factor production by signaling events that activate the cytoskeleton. Dermatan sulfate is derived from chondroitin sulfate by C5-epimerization of the h-D- glucuronic acid residue. developmental signaling (3) and provide a niche for Angiogenesis preservation of cell ‘‘stemness. ultimately resulting in their apoptosis resistance. September 2006 . perlecan-deficient mice (6. process that is targeted in cancer therapy (18). syndecan-1-deficient mice are angiogenesis (3. the melanoma chon- syndecan-1 in vivo results in increased leukocyte-endothe. at least partly. and hyaluronidases interest among scientists and oncologists. represent the cells of origin of these tumors (29). Heparan sulfate: N-acetyl- glucosamine-a-L-iduronic acid/h-D-glucuronic acid. Glycosaminoglycans and proteoglycans in the basement membranes of epithelia and endothelia and ECM are degraded by matrix metalloproteinases (MMP ). This Figure 1. 4. which ultimately become mature terminally differentiated cells (left ). 22 – 24). cancer stem cells may represent a colonization of distant tissues and organs (refs. Glycosaminoglycans and and induction of cyclooxygenase-2 and vascular endo- proteoglycans are major constituents of the ECM and cell. 6. To escape from the circulation. In addition. and platelets. Syndecan-1 may regulate the adhesion stem cells (30). and angiopoietins. The antimetastatic action of heparin cells of the developing telencephalon (32). The balance of adhesion and antiadhesion is modulated by glycosaminoglycans and proteoglycans. signaling through CD44 suppresses tumor angiogenesis through down-regulation (4). In cancer. stem cell – derived neuroectodermal glycosaminoglycans and proteoglycans are involved in tumors (31). ABC transporters. 1D). Thus. and similar findings were obtained in adhesion and promote cancer cell invasion. inhibits cell exerts antiangiogenic effects via inhibition of transendo- adhesion to fibronectin (13). cancer stem cells. drug resistance through expression of circulation and adhesive interactions with endothelial cells. Due to Metastasis depends on cancer cell dissemination into the their long life span. cancer cell invasion and metastasis (see text). Hyaluronan: N-acetyl-h-D-glucosamine-D-glucuronic acid. Syndecans.5(9). disseminated tumor cells aggregate with leukocytes and platelets and adhere to the vessel wall. been ascribed to its interference with glycans and proteoglycans play major supportive roles in endothelial P-selectin in vivo (21). Antisense inhibition of perlecan surface proteoglycans mediate cell-matrix interactions. stimulates stem cell/ commited progenitor cell proliferation. Structure and cancer-related functions of glycosaminoglycans. 3. Apart It has been proposed that reduction in NG2 expression from growth factors such as vascular endothelial growth may be part of a switch between proliferation and factors. 12. Cell adhesion and migration are modulated by glycosaminoglycans and proteoglycans such as versican. 26. D. 20. C. and leukocytes. 12. subpopulation of tumor cells particularly resistant to 15. For example. These functions also contribute to tumor angiogenesis (cf. chondroitin sulfate proteoglycan in neural stem cells (33) primary tumors and metastases require nutrient support and for heparan sulfate proteoglycan and chondroitin sul- from the vascular system. thelial growth factor (25). and the 473HD- or promote the association with different host cells during chondroitin sulfate epitope marks multipotent progenitor metastatic seeding. Heparanase stimu- molecules and the expression of ECM-degradative lates angiogenesis via angiogenic factor mobilization enzymes (refs.

