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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Basic fibroblast growth factor is an angiogenic molecule involved in several physiological and pathological processes, including wound repair, embryonic development, and tumor growth. In vitro, basic fibroblast growth factor induces an "angiogenic phenotype" in endothelial cells, which includes chemotaxis, mitogenesis, protease production, beta-integrin expression, and tube formation in three-dimensional gels. It acts by binding to specific tyrosine kinase receptors and to cell-associated heparan sulfate proteoglycans. The physiological significance of the interaction with cell-associated and soluble heparan sulfate proteoglycans is manyfold. Heparan sulfate proteoglycans protect basic fibroblast growth factor from inactivation in the extracellular environment and modulate its bioavailability. At the cell surface, soluble and cell-associated heparan sulfate proteoglycans may play different roles in modulating the dimerization of the growth factor and its interaction with tyrosine kinase receptors. Finally, they affect the internalization and the intracellular fate of basic fibroblast growth factor, suggesting that growth factor slash proteoglycan complexes are involved in intracellular delivery. The bioavailability and the biological activity of basic fibroblast growth factor on endothelial cells strictly depend on the glycosaminoglycan milieu of the extracellular environment. Hence the angiogenic activity of the growth factor in vivo might be modulated by using exogenous glycosaminoglycans. The capacity of glycosaminoglycans to bind to and to influence the biological activity of basic fibroblast growth factor depends on size, degree of sulfation, and disaccharide composition. In the present paper we discuss the physiological significance and the biochemical bases of the interaction of the growth factor with heparan sulfate proteoglycans and exogenous glycosaminoglycans with a view to the possible therapeutic use of heparin-related oligosaccharides as basic fibroblast growth factor agonists or antagonists in angiogenesis-dependent diseases.
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PMID:Interaction of angiogenic basic fibroblast growth factor with endothelial cell heparan sulfate proteoglycans. Biological implications in neovascularization. 873 51

Heparan sulfate (HS) functions as a co-factor in several signal-transduction systems that affect cellular growth, differentiation, adhesion and motility. HS, therefore, may also play a role in the malignant transformation of cells, tumor growth, cell invasiveness and the formation of tumor metastases. To explore this hypothesis, we analyzed the expression of HS and heparan sulfate proteoglycan (HSPG) in histological sections of human lung-cancer tissues and assayed for the presence of HSPGs in extracts of human lung-cancer cell lines, using a panel of native HS-, delta-HS- and HSPG (syndecan, glypican, CD44 and perlecan) core protein-specific monoclonal antibodies. Compared to normal epithelia, non-small-cell lung carcinomas, particularly poorly differentiated tumors, often expressed reduced amounts of the major cell surface-associated HSPGs (most consistently of syndecan-1). CD44 or CD44-variant proteins, in contrast, were found on all tumor cells, irrespective of their differentiation. Perlecan, a matrix-associated HSPG found in the basement membrane of normal bronchial epithelium, was consistently undetectable in invasive bronchogenic carcinomas. Staining reactions for native HS were consistently reduced in squamous-cell lung carcinomas, in the cells in contact with the stroma and in the less differentiated areas of these tumors. Reactions for delta-HS, however, were not reduced, suggesting a structural change in the HS of these tumor cells. Poorly differentiated adenocarcinomas, in contrast, yielded strong HS and delta-HS reactions. Marked differences in HSPG expression also were observed among various non-small-cell lung carcinoma cell lines. Our results suggest that poorly differentiated lung tumors have markedly altered patterns of HSPG expression, which may contribute to their invasive phenotype.
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PMID:Heparan sulfate proteoglycan expression in human lung-cancer cells. 922 15

