Prodding the Beast: Assessing the Impact of Treatment-Induced Metastasis

Ebos, John M.L.

doi:10.1158/0008-5472.can-15-0308

Cited by 50 publications

(61 citation statements)

References 139 publications

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“…4) supports this notion and encourages the identification and targeting of additional functional domains of heparanase by means of neutralizing mAbs or small molecule inhibitors. Importantly, evidence accumulating in recent years shows that targeting the tumor microenvironment (i.e., VEGF) unexpectedly results in accelerated metastasis and more aggressive disease (42). In contrast, heparanase targeting uniquely inhibits both tumor growth and metastasis, thus possibly offering new opportunities and a safer mode to obstruct the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

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

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%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

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

140

View full text Add to dashboard Cite

show abstract

“…Importantly, evidence accumulating in recent years shows that targeting the tumor microenvironment (i.e., VEGF), may unexpectedly result in accelerated metastasis and more aggressive disease. 20 In contrast, our results indicate that heparanase targeting uniquely inhibits both tumor growth and metastasis, thus offering new opportunities and a safer mode to obstruct the tumor microenvironment.…”

Section: Heparanase Neutralizing Antibodiesmentioning

confidence: 69%

Heparanase and cancer progression: New directions, new promises

Arvatz¹,

Weissmann²,

Ilan³

et al. 2016

Human Vaccines & Immunotherapeutics

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Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor progression. Heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Numerous clinical association studies have consistently demonstrated that upregulated heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. Notably, heparanase is ranked among the most frequently recognized tumor antigens in patients with pancreatic, colorectal or breast cancer, favoring heparanase-based immunotherapy. Development of heparanase inhibitors focused on carbohydrate-based compounds of which 4 are being evaluated in clinical trials for various types of cancer, including myeloma, pancreatic carcinoma and hepatocellular carcinoma. Owing to their heparin-like nature, these compounds may exert off target effects. Newly generated heparanase neutralizing monoclonal antibodies profoundly attenuated myeloma and lymphoma tumor growth and dissemination in preclinical models, likely by targeting heparanase in the tumor microenvironment. KEYWORDSHeparanase; immunotherapy; lymphoma; neutralizing monoclonal antibody; tumor microenvironment Heparanase and cancerHeparan sulfate (HS) proteoglycans (HSPGs) are ubiquitous macromolecules associated with the cell surface and extracellular matrix (ECM) of a wide range of tissues.1 The HS chains bind to and assemble ECM proteins, thus playing important roles in ECM integrity, barrier function and cell-ECM interactions.1 HSPGs not only provide a storage depot for heparin-binding molecules (i.e., growth factors, chemokines, enzymes) in the tumor microenvironment, but also decisively regulate their accessibility, function and mode of action. It is therefore not surprising that a HS degrading enzyme (i.e., heparanase) is critically involved in tumor growth, angiogenesis and metastasis. Mammalian cells express a single dominant functional heparanase, an endoglycosidase that cleaves HS, leading to disassembly of the ECM and release of HS-bound bioactive molecules, thereby affecting tumor progression, angiogenesis and inflammation.2-4 The heparanase mRNA encodes a 65 kDa pro-enzyme that is cleaved by cathepsin L into 8 and 50 kDa subunits that non-covalently associate to form the active enzyme.5 Heparanase is up-regulated in essentially all human tumors examined, most often associating with reduced patients' survival post operation, increased tumor metastasis and higher vessel density.2,6,7 A causal role of heparanase in tumor metastasis was demonstrated by the increased lung, liver and bone colonization of cancer cells following over-expression of the heparanase gene, and by a marked decrease in the metastatic potential of cells s...

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“…It has been shown earlier that radiation changes the tumour environment and enhances metastasis in vitro, as well as in vivo, by different mechanisms (170).…”

Section: Impact Of Aeg-1 In Radiation-enhanced Metastasismentioning

confidence: 99%

“…All cancer treatments currently used in clinical practice including surgery, chemotherapy, and RT have proven their effect in large clinical trials including several hundreds to thousands of patients, but they may also create phenotypes and niches that facilitate metastatic spread (170).…”

Section: Treatment-enhanced Metastasismentioning

confidence: 99%

“…Since then, several studies have analysed the effect of radiation-enhanced metastasis, mainly using in vitro cell culture models and in vivo mouse models. Two distinct effects have been established: increased localisation of metastases in radiated tissue, and increase in metastases upon local tumour radiation (170,172,173). …”

Section: Treatment-enhanced Metastasismentioning

confidence: 99%

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