Biomedical subjects

Dario Marchetti

Publications and source records attributed to Dario Marchetti.

17 recordsLinked to original sources

PubMed2006

Heparanase expression and TrkC/p75NTR ratios in human medulloblastoma.

Medulloblastoma (MB), the most devastating and common brain tumor in children, is highly invasive and extremely difficult to treat. Identifying the properties of MB tumors that cause them to invade and metastasize is therefore imperative for the development of novel treatments. We performed investigations to elucidate prognostic implications of heparanase (HPSE-1) and TrkC/p75(NTR) expression in MB using formalin-fixed, paraffin-embedded (FFPE) MB clinical specimens from children aged 1-19 years. Expressions of p75(NTR) and HPSE-1 correlated with each other (Pearson's correlation R = 0.899; P < 0.0001; R (2) = 81%; n = 14). In addition, TrkC:p75(NTR) ratios correlated with MB meningeal spread (R = 0.608; P = 0.0212; R (2) = 37%; n = 14). Secondly, using antibodies specific to TrkC and HPSE-1, we carried out immunohistochemistry (IHC) on 22 human MB tissue samples. IHC reaction scores revealed a significant expression of HPSE-1 in 76% of MB tissues from children aged 3 years and older (P = 0.0490; n = 17) while TrkC immunoreactivity was detected in 71% of these patient samples. Of note, TrkC was significantly present in 100% of MB female patients (P = 0.0313; n = 6). These studies support the role of p75(NTR) and HPSE-1 as two novel molecular determinants involved in the biology and clinical progression of MB.

Cerebellar Neoplasms↗

PubMed2006

Heparanase mechanisms of melanoma metastasis to the brain: Development and use of a brain slice model.

Heparanase (HPSE-1) is an endo-beta-D-glucuronidase that cleaves heparan sulfate (HS) chains of proteoglycans (HSPG), and its expression has been associated with increased cell growth, invasion, and angiogenesis of tumors as well as with embryogenesis and tissue development. Since metastatic cancer cells express HPSE-1, we have developed an orthotopic brain slice model to study HPSE-1 involvement in brain-metastatic melanoma. This model allows for the characterization of tumor cell invasion at both quantitative and qualitative levels. Brain-metastatic melanoma cells (B16B15b) showed augmenting levels of HPSE-1 protein expression in a time-dependent manner. Secondly, B16B15b cells pre-treated with HPSE-1 showed a significant increase in the number of cells that invaded into the brain tissue. Finally, HPSE-1 exposure-augmented invasion depth in brain sections by brain-metastatic melanoma cells. We concluded that applying this brain slice model can be beneficial to investigate HPSE-1- related in vivo modalities in brain-metastatic melanoma and brain invasion in general. These results also further emphasize the potential relevance of using this model to design therapies for controlling this type of cancer by blocking HPSE-1 functionality.

Animals↗

PubMed2006

HPSE-1 expression and functionality in differentiating neural cells.

The study of cellular differentiation encompasses many vital parts of biology and medicine. Heparan sulfate proteoglycans (HSPG) are essential and ubiquitous macromolecules associated with the cell surface and extracellular matrix (ECM) of a wide range of cells and tissues. Heparan sulfate chains (HS) of HSPG bind and sequester a multitude of extracellular ligands, including growth factors, cytokines, chemokines, enzymes, and lipoproteins. Enzymatic degradation of HS is therefore involved in processes such as cell proliferation, migration, and differentiation. Heparanase (HPSE-1) is an HS degradative enzyme associated with inflammation and lipid metabolism and is a critical molecular determinant in cancer metastasis. The enzyme acts as an endo-beta-D-glucuronidase, which degrades HS at specific intrachain sites, resulting in HS fragments of discrete molecular weights that retain biological function. HPSE-1's relevance as the only example of cloned/purified mammalian HS degradative enzyme led us to investigate its functionality in human olfactory epithelium (HOE) cells as a paradigm for HPSE-1's roles in neural cell differentiation. We provide the first evidence of 1) HPSE-1 presence in HOE cells and 2) a highly significant increase of HPSE-1 mRNA and enzyme activity in differentiating vs. proliferating HOE cells. Our data suggest that an augmented HPSE-1 activity may represent a physiological mechanism involved in neural cellular differentiation.

