Inhibition of matrix metalloproteinase-2 by halofuginone is mediated by the Egr1 transcription factor.

Halofuginone, a low-molecular-weight quinazolinone alkaloid that inhibits collagen α1(I), has been shown to suppress cancer growth, metastasis, and angiogenesis. These activities were attributed in part to the inhibition of matrix metalloproteinase-2 (MMP-2). The present study was carried out to explore the molecular mechanism underlying this effect.

Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-β in murine brain.

Neuroinflammation is typically observed in neurodegenerative diseases such as Alzheimer's disease, as well as after traumatic injury and pathogen infection. Resident immune cells, microglia and astrocytes, are activated and joined by blood-borne monocytes that traverse the blood-brain barrier and convert into activated macrophages. The activated cells express various cytokines, chemokines and proteolytic enzymes.

Dissociation between mature phenotype and impaired transmigration in dendritic cells from heparanase-deficient mice.

To reach the lymphatics, migrating dendritic cells (DCs) need to interact with the extracellular matrix (ECM). Heparanase, a mammalian endo-β-D-glucuronidase, specifically degrades heparan sulfate proteoglycans ubiquitously associated with the cell surface and ECM. The role of heparanase in the physiology of bone marrow-derived DCs was studied in mutant heparanase knock-out (Hpse-KO) mice.

Heparanase regulates thrombosis in vascular injury and stent-induced flow disturbance.

Objectives: The purpose of this study was to examine the role of heparanase in controlling thrombosis following vascular injury or endovascular stenting.

Background: The use of endovascular stents are a common clinical intervention for the treatment of arteries occluded due to vascular disease. Both heparin and heparan sulfate are known to be potent inhibitors of thrombosis.

Heparanase is essential for the development of diabetic nephropathy in mice.

Diabetic nephropathy (DN) is the major life-threatening complication of diabetes. Abnormal permselectivity of glomerular basement membrane (GBM) plays an important role in DN pathogenesis. Heparanase is the predominant enzyme that degrades heparan sulfate (HS), the main polysaccharide of the GBM.

Heparanase affects secretory granule homeostasis of murine mast cells through degrading heparin.

Background: Heparanase degradation of heparan sulfate plays important roles in a number of pathological processes, including inflammation. In vitro experiments show that heparanase is capable of degrading heparin, a polysaccharide present in mast cells (MCs), in which it has a key role in promoting the storage of secretory granule compounds.

Objective: We sought to investigate the functions of heparanase in MCs.

Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is closely associated with colon cancer. Expression of the enzyme heparanase is clearly linked to colon carcinoma progression, but its role in UC is unknown. Here we demonstrate for what we believe to be the first time the importance of heparanase in sustaining the immune-epithelial crosstalk underlying colitis-associated tumorigenesis.

Role of heparanase on hepatic uptake of intestinal derived lipoprotein and fatty streak formation in mice.

Background: Heparanase modulates the level of heparan sulfate proteoglycans (HSPGs) which have an important role in multiple cellular processes. Recent studies indicate that HSPGs have an important function in hepatic lipoprotein handling and processes involving removal of lipoprotein particles.

Principal Findings: To determine the effects of decreased HSPGs chain length on lipoprotein metabolism and atherosclerosis, transgenic mice over-expressing the human heparanase gene were studied.

Role of heparanase in radiation-enhanced invasiveness of pancreatic carcinoma.

Pancreatic cancer is characterized by very low survival rates because of high intrinsic resistance to conventional therapies. Ionizing radiation (IR)-enhanced tumor invasiveness is emerging as one mechanism responsible for the limited benefit of radiotherapy in pancreatic cancer. In this study, we establish the role of heparanase-the only known mammalian endoglycosidase that cleaves heparan sulfate-in modulating the response of pancreatic cancer to radiotherapy.

Local retention versus systemic release of soluble VEGF receptor-1 are mediated by heparin-binding and regulated by heparanase.

Rationale: The vascular endothelial growth factor (VEGF) decoy receptor soluble VEGF-R1 (sVEGF-R1) is thought to protect the cells that produce it from adverse VEGF signaling. To accomplish this role, a mechanism for pericellular retention of sVEGF-R1 is required. Local retention may also prevent the accumulation of high circulating levels of sVEGF-R1 and resulting interference with homeostatic VEGF functions in remote organs.

Involvement of heparanase in vaginal and cesarean section deliveries.

Background: Heparanase is an endo-β-D-glucuronidase dominantly involved in cell invasion, tumor angiogenesis and metastasis. Recently, we demonstrated increased levels of heparanase, tissue factor pathway inhibitor (TFPI)-2 and vascular endothelial growth factor (VEGF)-A in early miscarriages (Nadir et al., Thromb Res, 2010).

A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils.

During infection, chemokines sequestered on endothelium induce recruitment of circulating leukocytes into the tissue where they chemotax along chemokine gradients toward the afflicted site. The aim of this in vivo study was to determine whether a chemokine gradient was formed intravascularly and influenced intraluminal neutrophil crawling and transmigration. A chemokine gradient was induced by placing a macrophage inflammatory protein-2 (MIP-2)-containing (CXCL2) gel on the cremaster muscle of anesthetized wild-type mice or heparanase-overexpressing transgenic mice (hpa-tg) with truncated heparan sulfate (HS) side chains.

Heparanase promotes engraftment and prevents graft versus host disease in stem cell transplantation.

Background: Heparanase, endoglycosidase that cleaves heparan sulfate side chains of heparan sulfate proteoglycans, plays important roles in cancer metastasis, angiogenesis and inflammation.

Design And Methods: Applying a mouse model of bone marrow transplantation and transgenic mice over-expressing heparanase, we evaluated the effect of heparanase on the engraftment process and the development of graft-versus-host disease.