Heparan sulfate proteoglycans (HSPGs) play a key role in the self-assembly, insolubility and barrier properties of basement membranes and extracellular matrices. Hence, cleavage of heparan sulfate (HS) affects the integrity and functional state of tissues and thereby fundamental normal and pathological phenomena involving cell migration and response to changes in the extracellular microenvironment. Here, we describe the molecular properties, expression and function of a human heparanase, degrading HS at specific intrachain sites. The enzyme is synthesized as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and human tumor tissues. Overexpression of the heparanase cDNA in low-metastatic tumor cells conferred a high metastatic potential in experimental animals, resulting in an increased rate of mortality. The heparanase enzyme also releases ECM-resident angiogenic factors in vitro and its overexpression induces an angiogenic response in vivo. Heparanase may thus facilitate both tumor cell invasion and neovascularization, both critical steps in cancer progression. The enzyme is also involved in cell migration associated with inflammation and autoimmunity. The unexpected identification of a single predominant functional heparanase suggests that the enzyme is a promising target for drug development. In fact, treatment with heparanase inhibitors markedly reduces tumor growth, metastasis and autoimmune disorders in animal models. Studies are underway to elucidate the involvement of heparanase in normal processes such as implantation, embryonic development, morphogenesis, tissue repair, inflammation and HSPG turnover. Heparanase is the first functional mammalian HS-degrading enzyme that has been cloned, expressed and characterized. This may lead to identification and cloning of other glycosaminoglycan degrading enzymes, toward a better understanding of their involvement and significance in normal and pathological processes.
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PMID:Molecular properties and involvement of heparanase in cancer progression and normal development. 1153 Feb 16

Heparan sulfate proteoglycans (HSPGs) play a crucial role in growth regulation by assembling signaling complexes and presenting growth factors to their cognate receptors. Within the immune system, expression of the HSPG syndecan-1 (CD138) is characteristic of terminally differentiated B cells, ie, plasma cells, and their malignant counterpart, multiple myeloma (MM). This study explored the hypothesis that syndecan-1 might promote growth factor signaling and tumor growth in MM. For this purpose, the interaction was studied between syndecan-1 and hepatocyte growth factor (HGF), a putative paracrine and autocrine regulator of MM growth. The study demonstrates that syndecan-1 is capable of binding HGF and that this growth factor is indeed a potent stimulator of MM survival and proliferation. Importantly, the interaction of HGF with heparan sulfate moieties on syndecan-1 strongly promotes HGF-mediated signaling, resulting in enhanced activation of Met, the receptor tyrosine kinase for HGF. Moreover, HGF binding to syndecan-1 promotes activation of the phosphatidylinositol 3-kinase/protein kinase B and RAS/mitogen-activated protein kinase pathways, signaling routes that have been implicated in the regulation of cell survival and proliferation, respectively. These results identify syndecan-1 as a functional coreceptor for HGF that promotes HGF/Met signaling in MM cells, thus suggesting a novel function for syndecan-1 in MM tumorigenesis.
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PMID:Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. 1183 Apr 93

Angiogenesis is the process of generating new capillary blood vessels. Uncontrolled endothelial cell proliferation is observed in tumor neovascularization and in angioproliferative diseases. Tumors cannot growth as a mass above few mm(3) unless a new blood supply is induced. It derives that the control of the neovascularization process may affect tumor growth and may represent a novel approach to tumor therapy. Angiogenesis is controlled by a balance between proangiogenic and antiangiogenic factors. The angiogenic switch represents the net result of the activity of angiogenic stimulators and inhibitors, suggesting that counteracting even a single major angiogenic factor could shift the balance towards inhibition. Heparan sulfate proteoglycans are involved in the modulation of the neovascularization that takes place in different physiological and pathological conditions. This modulation occurs through the interaction with angiogenic growth factors or with negative regulators of angiogenesis. Thus, the study of the biochemical bases of this interaction may help to design glycosaminoglycan analogs endowed with angiostatic properties. The purpose of this review is to provide an overview of the structure/function of heparan sulfate proteoglycans in endothelial cells and to summarize the angiostatic properties of synthetic heparin-like compounds, chemically modified heparins, and biotechnological heparins.
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PMID:Heparin derivatives as angiogenesis inhibitors. 1257 Aug 3