Cell Differentiation↗

PubMed2006

Bioactive natural and semisynthetic latrunculins.

Marine-derived macrolides latrunculins A and B, of the Red Sea sponge Negombata magnifica, are the first marine natural products that have been found to reversibly bind to actin monomers and to disrupt its organization. Latrunculins are structurally related to many antimicrobial and antiangiogenic macrolides. Several grams of latrunculin B (1), together with a new latrunculin named latrunculin T (2), were isolated from a recent collection of N. magnifica. Semisynthetic modifications of 1, including acetylation, acetalization, and N-hydroxymethylation, afforded four new (4, 5, 7, 8) and two known (6 and 9) semisynthetic analogues. Specifically, 15-O-methyllatrunculin B (6) showed a promising antiangiogenic activity in a chick chorioallantoic membrane assay and antimigratory activity in Boyden's chamber assay. Moreover, latrunculin B (1) and the new N-acetyllatrunculin B (4) displayed potent antimigratory activity in a wound-healing assay. Natural and semisynthetic latrunculins showed potent antimicrobial activity against Candida albicans, Saccharomyces cerevisiae, Staphylococcus aureus, and Bacillus cereus. Latrunculins are potential leads that can be developed as anticancer and antimicrobial agents.

Animals↗

PubMed2006

Biocatalytic and antimetastatic studies of the marine cembranoids sarcophine and 2-epi-16-deoxysarcophine.

The soft coral Sarcophyton glaucum is a rich resource of several bioactive cembranoids. Sarcophytol A (1) and sarcophine (2) are cembranoid diterpenes reported from this soft coral and extensively investigated for their cancer chemopreventive properties. This study aimed at investigating the antimetastatic potential of the major cembranoids, sarcophine (2) and 2-epi-16-deoxysarcophine (3), from the Red Sea soft coral S. glaucum. Biocatalytic transformation of 3 using Rhizopus stolonifer ATCC 6227a and Absidia spinosa ATCC 6648 afforded four new metabolites, 5-7 and 9, along with the known 9alpha-hydroxysarcophine (8). Sarcophine, 2-epi-16-deoxysarcophine, and metabolites 5-9 revealed significant antimetastatic activity against the highly metastatic mouse melanoma cell line (B16B15b). Cembranoids demonstrate a great potential for further development as antimetastatic agents.

4-Butyrolactone↗

PubMed2006

FGF2 binding, signaling, and angiogenesis are modulated by heparanase in metastatic melanoma cells.

Heparanase (HPSE) and fibroblast growth factor-2 (FGF2) are critical regulators of melanoma angiogenesis and metastasis. Elevated HPSE expression contributes to melanoma progression; however, further augmentation of HPSE presence can inhibit tumorigenicity. HPSE enzymatically cleaves heparan sulfate glycosaminoglycan chains (HS) from proteoglycans. HS act as both low-affinity FGF2 receptors and coreceptors in the formation of high-affinity FGF2 receptors. We have investigated HPSE's ability to modulate FGF2 activity through HS remodeling. Extensive HPSE degradation of human metastatic melanoma cells (70W) inhibited FGF2 binding. Unexpectedly, treatment of 70W cells with low HPSE concentrations enhanced FGF2 binding. In addition, HPSE-unexposed cells did not phosphorylate extracellular signal-related kinase (ERK) or focal adhesion kinase (FAK) in response to FGF2. Conversely, in cells treated with HPSE, FGF2 stimulated ERK and FAK phosphorylation. Secondly, the presence of soluble HPSE-degraded HS enhanced FGF2 binding and ERK phosphorylation at low HS concentrations. Higher concentrations of soluble HS inhibited FGF2 binding, but FGF2 signaling through ERK remained enhanced. Soluble HS were unable to support FGF2-stimulated FAK phosphorylation irrespective of HPSE treatment. Finally, cell exposure to HPSE or to HPSE-degraded HS modulated FGF2-induced angiogenesis in melanoma. In conclusion, these effects suggest relevant mechanisms for the HPSE modulation of melanoma growth factor responsiveness and tumorigenicity.

Cell Line, Tumor↗

PubMed2005

Role of omega-3 polyunsaturated fatty acids on cyclooxygenase-2 metabolism in brain-metastatic melanoma.