These findings have raised considerable Therapeutics Online (http://mct. 36. perlecan. all stages of tumorigenesis. examples illustrating the catabolizing enzyme a-L-iduronidase (40). 1C). and fibro- shown in patient cells deficient in the heparan sulfate sarcoma tissue (45 – 47). Colon carcinoma cells have a 33% reduction in 2-O-sulfation on iduronic acid and a 20% reduction in overall N-sulfation compared with adenoma cells (48). B. even in minute amounts of 3-expressing B16-F10 melanoma cells (37). and of progenitor cells and protects against apoptosis. Fig. Mol Cancer Ther 2006. a targeted modulation of glycos. could be attributed to a decreased wnt-1-responsive interest in the generation of glycosaminoglycan/proteogly- progenitor cell population in syndecan-1-deficient mam. competitive binding of (modified) heparins and mimetic glycosaminoglycans to growth factors (GF ) reduces cancer cell proliferation and angiogenesis (cf. a prognostic value for the clinical outcome of cancer has recently been assigned to changes in expression of several glycosaminoglycans and 3 Supplementary material for this article is available at Molecular Cancer proteoglycans. Of note. can – based diagnostic tools.5(9). Heparan sulfate inhibiting sequences in heparan sulfate (44) and to detect proteoglycan expression is associated with differentiation decorin. prognostic and teoglycans. biglycan. analysis of glycosaminoglycans. shown in a mouse model that embryonic stem cell – derived the recent development of highly sensitive mass spectrom- dendritic cells engineered to express glypican-3 confer etry techniques has facilitated structural and sequence protective immunity against highly Selected therapeutic applications of glycosaminoglycans (see text for details).2142 Glycosaminoglycans as Cancer Therapeutics Figure 2. Fig. inhibition of hepar- anase activity by the substrate ana- log PI-88 prevents heparan sulfate degradation and reduces tumor cell invasion. C.aacrjournals. metastasis. Consequently. tissue samples (5. and angiogen- esis. sulfate proteoglycan (2). as well as of enzymes involved in their predictive values could be assigned to qualitative and biosynthesis and degradation. Glycosaminoglycans and Proteoglycans as These changes strongly influence binding of ligands Diagnostic and Prognostic Factors and alter the biological functions of the affected heparan Dysregulated expression of glycosaminoglycans and pro. Because nuclear prognostic values of glycosaminoglycans and proteogly- targeting of heparanase induces differentiation of human cans in cancer are discussed. 41 – 43). Of note. incorporation of HA into doxycycline-loaded liposomes leads to more specific delivery to CD44- overexpressing cancer cells and to CD44-mediated internalization. These methods were used to An additional antitumor strategy is the induction of identify tumor growth – promoting and tumor growth – terminal differentiation in cancer cells (38). versican. 1B). Supplementary Table S13 online. September2006 . it has recently been molecular biology and immunohistochemical approaches. leading to either apoptosis during the progression of human colon adenoma to or loss of the malignant properties of the cells. toxin (TX )-coupled antibodies selec- tively target proteoglycans highly expressed by cancer cells. has been reported to affect quantitative changes in heparan sulfate expression (48. In addition to more traditional mary glands (ref. In the succeeding sections and in copolymerases EXT1/EXT2 (39) or the glycosaminoglycan. syndecan-1. A. pancreatic cancer. Heparan Sulfate aminoglycan/proteoglycan expression in cancer stem cells Heparan sulfate undergoes specific structural changes may be a promising approach. D. 49). as syndecan-4 in colon cancer. glypican. carcinoma. breast cancer cells (38).

56 – 62). whereas the dermatan sulfate the published data has focused on two model members. and head and neck squamous cell carcinoma been shown in multiple myeloma. The en. melanoma. host defense. which encode heparan lymphoma. It is epigenetically silenced by promoter Expression changes in hyaluronan and its receptors hypermethylation in breast cancer. expres. 25). and inhibitory effect on tumor cell improved survival and reduced metastasis and tumor adhesion and motility (refs. cell adhesion. 20. exostoses and malignant chondrosarcomas (51). EXT2. cDNA transfection methods. 64). 70). including ovarian. Small Leucine-Rich Proteoglycans phatidylinositol-anchored glypicans. Although several family members The keratan sulfate proteoglycan lumican inhibits mela- seem to be involved in the pathogenesis of cancer. and cancer is context dependent (Supplementary Table S1). hyaluronan was overexpressed in aggressive subtypes zyme HSulf-1 modifies heparan sulfate sulfation and is whereas hyaluronidase-2 expression was down-regulated. 