Heparan sulfate proteoglycans are integral components of the extracellular matrix that surrounds all mammalian cells. In addition to providing structural integrity, they act as a storage depot for a variety of heparan sulfate (HS)-binding proteins, including growth factors and chemokines. Heparanase is a matrix-degrading enzyme that cleaves heparan sulfate side chains from the core proteoglycans, thus liberating such HS-binding proteins, as well as potentially contributing to extracellular matrix degradation. Here, we report that heparanase mRNA and protein expression are increased in the neoplastic stages progressively unfolding in a mouse model of multistage pancreatic islet carcinogenesis. Notably, heparanase is delivered to the neoplastic lesions in large part by infiltrating Gr1+/Mac1+ innate immune cells. A sulfated oligosaccharide mimetic of heparan sulfate, PI-88, was used to inhibit simultaneously both heparanase activity and HS effector functions. PI-88 had significant effects at distinct stages of tumorigenesis, producing a reduction in the number of early progenitor lesions and an impairment of tumor growth at later stages. These responses were associated with decreased cell proliferation, increased apoptosis, impaired angiogenesis, and a substantive reduction in the number of invasive carcinomas. In addition, we show that the reduction in tumor angiogenesis is correlated with a reduced association of VEGF-A with its receptor VEGF-R2 on the tumor endothelium, implicating heparanase in the mobilization of matrix-associated VEGF. These data encourage clinical applications of inhibitors such as PI-88 for the many human cancers where heparanase expression is elevated or mobilization of HS-binding regulatory factors is implicated.
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PMID:A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. 1580 57

Heparan sulfate proteoglycans (HSPGs), via their interactions with numerous effector molecules such as FGF-2, IL-8, and VEGF, regulate the biological activity of cells by acting as co-receptors that promote signaling. The extent and nature of their role as co-receptors is often misregulated in cancer as manifested by alterations in HSPG structure and expression level. This misregulation of HSPGs can aid in promoting the malignant phenotype. In addition to expression-related changes in HSPGs, recent discoveries indicate that HSPGs localized within the tumor microenvironment can be attacked by enzymes that alter proteoglycan structure resulting in dramatic effects on tumor growth and metastasis. This review focuses on remodeling of HSPGs by three distinct mechanisms that occur in vivo; (i) shedding of proteoglycan extracellular domains from cell surfaces, (ii) fragmentation of heparan sulfate chains by heparanase, and (iii) removal of sulfates from the 6-O position of heparan sulfate chains by extracellular sulfatases. Assessing or monitoring the remodeling of HSPGs has important implications for tumor diagnosis and patient prognosis while therapeutic manipulation of the remodeling process represents an exciting new possibility for treating cancer.
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PMID:Enzymatic remodeling of heparan sulfate proteoglycans within the tumor microenvironment: growth regulation and the prospect of new cancer therapies. 1614 80

The heterogeneity of proteoglycans (PG)s contributes to their functional diversity. Many functions depend on their ability to bind and modulate the activity of components of the extracellular matrix (ECM). The ability of PGs to interact with other molecules, such as growth factors, is largely determined by the fine structure of the glycosaminoglycan (GAG) chains. Tumorigenesis is associated with changes in the PG synthesis. Heparan sulfate (HS) PGs are involved in several aspects of cancer biology including tumor progression, angiogenesis, and metastasis. PGs can have both tumor promoting and tumor suppressing activities depending on the protein core, the GAG attached, molecules they associate with, localization, the tumor subtype, stages, and degree of tumor differentiation. Perlecan is an angiogenic factor involved in tumor invasiveness. The C-terminal domain V of perlecan, named endorepellin, has however been shown to inhibit angiogenesis. Another angiogenic factor is endostatin, the COOH-terminal domain of the part-time PG collagen XVIII. Glypicans and syndecans may promote local cancer cell growth in some cancer tissues, but inhibit tissue invasion and metastasis in others. The GAG hyaluronan (HA) promotes cancer growth by providing a loose matrix for migrating tumor cells and mediates adhesion of cancer cells. HSPG degrading enzymes like heparanase, heparitinase, and other enzymes such as hyaluronidase and MMP are also important in tumor metastasis. Several different treatment strategies that target PGs have been developed. They have the potential to be effective in reducing tumor growth and inhibit the formation of metastases. PGs are also valuable tumor markers in several cancers.
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PMID:Decreasing the metastatic potential in cancers--targeting the heparan sulfate proteoglycans. 1617