Cyclooxygenase-2 (COX-2) is important in the progression of epithelial tumors. Evidence indicates that omega-6 PUFAs such as arachidonic acid (AA) promote the growth of tumor cells; however, omega-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] inhibit tumor cell proliferation. We investigated the effects of omega-3 PUFA on the expression and function of COX-2 in 70W, a human melanoma cell line that metastasizes to the brain in nude mice. We show that 1) tumor necrosis factor-alpha upregulates the expression of both COX-2 mRNA and prostaglandin E2 (PGE2) production, and 2) omega-3 and omega-6 PUFA regulate COX-2 mRNA expression and PGE2 production. AA increased COX-2 mRNA expression and prostaglandin production in omega-6-stimulated 70W cells. Conversely, COX-2 mRNA expression decreased in cells incubated with EPA or DHA. AA increased Matrigel invasion 2.4-fold, whereas EPA or DHA did not. Additionally, PGE2 increased in vitro invasion 2.5-fold, whereas exposure to PGE3 significantly decreased invasion. Our results demonstrate that incubation of 70W cells with either AA or PGE2 increased invasiveness, whereas incubation with EPA or DHA downregulated both COX-2 mRNA and protein expression, with a subsequent decrease in Matrigel invasion. Taken together, these results indicate that omega-3 PUFA regulate COX-2-mediated invasion in brain-metastatic melanoma.

Animals↗

PubMed2005

Antisense-mediated suppression of Heparanase gene inhibits melanoma cell invasion.

Cancer metastasis, is a frequent manifestation of malignant melanoma progression. Successful invasion into distant organs by tumor cells must include attachment to microvessel endothelial cells, and degradation of basement membranes and extracellular matrix (ECM). Heparan sulfate proteoglycans (HSPG) are essential and ubiquitous macromolecules associated with the cell surface and ECM of a wide range of cells and tissues. Heparanase (HPSE-1) is an ECM degradative enzyme, which degrades the heparan sulfate (HS) chains of HSPG at specific intrachain sites. To investigate effects of changes in heparanase gene expression in metastatic melanoma cells, we constructed adenoviral vectors containing the full-length human HPSE-1 cDNA in both sense (Ad-S/hep) and antisense orientations (Ad-AS/hep). We found increased HPSE-1 expression and activity in melanoma cell lines following Ad-S/hep infection by Western blot analyses and specific HPSE-1 activity assay. Conversely, HPSE-1 content was significantly inhibited following infection with Ad-AS/Hep. Importantly, HPSE-1 modulation by these adenoviral constructs correlated with invasive cellular properties in vitro and in vivo. Our results suggest that HPSE-1 not only contributes to the invasive phenotype of melanoma cells, but also that the Ad-AS/hep-mediated inhibition of its enzymatic activity can be efficacious in the prevention and treatment of melanoma metastasis.

Adenoviridae↗

PubMed2005

Selective heparanase localization in malignant melanoma.

Heparanase (HPSE-1) is an endo-beta-D-glucuronidase that cleaves heparan sulfate proteoglycans (HSPG), and its expression has been associated with increased growth, metastasis, and angiogenesis of tumors. Since metastatic melanoma cells express high levels of HSPG and because melanoma tumors grow highly vascularized, we analyzed melanoma tissue specimens for HPSE-1 expression from experimental animals as well as from patients. Laser capture microdissection microscopy was used to extract melanoma cell populations and to isolate them from adjacent tissue. In experimental animals, a 29-fold upregulation of HPSE-1 expression was detected by real-time PCR in metastatic melanoma compared to normal lung tissue. Additionally, immunohistochemistry (IHC) revealed selective HPSE-1 staining in human metastatic melanoma when compared to primary melanoma tumors from the same patient. IHC also showed a marked staining for the enzyme around blood vessels and in vascularized regions. Our results provide evidence demonstrating that HPSE-1 likely plays important roles in regulating the in vivo growth and progression of melanoma. These results further emphasize the importance that therapies designed to block HPSE-1 activity may aid in controlling this type of cancer.

Animals↗

PubMed2005

Heparanase, TrkC and p75NTR: their functional involvement in human medulloblastoma cell invasion.