3. is located primarily within the ECM and shows Although the anticoagulant activity may contribute to the increased expression in several cancers (Supplementary antitumoral properties of heparin. 20. anticoagulation consti- Table S1). and hyaluronidase regulate extracellular hyalur- proteoglycan. Hyaluronan receptors. 65). Importantly. In non-Hodgkin’s Mutations in EXT1 and EXT2. 36). Drago et al.3 Using antisense all cancer types and may depend on the cellular context. gastric. Glycosaminoglycan.3 It interacts with a multitude of binding partners. based on its anticoagulant activity. angiogenesis (55). hyaluronan Glypican-3. silencing of heparanase in anase. Sulfation is a critical determinant of ligand binding to heparan sulfate and affects multiple processes relevant to cancer progression. In cancer. pancreatic. Supplementary Table S1). angiogenesis. Via their heparan The secreted dermatan sulfate proteoglycan decorin sulfate chains. Bigly- Syndecan-1 is a prognostic marker for several cancer types can-binding proteins are up-regulated in malignant cell (Supplementary Table S1).3 It contributes to cell proliferation lines relative to benign cells (65). 71. hyaluronan (4. (73) demonstrated that factor in a number of neoplasms. tenascin-R. and stem cell function A role in cancer metastasis has been established for (2. 68). Hyaluronan Synthases. Heparanase is an important prognostic As early as 1984. ity. heparin and heparan sulfate reduced cancer metastasis in colon. Molecular Cancer Therapeutics 2143 Cell-Surface Heparan Sulfate Proteoglycans including hyaluronan. syndecans and glypicans bind a large modulates growth factor receptor activities and availabil- variety of extracellular ligands. fibronectin. thus modulating morpho. Thus. 24. most of noma progression (66). interference with P-selectin-heparan sulfate proteo- lymphoma. 23.5(9).3 energy metabolism (2). the growth factor receptor (63. Indeed. a large aggregating chondroitin sulfate proteo. and angiogenesis (9. In contrast. and Hyaluronidase chemokine action. sor in some cancers. and breast cancer cells leads to glycan interactions. transmembrane-anchored syndecans and the glycosylphos. forms. and head the Nb rat prostatic adenocarcinoma model. Several proliferation and angiogenesis via mobilization of angio. and epidermal two families of membrane-bound proteoglycans. as a coreceptor for several growth factor receptors and acts Hyaluronan. inflammation. breast. pancreatic cancer (53). CD44. but also reduced their intraabdominal growth in vivo (74). Fig. The low mole- and neck cancers (16. are linked to hereditary multiple correlated with lymphoma subtype (69). proteoglycan biglycan is part of an expression signature syndecan-1 and glypican-3. glycan. ovarian cancer. markedly diminished in ovarian cancer. Hyaluronan as a cell adhesion molecule and modulator of proteolysis.and Proteoglycan-Based sion of both HSulf-1 and HSulf-2 in transfected human Approaches of Cancer Therapy myeloma cells leads to dramatically decreased tumor Chemically Modified Heparins and Glycosamino- growth in vivo accompanied by reduced formation of the glycans ternary fibroblast growth factor-2 signaling complex and Heparin is a potent anticoagulant used for decades to increased matrix deposition (54). Mutations in the GPC3 (receptor for hyaluronan-mediated motility. cervical. September 2006 . and HSulf-1 cancer in a xenograft model (68). endo- (3. has been proposed to act as a tumor suppres. CD44 iso- gene lead to the Simpson-Golabi-Behmel syndrome (7. its antico- Heparanase agulant activity affects tumor progression by decreasing Heparanase promotes metastasis and modulates cell thrombin generation and fibrin formation (71). animal studies suggest that its antimetastatic activity is genic and growth factors from heparan sulfate proteogly. In animal models. 17. hepatocellular A diagnostic value for hyaluronan synthase expression has carcinoma. 72. hyaluronan and hyaluronidase-2 expression sulfate copolymerases. Mol Cancer Ther 2006. prevent and treat thromboembolism. Receptors. 4. its role as a tumor suppressor does not apply to cancers (ref. a lipid-anchored membrane heparan sulfate synthases. a role for hyaluronidase-1 in Heparan Sulfate Synthesis and Modification Enzymes: tumor growth and invasion was established for bladder EXT1. onan concentration and/or signal on hyaluronan binding. tutes a potential adverse effect in cancer therapy. The majority of cell-surface heparan sulfate is found in fibulins. characterizing chemoresistant osteosarcoma (67). 50). type I collagen. cular weight heparin reviparin not only inhibited collagen Chondroitin Sulfate adhesion and Matrigel invasion of adenocarcinoma cells Versican. 2A). inhibition of hepar- can (15. 52). Its role in genesis and wound repair. and colon cancer (14. selectins. HSulf-1 expression is increased in metrial cancer. chemokines. esophageal. and LYVE-1) are of prognostic value in several However.