Despite the large amount of research dedicated to the understanding and treatment of tumor growth, the majority of cancers continue to lack effective therapeutic options. As in the case of most solid tumors, growth requires evasion of the host immune system. Our previous work using the Lewis Lung Carcinoma (LLC) model of tumor bearing (TB)-mice has shown several tumor-induced immune suppressing effects to be present. These effects include a decreased T-cell proliferative response to Con A and altered cytokine secretion patterns that favor neither a Th1 nor a Th2 response. To address these immune alterations, immune modulating approaches have been a central area of study. Of the many potential immune modulating compounds, we believe promising therapeutic potential lies in the heparin family. Heparan sulfate (HS), in particular, has been shown to increase T-cell proliferative response in non TB-mouse splenocytes as well as promotion of a beneficial Th1 response. In this paper, we studied the potential of HS to decrease tumor burden via in vivo treatment of TB-mice. Results showed both normal and TB-mice splenocytes had a dose response change in proliferation as a result of HS treatment. Furthermore, splenocytes from HS treated TB-mice showed a potentially beneficial decrease in basal level proliferation. On gross examination, HS treatment produced a decrease in tumor surface necrosis with a visible (2 +/- 1.8%) surface necrotic area in treated mice as opposed to a (43 +/- 16%) surface necrotic area in untreated mice. HS treatment decreased TB-mice splenomegaly when comparing mice spleen weights in treated (0.3 +/- 0.05 g) vs. untreated (0.14 +/- 0.02 g) groups. These results show a potential role of HS as an immune modulating agent with antitumor properties.
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PMID:In vivo heparan sulfate treatment alters the immune response of normal and LLC-bearing mice. 1668 68

Heparan sulfate (HS) is a linear polysaccharide composed of 50-200 glucosamine and uronic acid (glucuronic acid or iduronic acid) disaccharide repeats with epimerization and various sulfation modifications. HS is covalently attached to core proteins to form HS-proteoglycans. Most of the functions of HS-proteoglycans are mediated by their HS moieties. The biosynthesis of HS is initiated by chain polymerization and is followed by stepwise modification reactions, including sulfation and epimerization. These modifications generate ligand-binding sites that modulate cell functions and activities of proteinases and/or proteinase inhibitors. HS is abundantly expressed in developing and mature vasculature, and understanding its roles in vascular biology and related human diseases is an area of intense investigation. In this chapter, we summarize the significant recent advances in our understanding of the roles of HS in developmental and pathological angiogenesis with a major focus on studies using transgenic as well as gene knockout/knockdown models in mice and zebrafish. These studies have revealed that HS critically regulates angiogenesis by playing a proangiogenic role, and this regulatory function critically depends on HS fine structure. The latter is responsible for facilitating cell-surface binding of various proangiogenic growth factors that in turn mediate endothelial growth signaling. In cancer, mouse studies have revealed important roles for endothelial cell-surface HS as well as matrix-associated HS, wherein signaling by multiple growth factors as well as matrix storage of growth factors may be regulated by HS. We also discuss important mediators that may fine-tune such regulation, such as heparanase and sulfatases; and models wherein targeting HS (or core protein) biosynthesis may affect tumor growth and vascularization. Finally, the importance of targeting HS in other human diseases wherein angiogenesis may play pathophysiologic (or even therapeutic) roles is considered.
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PMID:Endothelial heparan sulfate in angiogenesis. 2080 46


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