Medulloblastoma is the most common malignant childhood brain tumor. Although some previous reports have shown up to a 70% 5-year survival for some of these patients, it is at the cost of significant long-term treatment-related morbidity. The cellular mechanisms leading to metastatic disease in medulloblastoma are mainly unknown. For the first time, we demonstrate the differential expression of heparanase in medulloblastomas and how these differences at the mRNA and protein levels affect the activity and invasive properties of three newly developed cell lines. Furthermore, heparanase expression was confirmed in 7 (88%) of 8 medulloblastoma clinical samples by immunohistochemical staining. Heparanase was found to be localized in the cytoplasm and nucleus. Quantitative polymerase chain reaction revealed a negative correlation between heparanase and TrkC (which is associated with a favorable clinical outcome). The activation of TrkC or TrkC/p75NTR by NT-3 affected heparanase activity and cell-invasive properties of medulloblastoma cells in vitro. Taken together, our data extend the body of evidence that invasion and expression/functionality of heparanase, in a context linked to TrkC and p75NTR, may play critical roles in the disease progression of medulloblastoma.

Analysis of Variance↗

PubMed2004

Dominant-negative CREB inhibits heparanase functionality and melanoma cell invasion.

Heparanase (HPSE-1) is an endo-beta-D-glucuronidase involved in the degradation of cell-surface/extracellular matrix heparan sulfate (HS) in normal and neoplastic tissues. HPSE-1 represents the first example of purification and cloning of a mammalian HS-degradative enzyme. Elevated HPSE-1 levels are known to be associated with metastatic cancers, directly implicating HPSE-1 in metastatic events. The purpose of this study was to determine the role of cAMP response element-binding protein (CREB) in modulating HPSE-1-mediated effects on human melanoma cell invasion. Highly invasive, brain-metastatic melanoma cells (70W) were transfected with the dominant-negative CREB (KCREB) and subsequently analyzed for changes in their HPSE-1 content, functionality, and cell invasive properties. KCREB-transfected cells showed a decrease in HPSE-1 mRNA expression and activity. This correlated with a significantly decreased invasion of these cells through Matrigel-coated filters. Furthermore, adenoviral vectors containing the full-length human HPSE-1 cDNA in sense orientation (Ad-S/hep) were constructed to investigate CREB effects on HPSE-1. Restoration of HPSE-1 expression and functionality following Ad-S/hep infection of KCREB-transfected 70W cells recovered melanoma cell invasiveness. These results demonstrate that KCREB inhibits HPSE-1 and suggest that one of the roles CREB plays in the acquisition of melanoma cells metastatic phenotype is affecting HPSE-1 activity.

Adenoviridae↗

PubMed2004

p75 neurotrophin receptor functions as a survival receptor in brain-metastatic melanoma cells.

The p75 neurotrophin receptor (p75(NTR)), a common receptor for members of the neurotrophins (NT) family, was previously identified as a molecular determinant of brain metastasis. We have also reported that NT treatment of murine and human brain-metastatic melanoma cells affects their invasive capacities and increases the production of heparanase, an important and unique extracellular matrix (ECM) degradative enzyme. Neurotrophism can be a survival-support mechanism for brain-metastatic cells and a survival assay was devised to mimic the growth limiting conditions of rapidly expanding metastatic tumors prior to neoangiogenesis. We report that p75(NTR) promoted the survival of brain-metastatic melanoma cells but not melanocytes in stress cultures conditions. Secondly, melanoma cells fluorescently sorted for high p75(NTR) expression (p75(NTR-H) cells) had an up to a 15-fold greater survival than those sorted for low p75(NTR) expression (p75(NTR-L) cells). Thirdly, cells overexpressing p75(NTR) associated with the growth fraction and provided these cells with an inherent growth advantage. Finally, we observed an increased survival of sorted p75(NTR-L) cells, dependent upon treatment of NT members whose functional receptors are present on these cells. Together, these results delineate that p75(NTR)-mediated trophic support profoundly affects competitive melanoma-cell survival when the tumor cell microenvironment becomes growth limiting.

Animals↗

PubMed2004

Brain metastases in melanoma: roles of neurotrophins.