and invasion in vitro. growth. nithine – mediated polyamine depletion than wild-type mary cancer growth (75). In the Fragmin belliferone. but not its unsulfated modified glycosaminoglycans reduced breast cancer and form. The antiangio- been studied as potential cancer therapeutics. Belting et al. substantially Inhibitors of Glycosaminoglycan-Degrading Enzymes improved survival was noted in a subgroup of patients Because dysregulated glycosaminoglycan degradation is with a better prognosis. (90) synthesized heparan sulfate mimetics as one therapeutic approach is inhibition of glycosaminogly. Thus. 4-methylumbelliferone weight heparin deltaparin or placebo for 1 year (78). In a randomized clinical trial of pharmacologic trials on the RIP-Tag2 mouse model of small-cell lung cancer patients. fibroblast growth factor-2 from ECM. In vitro. Attempts have also been made to transform heparan benzoyl)benzoic acetic anhydride] inhibited tumor cell sulfate/heparin into a heparanase inhibitor by selective adhesion. Kragh et al. progressively through multiple stages of tumorigenesis. Fig. Klerk et al. a potential mechanism of escaping tinzaparin and several non-anticoagulant heparin deriva. A non-anticoagulant heparin derivative of biosynthesis were more susceptible to a-difluoromethylor- 8 kDa reduced metastasis by 58% but did not affect pri. 385 patients with 4-methylumbelliferone pretreatment of melanoma cells led advanced malignancy were randomly assigned to receive to reduced cell-surface hyaluronan formation and suppres- either single daily s. 2B) reduced early progenitor and median overall survival compared with chemotherapy lesions and inhibited cancer growth at late stages. In a syngeneic mouse metastasis model. as well decreased cancer cell proliferation and angiogenesis and as modified heparan sulfate and chondroitin sulfate. In a mouse metastasis model. cancer cell adhesion and venous thromboembolism and reported that heparin invasion were dose-dependently inhibited by 4-methylum- treatment favorably influenced survival. rubicine. Of note. The antimetastatic reagent 5-hexyl-2. (77) studied the effect Hyaluronan biosynthesis in murine melanoma cells can of the low molecular weight heparin nadroparin on sur.5(9). tumors with dysregulated hyaluronan synthesis. resulting in Besides heparin. as structure of the heparan sulfate disaccharide unit HexUA- they are essential for a variety of DNA-related functions. be effectively inhibited by 4-methylumbelliferone without vival of 302 patients with advanced malignancy without cytotoxic effects (85). Of note. (87). seems to be a good candidate for an antimetastatic agent in Although deltaparin treatment did not substantially im. Glycol-split N-acetyl heparins are contrast. Low anticoagulant heparin was cells.c. anticancer properties such as KI-111 [2-(4-fluoro-3-nitro. inhibits heparanase activity (88). have increased apoptosis in the RIP-Tag2 mice. September2006 . combined treatment with pancreatic cancer (61). cells et al.2144 Glycosaminoglycans as Cancer Therapeutics syntheses and studies of antitumoral activity of heparins including replication and transcription. Furthermore. and heparan sulfate effector functions. In chemical modification. These encouraging initial results need to be a structural mimetic and inhibits both heparanase activity confirmed in further clinical trials. several heparan sulfate ligands. randomized clinical trial. PI-88 is in phase II clinical trials (82). and vincristine led to significant improvements Importantly. myeloma cell viability by inducing apoptosis. h-1. Thus. the sulfated oligosaccharide phosphomanno- in tumor response rates. mutant tives in the syngeneic B16-F10 melanoma mouse model Chinese hamster ovary cells deficient in heparan sulfate of metastasis. pentose sulfate (PI-88. PI-88 is alone (79). it may be necessary to define mechanistically important in cancer. Heparanase expression increased low molecular weight heparin and cyclophosphamide. Pumphrey et al. GlcNAc(6S) to develop heparanase-inhibiting heparan Mol Cancer Ther 2006. Advanced Malignancy Outcome Study. 