Heparanase as mediator of angiogenesis: mode of action

Elkin, Michael; Ilan, Neta; Ishai-Michaeli, Rivka; Friedmann, Yael; Papo, Orit; Pecker, Iris; Vlodavsky, Israël

doi:10.1096/fj.00-0895fje

Cited by 296 publications

(311 citation statements)

References 30 publications

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“…5) critically stamp the proangiogenic capacity of heparanase (3). This is most likely a result of reduced release by heparanase of angiogenicpromoting factors sequestered in the bone marrow ECM (41). Similar inhibition of angiogenesis was evident in tumors produced by SU-DHL-6 cells and treated with heparanase-neutralizing polyclonal Ab 1453 (Fig.…”

Section: Discussionsupporting

confidence: 53%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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106

140

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Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanaseneutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment.heparanase | lymphoma | neutralizing antibody | tumor growth | metastasis H eparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, releasing saccharide products with appreciable size (4-7 kDa) and biological potency. Enzymatic degradation of HS leads to disassembly of the extracellular matrix (ECM) and correlates with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the ECM and basement membrane underlying epithelial and endothelial cells (1, 2). Heparanase expression is induced in human cancer, most often associating with reduced patients' survival postoperation, increased tumor metastasis, and higher vessel density (3-5). In addition, heparanase up-regulation is associated with tumors larger in size (3, 5). Likewise, heparanase over-expression enhanced (6, 7), whereas local delivery of anti-heparanase siRNA inhibited (8), the growth of tumor xenografts. These results imply that heparanase function is not limited to tumor metastasis but is engaged in progression of the primary lesion, thus critically supporting the intimate involvement of heparanase in tumor progression and encouraging the development of heparanase inhibitors as anticancer therapeutics (9-12). As a consequence, heparanase inhibitors are currently evaluated in phase 1 clinical trials (13).Heparanase activity is similarly implicated in the progression of multiple myeloma (14-16), but its significan...

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Section: Discussionsupporting

confidence: 53%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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106

140

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“…HPSE is known to release the surface-bound VEGF by shedding the cellular glycocalyx as well as the ECM 1 . More recently, we could demonstrate that VEGF availability is also related to the extracellular activity of MMP-9 and MMP-2 22,27 .…”

Section: Knockdown Of Hpse Enhances the Expression Of Mmp But Reducesmentioning

confidence: 99%

“…As the only known enzyme for heparan sulfate (HS) degradation from extracellular matrix (ECM), heparanase-1 (HPSE) mediates the release of HS-bound growth factors (i.e., vascular endothelial growth factor (VEGF)), thus promoting endothelial cell activation and angiogenic responses 1,2 , a process that is further supported by HPSE-generated fragments of HS 3 .…”

Section: Introductionmentioning

confidence: 99%

Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity

et al. 2015

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Heparanase-1 (HPSE) plays a pivotal role in structural remodeling of the ECM and glycocalyx thus conferring protumorigenic, proangiogenic and prometastatic properties to many cancer entities. In addition to its extracellular function, recent studies suggest an intracellular activity of HPSE with a largely unknown significance during tumor progression. Therefore, we investigated the relevance of HPSE duality in malignant melanoma in vitro as well as in mouse melanoma models basing on the intradermal injection of transfected melanoma cells. In line with its extracellular action, HPSE-deficiency led to a reduced shedding of the glycocalyx accompanied by a reduced availability of VEGF affecting tumor growth and vascularization. In contrast, we measured an elevated expression of the protumorigenic factors pentraxin-3, tissue factor, TNF-and most prominently MMP-9 upon HPSE knockdown. In vivo, HPSE-deficiency was related to increased lymph node metastasis. While inhibition of its extracellular function heparin was unable to block the gene regulatory impact of HPSE we proposed an intracellular mechanism. Immunostainings revealed a counter-staining of HPSE and NF-B in the nucleus suggesting a close relationship between both proteins. This finding was further supported by the discovery of a direct charge-driven molecular interaction between HPSE and DNA by using atomic force microscopy and a co-precipitation approach. Our findings are novel and point towards a dual identity of HPSE in malignant melanoma with a protumorigenic extracellular activity and a tumor suppressive nuclear action. Identification of molecular strategies to shuttle extracellular HPSE into the nuclei of cancer cells envisions new therapeutic options. AbstractHeparanase-1 (HPSE) plays a pivotal role in structural remodeling of the ECM and glycocalyx thus conferring protumorigenic, proangiogenic and prometastatic properties to many cancer entities. In addition to its extracellular function, recent studies suggest an intracellular activity of HPSE with a largely unknown significance during tumor progression.Therefore, we investigated the relevance of HPSE duality in malignant melanoma in vitro as well as in mouse melanoma models basing on the intradermal injection of transfected melanoma cells. In line with its extracellular action, HPSE-deficiency led to a reduced shedding of the glycocalyx accompanied by a reduced availability of VEGF affecting tumor growth and vascularization. In contrast, we measured an elevated expression of the protumorigenic factors pentraxin-3, tissue factor, TNF-α and most prominently MMP-9 upon HPSE knockdown. In vivo, HPSE-deficiency was related to increased lymph node metastasis.While inhibition of its extracellular function heparin was unable to block the gene regulatory impact of HPSE we proposed an intracellular mechanism. Immunostainings revealed a counter-staining of HPSE and NF-κB in the nucleus suggesting a close relationship between both proteins. This finding was further supported by the discovery of a dir...

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“…Heparanase activity is traditionally associated with modulating of the molecular structure of ECM and subendothelial basement membrane, resulting in release of various factors, thereby affecting normal and pathological processes. 9,35 Heparanase has also been shown to exert non-enzymatic effects, including phosphorylation of a number of factors. 36,37 Its translocation to the nucleus in various cell types may be an additional, potential, mechanism affecting gene transcription.…”

Section: Figurementioning

confidence: 99%

Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats

Ohayon

Mawasi

Pevzner

et al. 2008

Laboratory Investigation

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Heparanase as mediator of angiogenesis: mode of action

Cited by 296 publications

References 30 publications

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity

Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats

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