Brain metastasis, which occurs in 20% to 40% of all cancer patients, is an important cause of neoplastic morbidity and mortality. Successful invasion into the brain by tumor cells must include attachment to microvessel endothelial cells, penetration through the blood-brain barrier, and, of relevance, a response to brain survival and growth factors. Neurotrophins (NTs) are important in brain-invasive steps. Human melanoma cell lines express low-affinity NT receptor p75NTR in relation to their brain-metastatic propensity with their invasive properties being regulated by NGF, or nerve growth factor, the prototypic NT. They also express functional TrkC, the putative receptor for the invasion-promoting NT-3. In brain-metastatic melanoma cells, NTs promote invasion by enhancing the production of extracellular matrix (ECM)-degradative enzymes such as heparanase, an enzyme capable of locally destroying both ECM and the basement membrane of the blood-brain barrier. Heparanase is an endo-beta-d-glucuronidase that cleaves heparan sulfate (HS) chains of ECM HS proteoglycans, and it is a unique metastatic determinant because it is the dominant mammalian HS degradative enzyme. Brain-metastatic melanoma cells also produce autocrine/paracrine factors that influence their growth, invasion, and survival in the brain. Synthesis of these factors may serve to regulate NT production by brain cells adjacent to the neoplastic invasion front, such as astrocytes. Increased NT levels have been observed in tumor-adjacent tissues at the invasion front of human brain melanoma. Additionally, astrocytes may contribute to the brain-metastatic specificity of melanoma cells by producing NT-regulated heparanase. Trophic, autocrine, and paracrine growth factors may therefore determine whether metastatic cells can successfully invade, colonize, and grow in the CNS.

Animals↗

PubMed2003

Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion.

Heparanase (HPSE-1) is involved in the degradation of both cell-surface and extracellular matrix (ECM) heparan sulfate (HS) in normal and neoplastic tissues. Degradation of heparan sulfate proteoglycans (HSPG) in mammalian cells is dependent upon the enzymatic activity of HPSE-1, an endo-beta-d-glucuronidase, which cleaves HS using a specific endoglycosidic hydrolysis rather than an eliminase type of action. Elevated HPSE-1 levels are associated with metastatic cancers, directly implicating HPSE-1 in tumor progression. The mechanism of HPSE-1 action to promote tumor progression may involve multiple substrates because HS is present on both cell-surface and ECM proteoglycans. However, the specific targets of HPSE-1 action are not known. Of particular interest is the relationship between HPSE-1 and HSPG, known for their involvement in tumor progression. Syndecan-1, an HSPG, is ubiquitously expressed at the cell surface, and its role in cancer progression may depend upon its degradation. Conversely, another HSPG, perlecan, is an important component of basement membranes and ECM, which can promote invasive behavior. Down-regulation of perlecan expression suppresses the invasive behavior of neoplastic cells in vitro and inhibits tumor growth and angiogenesis in vivo. In this work we demonstrate the following. 1) HPSE-1 cleaves HS present on the cell surface of metastatic melanoma cells. 2) HPSE-1 specifically degrades HS chains of purified syndecan-1 or perlecan HS. 3) Syndecan-1 does not directly inhibit HPSE-1 enzymatic activity. 4) The presence of exogenous syndecan-1 inhibits HPSE-1-mediated invasive behavior of melanoma cells by in vitro chemoinvasion assays. 5) Inhibition of HPSE-1-induced invasion requires syndecan-1 HS chains. These results demonstrate that cell-surface syndecan-1 and ECM perlecan are degradative targets of HPSE-1, and syndecan-1 regulates HPSE-1 biological activity. This suggest that expression of syndecan-1 on the melanoma cell surface and its degradation by HPSE-1 are important determinants in the control of tumor cell invasion and metastasis.

Adenocarcinoma↗

PubMed2003

Brain-metastatic melanoma: a neurotrophic perspective.