82). (81) compared a database of 50.000 compounds to the depend on nucleic acid – binding polyamines for growth. Moreover. In a lungs by heparan sulfate – deficient mutant cells. injections of the low molecular sion of liver metastases (86).v. (84) and heparinoids with low anticoagulant activity have tested the hypothesis that heparan sulfate proteoglycans gained a lot of attention. prove 1-year survival in the cancer patients. migration. (75) examined the could be involved in a salvage pathway for uptake of antimetastatic activity of the low molecular weight heparin circulating polyamines. heparanase deoxyuridine reduces biosynthesis of heparan sulfate activity was most effectively blocked by heparan sulfate and other glycoconjugates by inhibiting the conversion mimetics resembling a sulfated pentasaccharide (90). median progression-free survival. In rodent models. thus mediating Inhibitors of Glycosaminoglycan Biosynthesis potential antimetastatic and antiangiogenic effects (89). In an attempt genic activity of PI-88 is comparable to that of endostatin to generate a potentially therapeutic mimetic of syndecan. The 1. other KI compounds inhibited cancer invasion potent inhibitors of heparanase and do not release and migration but promoted tumor cell adhesion (81. Given the importance of glycosaminoglycans in cancer. as recently shown in stage-specific may be the way to go. Several studies suggest that a combination strategy. (80) discovered that carbodiimide. epi. Heparan sulfate mimetics with carcinoma cells by 80% to 90%. a-difluoromethylorni- found to be as effective as heparin in inhibition of lung thine reduced seeding and growth of tumor foci in the colonization by Lewis lung carcinoma cells (76). Freeman et al. targeting glycosami- patient groups in which heparin treatment could prolong noglycan-degrading enzymes is a logical anticancer survival (78). polyamine-depletion anticancer therapy. heparin analogues and mimetics. Ishida of glucosamine to UDP-sugars (83). laminarin sulfate reduced the extent of lung colonization modified chondroitin sulfate abolished breast tumor with i. Currently. injected mouse melanoma and rat mammary growth in nude mice.3-sulfated glycan laminarin. a tool to probe the heparan sulfate binding specificity of can biosynthesis. Heparanase is implicated in several steps of of conventional chemotherapy with heparin treatment tumor progression.

Hyaluronan is efficiently protein reduced primary tumor growth by 70% and internalized by a variety of cells via its receptors receptor eliminated metastases (9). A similar term treatment or combined treatment with conventional approach could be applied to other glycosaminoglycans.3 This property was recently interferes with glycosaminoglycan catabolism. Fig. 2C). resulting in prolonged transfected cells in comparison with control cells (105). treatment with decorin core this context is hyaluronan. In leading to overexpression of p21WAF1. a moderate inhibitor of heparanase activity. patient Biologically Active Glycosaminoglycan-Binding multiple myeloma cells. primary tumor growth and expression of decorin in CNS-1 cells resulted in signifi- lung and liver metastases were drastically reduced by cantly increased survival of animals bearing decorin- hyaluronan-butyric acid treatment. a major draw- binding to hyaluronan. munodeficient (SCID) mice. and its derivatives have also SpecificTargets for Toxin Delivery been used as heparanase inhibitors. Decorin seems to be involved for hyaluronan-mediated motility. The immuno- suramin. selectively decreasing antitumoral potency have recently been developed (92). chemotherapy may be therapeutically beneficial. an xenograft study employing decorin-transfected cancer cell inhibitor of histone deacetylase. xenograft models and human aminoglycan function is represented by the use of fetal bone transplants bearing patient multiple myeloma inhibitory glycosaminoglycan-binding peptides. Vehicles forToxins and Chemotherapeutics Glycosaminoglycans and Proteoglycans as Thera- An important supportive role can be assigned to some peutics glycosaminoglycans. Due to the toxicity of clonal antihuman syndecan-1 antibody B-B4. short- and vascularization in a nude mouse model (93). 