The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics

Hammond, Edward; Khurana, Ashwani; Shridhar, Viji; Dredge, Keith

doi:10.3389/fonc.2014.00195

Cited by 162 publications

(189 citation statements)

References 153 publications

(183 reference statements)

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“…Since then, a variety of inhibitory molecules have been developed, including peptides, small molecules, and modified nonanticoagulant species of heparin, as well as several other polyanionic molecules such as laminaran sulfate, suramin, PI-88, and PG545 (13). Similarly, antiheparanase polyclonal Abs were developed and demonstrated to neutralize heparanase enzymatic activity and to inhibit cell invasion (27), proteinuria (28), and neointima formation (29).…”

Section: Discussionmentioning

confidence: 99%

“…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)(10)(11)(12). As a consequence, heparanase inhibitors are currently evaluated in phase 1 clinical trials (13).…”

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confidence: 99%

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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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104

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: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

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

Self Cite

104

140

View full text Add to dashboard Cite

show abstract

“…Tumor cell-derived heparanase contributes to all these processes, thereby sustaining tumor cell proliferation, vascularization, and metastasis. It is therefore not surprising that the expression of heparanase is frequently upregulated in malignant cells and correlates with poor prognosis and metastatic potential (14)(15)(16). Heparanase is thus considered a highly promising target for anticancer therapy, and the first clinical trials using heparan sulfate (HS) mimetics have enrolled patients.…”

Section: Introductionmentioning

confidence: 99%

NK cell heparanase controls tumor invasion and immune surveillance

Putz

Mayfosh

Kos

et al. 2017

Journal of Clinical Investigation

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“…[8][9][10] Cancer-related changes are typically characterized by degradation of heparan sulfate (HS) chains/sulfation patterns via the endo-6-Osulfatases (Sulf1 and Sulf2) or by heparanase, which results not just in structural but also functional consequences, which significantly impact tumor microenvironment and cancer progression. [11][12][13] Understanding of molecular mechanisms involved in the pathological changes in HS composition and fine structure in cancer tissues is directly related to the nature of their biosynthesis and degradation. A principal difference between template-based biosynthesis (proteins, DNA, RNA) and non-template driven process of HS biosynthesis exists.…”

Section: Introductionmentioning

confidence: 99%

Tissue-specificity of heparan sulfate biosynthetic machinery in cancer

Suhovskih

Domanitskaya

Tsidulko

et al. 2015

Cell Adhesion & Migration

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Heparan sulfate (HS) proteoglycans are key components of cell microenvironment and fine structure of their polysaccharide HS chains plays an important role in cell-cell interactions, adhesion, migration and signaling. It is formed on non-template basis, so, structure and functional activity of HS biosynthetic machinery is crucial for correct HS biosynthesis and post-synthetic modification. To reveal cancer-related changes in transcriptional pattern of HS biosynthetic system, the expression of HS metabolism-involved genes (EXT1/2, NDST1/2, GLCE, 3OST1/HS3ST1, SULF1/ 2, HPSE) in human normal (fibroblasts, PNT2) and cancer (MCF7, LNCaP, PC3, DU145, H157, H647, A549, U2020, U87, HT116, KRC/Y) cell lines and breast, prostate, colon tumors was studied. Real-time RT-PCR and Western-blot analyses revealed specific transcriptional patterns and expression levels of HS biosynthetic system both in different cell lines in vitro and cancers in vivo. Balance between transcriptional activities of elongation-and post-synthetic modificationinvolved genes was suggested as most informative parameter for HS biosynthetic machinery characterization. Normal human fibroblasts showed elongation-oriented HS biosynthesis, while PNT2 prostate epithelial cells had modificationoriented one. However, cancer epithelial cells demonstrated common tendency to acquire fibroblast-like elongationoriented mode of HS biosynthetic system. Surprisingly, aggressive metastatic cancer cells (U2020, DU145, KRC/Y) retained modification-oriented HS biosynthesis similar to normal PNT2 cells, possibly enabling the cells to keep like-tonormal cell surface glycosylation pattern to escape antimetastatic control. The obtained results show the cell typespecific changes of HS-biosynthetic machinery in cancer cells in vitro and tissue-specific changes in different cancers in vivo, supporting a close involvement of HS biosynthetic system in carcinogenesis.

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The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics

Cited by 162 publications

References 153 publications

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

NK cell heparanase controls tumor invasion and immune surveillance

Tissue-specificity of heparan sulfate biosynthetic machinery in cancer

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