The brain is a unique microenvironment enclosed by the skull and maintaining a highly regulated vascular transport barrier. To metastasize to the brain, malignant tumor cells must attach to microvessel endothelial cells, invade the blood-brain barrier (BBB), and respond to brain survival and growth factors. Neurotrophins (NT) are important in brain invasion because they stimulate this process. In brain-metastatic melanoma cells, NT can promote invasion by enhancing the production of extracellular matrixdegradative enzymes such as heparanase, an enzyme capable of locally destroying both the extracellular matrix and the basement membrane of the BBB. We have examined human and murine melanoma cell lines exhibiting varying abilities to form brain metastases, and have found that they express low-affinity neurotrophin receptor p75NTR in relation to their brain-metastatic potentials. They do not, however, express trkA, the gene encoding the tyrosine kinase receptor TrkA, the high-affinity receptor for nerve growth factor (NGF), the prototypic NT. Presence of functional TrkC, the putative receptor for the invasion-promoting neurotrophin NT-3, was also expressed in these cells. Brain-metastatic melanoma cells can also produce autocrine factors and inhibitors that influence their growth, invasion, and survival in the brain. Synthesis of these factors may influence NT production by brain cells adjacent to the neoplastic invasion front, such as oligodendrocytes and astrocytes. In brain biopsies, we observed increased amounts of NGF and NT-3 in tumor-adjacent tissues at the invasion front of human melanoma tumors. Additionally, we found that astrocytes contribute to the brain-metastatic specificity of melanoma cells by producing NT-regulated heparanase. Trophic, autocrine, and paracrine growth factors may therefore determine whether metastatic cells can successfully invade, colonize, and grow in the central nervous system (CNS).

Animals↗

PubMed2003

Human melanoma TrkC: its association with a purine-analog-sensitive kinase activity.

The various members of the Trk tyrosine kinase family and p75 neurotrophin receptor (p75(NTR)) have been identified as signaling receptors for the structurally related members of the neurotrophins (NT) family. We have previously reported that NT treatment of murine and human brain-metastatic melanoma cells affects their invasive capacities and increases the production of extracellular-matrix degradative enzymes. These cells express aberrant levels of functional p75(NTR) and TrkC, the putative high-affinity receptor for the neurotrophin NT-3. Here we demonstrate that, by using sensitive immune-complex kinase assays in human brain-metastatic (70W) melanoma cells, TrkC receptors associate with a kinase activity exhibiting a dose-dependent susceptibility to inhibition by the purine-analogs 6-thioguanine and 2-aminopurine. The activity of this purine-analog-sensitive kinase (PASK) was induced by NT-3 in a time-dependent fashion, phosphorylating exogenous myelin basic protein (MBP) but not denatured enolase. It is similar to the one reported to relate with p75(NTR) and TrkA receptors and stimulated by the prototypic NT, nerve growth factor. Thus, PASKs may represent unique signaling components common to NT receptors that could engage joint downstream signaling effectors in brain-metastatic melanoma.

2-Aminopurine↗

PubMed2003

Inhibition of heparanase activity and heparanase-induced angiogenesis by suramin analogues.

Heparanase, a heparan sulfate-specific endo-beta-D-glucuronidase, plays an important role in tumor cell metastasis through the degradation of extracellular matrix heparan sulfate proteoglycans (ECM HSPG). Heparanase activity correlates with the metastatic propensity of tumor cells. Suramin, a polysulfonated naphthylurea, is an inhibitor of heparanase with suramin analogues shown to possess antiangiogenic and antiproliferative properties. We investigated the effects of selected suramin analogues (NF 127, NF 145 and NF 171) on heparanase activity and heparanase-driven angiogenesis. Studies of the ability of cellular extracts and purified heparanase from human, highly invasive and brain-metastatic melanoma (70W) cells revealed that heparanase expressed by these cells was effectively inhibited by suramin analogues in a dose-dependent manner. These analogues possessed more potent heparanase inhibitory activities than suramin: The concentrations required for 50% heparanase inhibition (IC(50)) were 20-30 microM, or at least 2 times lower than that for suramin. One hundred percent inhibition was observed at concentrations of 100 microM and higher. Of relevance, these compounds significantly decreased (i) the invasive capacity of human 70W cells by chemoinvasion assays performed with filters coated with purified HSPG or Matrigel trade mark, and (ii) blood vessel formation by in vivo angiogenic assays, thus linking their antiangiogenic properties with impedance of heparanase-induced angiogenesis. Specifically, inhibition of invasion by NF 127, NF 145 and NF 171 was found at 10 microM concentrations of compounds with a significant decrease of invasive values at concentrations as low as 1.5 microM. In addition, NF 127, NF 145 and NF 171 promoted nearly complete inhibition of heparanase-induced angiogenesis at values ranging from 236 microM (for NF 145) to 362 microM (for NF 127). These results further emphasize the importance of heparanase in invasive and angiogenic mechanisms and the potential clinical application of heparanase inhibitors such as suramin analogues in cancers and angiogenesis-dependent diseases.

Antineoplastic Agents↗