99. the therapy and increasing cancer cell specificity (96). A peptide (P4). receptors. direct Doxycycline-hyaluronan liposomes showed almost 10 administration of decorin faces the problem of molecular times higher cytotoxicity compared with the drug alone heterogeneity caused by structural and size variability of and more than 100 times higher activity than liposomes the glycosaminoglycan chain. In rate and angiogenesis (24). via TRX-20 liposomes was more efficient than delivery Glycosaminoglycans as Tumor-Specific Targeting via plain liposomes both in vitro and in vivo (102. It was also effective in inhibiting on endocytosis of hyaluronan. been shown in vitro and in vivo. CD44-isoforms. In severe combined im- Another therapeutic strategy for interfering with glycos. less toxic suramin analogues of equal or higher conjugate was effective in vitro. delivery of toxins and chemotherapeutics to cancerous seem to be effective potential therapeutics. P4 reduced growth origin and potentially cause side effects. Liposomes containing the cationic lipid affinities for both heparin and endothelial cell heparan 3. and multiple myeloma cells adhe- Peptides rent to bone marrow stromal cells.5(9). retains its inhibitory lines. proteoglycans per se. the coupling of cytotoxic drugs to hyaluronan 65). ectopic studies on syngeneic mice. In an orthotopic tissues. However. ectopic decorin expression reduced cancer growth activity when coupled to hyaluronan by esterification. with strong Whereas these results were encouraging. cells. 98). 101. peptides containing concatameric consensus Chondroitin sulfate is also a molecular target for chemo- sequences of heparin-binding proteins exhibit high binding therapy delivery. At mediated toxin-delivery to cancer cells (ref. In a separate anticancer drugs and toxins (97. Delivery arin-binding peptides induced apoptosis in promyelocytic of cisplatin to chondroitin sulfate – expressing cancer cells leukemia cells (95). Because many tumors overexpress these and endocytosis-mediated receptor down-regulation (9. growth and survival of multiple myeloma cell lines. Among several 2-(3-nitrobenzoyl)benzoic devoid of hyaluronan. Hyaluronan has also been incorporated into Based on these data. Adenovirus-mediated decorin delivery resulted in is a promising strategy. the application of decorin in a clinical liposomes for tumor-targeting purposes (ref. The nontoxic prodrug is activated comparable effects (9). setting may be a promising approach. display preferential binding to chondroitin sulfate. Suramin inhibits the Syndecan-1 is a tumor marker for a number of cancers binding of several growth factors to their receptors and (Supplementary Table S1). Suramin. an inhibitor of some instances. These in vitro studies were recently acid derivatives. B-B4-DM1 could react with tissues of epithelial vector-based expression in cancer cells. On host setting. In a human endothelial growth factor – mediated angiogenesis. September 2006 . Butyric acid. KI-105 inhibited migration and invasion of confirmed and extended in syngeneic and human xeno- human HT-1080 fibrosarcoma cells although it was only graft mouse models (100). The rele.5-dipentadecycloxybenzamidine hydrochloride (TRX-20) sulfate proteoglycan (94). Fig. inhibited cell growth in culture and back of the study is that some toxic side effects of B-B4-DM1 in chorioallantoic membrane assays and reduced vascular could not be tested in the SCID mouse model. This constitutes a technical Mol Cancer Ther 2006. B-B4-DM1 treatment resulted in tumor growth inhib- vance of this approach in anticancer therapy has recently ition and regression and improvement in overall survival. 2D). The most extensively used glycosaminoglycan in mammary carcinoma model. resulting in exploited using syndecan-1 as a target for antibody- reduced cancer cell proliferation and angiogenesis (91). survival (98). in regulation of epidermal growth factor receptor signaling and HARE (4). Thrombospondin-1-derived hep. which serve as targeting vehicles for In some cases. reducing side effects of growth of tumors in a nude mouse xenograft model. hyaluronan has been directly coupled to cyclin-dependent kinase activity (104). LYVE-1. In a rat glioma model. Molecular Cancer Therapeutics 2145 sulfate mimetics. 103). least some of the antineoplastic properties of suramin seem The antimicrotubule agent DM1 was coupled to the mono- to be based on heparanase inhibition. such as decorin. For example. Nevertheless. a Glycosaminoglycans and Proteoglycans as Tumor- polysulfonated naphthylurea.