Results: Analysis of F1 mice undergoing allogeneic bone marrow transplantation from C57BL/6 mice demonstrated a better and faster engraftment in mice receiving cells from donors that were pretreated with heparanase.

Heparanase upregulates Th2 cytokines, ameliorating experimental autoimmune encephalitis.

Heparanase is an endo-beta-d-glucuronidase that cleaves heparan sulfate (HS) saccharide chains. The enzyme promotes cell adhesion, migration and invasion and plays a significant role in cancer metastasis, angiogenesis and inflammation. The present study focuses on the involvement of heparanase in autoimmunity, applying the murine experimental autoimmune encephalitis (EAE) model, a T-cell dependent disease often used to investigate the pathophysiology of multiple sclerosis (MS).

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase.

Heparanase is a heparan sulfate (HS) degrading endoglucuronidase that has been implicated in cell migration and inflammatory conditions. Here we used mice deficient of heparanase (Hpse(-/-)) to study the impact of heparanase on airway leukocytes. Normal numbers of macrophages and lymphocytes were present in bronchoalveolar lavage fluid of Hpse(-/-) mice, indicating that heparanase is not essential for proper homing of leukocytes to airways.

Newly generated heparanase knock-out mice unravel co-regulation of heparanase and matrix metalloproteinases.

Background: Heparanase, a mammalian endo-beta-D-glucuronidase, specifically degrades heparan sulfate proteoglycans ubiquitously associated with the cell surface and extracellular matrix. This single gene encoded enzyme is over-expressed in most human cancers, promoting tumor metastasis and angiogenesis.

Principal Findings: We report that targeted disruption of the murine heparanase gene eliminated heparanase enzymatic activity, resulting in accumulation of long heparan sulfate chains.

Alternatively spliced Spalax heparanase inhibits extracellular matrix degradation, tumor growth, and metastasis.

Heparanase is an endoglycosidase that degrades heparan sulfate (HS) at the cell surface and in the extracellular matrix. Heparanase is expressed mainly by cancer cells, and its expression is correlated with increased tumor aggressiveness, metastasis, and angiogenesis. Here, we report the cloning of a unique splice variant (splice 36) of heparanase from the subterranean blind mole rat (Spalax).

Heparanase alters arterial structure, mechanics, and repair following endovascular stenting in mice.

Heparan sulfate proteoglycans (HSPGs) are potent regulators of vascular remodeling and repair. Heparanase is the major enzyme capable of degrading heparan sulfate in mammalian cells. Here we examined the role of heparanase in controlling arterial structure, mechanics, and remodeling.

Heparanase regulates retention and proliferation of primitive Sca-1+/c-Kit+/Lin- cells via modulation of the bone marrow microenvironment.

Heparanase is involved in tumor growth and metastasis. Because of its unique cleavage of heparan sulfate, which binds cytokines, chemokines and proteases, we hypothesized that heparanase is also involved in regulation of early stages of hematopoiesis. We report reduced numbers of maturing leukocytes but elevated levels of undifferentiated Sca-1(+)/c-Kit(+)/Lin(-) cells in the bone marrow (BM) of mice overexpressing heparanase (hpa-Tg).

Heparanase induces tissue factor pathway inhibitor expression and extracellular accumulation in endothelial and tumor cells.

Heparanase activity is implicated in cell invasion, tumor metastasis and angiogenesis. Recently, we have reported that heparanase stimulates tissue factor (TF) expression in endothelial and cancer cells, resulting in elevation of coagulation activity. We hypothesized that heparanase regulates other coagulation modulators, and examined the expression and localization of tissue factor pathway inhibitor (TFPI) following heparanase over-expression or exogenous addition.

Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate.

Heparan sulfate proteoglycans (HSPGs) interact with numerous proteins of importance in animal development and homeostasis. Heparanase, which is expressed in normal tissues and upregulated in angiogenesis, cancer and inflammation, selectively cleaves beta-glucuronidic linkages in HS chains. In a previous study, we transgenically overexpressed heparanase in mice to assess the overall effects of heparanase on HS metabolism.

Tamoxifen induces heparanase expression in estrogen receptor-positive breast cancer.

Purpose: Mammalian heparanase degrades heparan sulfate, the main polysaccharide of the basement membrane. Heparanase is an important determinant in cancer progression, acting via the breakdown of extracellular barriers for invasion, as well as release of heparan sulfate-bound angiogenic and growth-promoting factors. The present study was undertaken to elucidate molecular mechanisms responsible for heparanase overexpression in breast cancer.

Heparanase enhances syndecan-1 shedding: a novel mechanism for stimulation of tumor growth and metastasis.

When shed from the cell surface, the heparan sulfate proteoglycan syndecan-1 can facilitate the growth, angiogenesis, and metastasis of tumors. Here we report that tumor cell expression of heparanase, an enzyme known to be a potent promoter of tumor progression and metastasis, regulates both the level and location of syndecan-1 within the tumor microenvironment by enhancing its synthesis and subsequent shedding from the tumor cell surface. Heparanase regulation of syndecan-1 is detected in both human myeloma and breast cancer cell lines.

Translocation of active heparanase to cell surface regulates degradation of extracellular matrix heparan sulfate upon transmigration of mature monocyte-derived dendritic cells.

After Ag capture and exposure to danger stimuli, maturing dendritic cells (DCs) migrate to regional lymph nodes, where antigenic peptides are presented to T lymphocytes. To migrate from peripheral tissue such as the epidermis to regional lymph nodes, Ag-bearing epidermal Langerhans cells must move through an extracellular matrix (ECM) of various compositions. The nature of their capacity to transmigrate via ECM is not well understood, although MIP-3beta and CCR7 play critical roles.