Ghatak S. Toole BP. 7.63: increase our knowledge on the roles of specific glycosami.2146 Glycosaminoglycans as Cancer Therapeutics challenge with regard to biotechnological production of However.44:12355 – 61. ing array techniques will facilitate detailed analysis and 12. ology. Development of suppression of hyaluronan synthase 2 inhibits the tumorigenesis and novel diagnostic tools such as glycomic-based glycoprofil. J Biol Chem 2004. but may cause Pharmacologic inhibition of angiogenesis is a well. 132:326 – 33. heparin species helps to prevent formation of an immuno- esis Inhibitors protective fibrin coat around tumor cells.23:341 – 52. Selective expression and functional characteristics of three mammalian hyaluronan synthases in oncogenic glycosaminoglycans and proteoglycans and the use of malignant transformation. Among the with conventional chemotherapy has already shown glycosaminoglycan-based pharmaceutics already in clinical synergistic effects in cancer treatment. 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Heparin. pathologic methods. and decorin are also implicated 6.165:881 – 91. Waltham M. Bernfield M. Cancer Res 2003. tantly. Glypicans in growth control and cancer.68:729 – 77. Juan Larrain. Atsumi F. 22). Pappo O. Nat Rev Cancer 2002. Thus. the diverse functions of glycosaminoglycans and 17. Ohkawa T. targeting of 14. Götte M. antiangiogenic effect is due to heparin-induced cellular release of tissue factor pathway inhibitor. Melanoma chondroitin sulfate proteoglycan enhances FAK and ERK activation by distinct mechanisms. Stewart R. Heparanase promotes growth. 8. In therapeutics. Modulation of prostate lytic and glycosaminoglycan sequencing techniques will cancer cell attachment to matrix by versican. et al. 1999. undesirable side effect in cancer therapy. Int J Cancer 2006. Proteoglycans and glycosaminoglycans. Narayanasami U.145 – 60. including heparan sulfate. itors of angiogenic factors such as fibroblast growth factor-2 Matrix Biol 2004. Jorge Filmus. Furthermore. Heparanase species may inhibit cancer cell attachment and prevent mechanisms of melanoma metastasis to the brain: development and use of distant metastatic seeding of circulating tumor cells. the anticoagulant function of Glycosaminoglycans and Proteoglycans as Angiogen. the low molecular weight heparin Acknowledgments tinzaparin was found to be a potent angiogenesis inhibitor We thank Dr. Brownlee GR. Glycosaminoglycans and proteoglycans are involved in the 9. glycosaminoglycans. Hart G. and József Tı́már for in vitro (106) and heparin octasaccharides inhibited tumor discussions. Gotte M. at a specific juxtamembrane site. Ludwig Kiesel for support and Drs. Shriver Z. et al. Glenn Prestwich. 4. Toole BP. Esko JD. in angiogenesis (4. Essentials of glycobiology. Marth J. Esko J. interference with their function frequently results in 16. Many classes ment of glycosaminoglycan/proteoglycan mimetics that act of glycosaminoglycans and proteoglycans participate in only on specific steps of tumor progression will allow for angiogenesis. of choice in cases where tumor angiogenesis depends on 5. Takaoka M. use. September2006 . spreading of breast cancer. Mol Cancer Ther 2006.279:18679 – 87. Wang Z. For example.2: cell-surface heparan sulfate proteoglycans (3. context-dependent ther. Conclusions J Cell Biol 2004. Constitutive and accelerated shedding of murine syndecan-1 is mediated by cleavage of its core protein will complement classic ELISA and antibody-based histo. Iozzo RV. and their mimetics are 15. 521 – 8. et al. Ricciardelli C. Due to the multifaceted functions of angiogenesis and survival of primary breast tumors.5(9). Park PW. bleeding problems in cancer patients. Lab Invest 2004. chondroitin sul. 24. proteoglycans.97:217 – 25. cases the anticoagulant properties of heparin represent an Cummings R. 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