title: Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis.
abstract: 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 heparanase-neutralizing 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.
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel;
authors.forename: Marina
authors.initials: M
authors.lastname: Weissmann
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel;
authors.forename: Gil
authors.initials: G
authors.lastname: Arvatz
authors.affiliation: Department of Hematology, Rambam Health Care Campus, Haifa 31096, Israel;
authors.forename: Netanel
authors.initials: N
authors.lastname: Horowitz
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel;
authors.forename: Sari
authors.initials: S
authors.lastname: Feld
authors.affiliation: Department of Pathology, Rambam Health Care Campus, Haifa 31096, Israel;
authors.forename: Inna
authors.initials: I
authors.lastname: Naroditsky
authors.affiliation: Eli Lilly and Company, Alexandria Center for Life Sciences, New York, NY 10048;
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Eli Lilly and Company, Alexandria Center for Life Sciences, New York, NY 10048;
authors.forename: Mary
authors.initials: M
authors.lastname: Ng
authors.affiliation: Progen Pharmaceuticals, Brisbane 4076, Queensland, Australia;
authors.forename: Edward
authors.initials: E
authors.lastname: Hammond
authors.affiliation: Institute of Evolution, University of Haifa, Haifa 3498838, Israel nevo@research.haifa.ac.il vlodavsk@mail.huji.ac.il.
authors.forename: Eviatar
authors.initials: E
authors.lastname: Nevo
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel; nevo@research.haifa.ac.il vlodavsk@mail.huji.ac.il.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel;
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology* / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D005966:Glucuronidase / Q000276:immunology* / Q000302:isolation & purification; D057809:HEK293 Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008223:Lymphoma / Q000473:pathology*; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008970:Molecular Weight; D009362:Neoplasm Metastasis; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D012503:Saponins / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099175:Heparanase
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D005966:Glucuronidase; D008156:Luciferases; D011994:Recombinant Proteins; D012503:Saponins; D000099175:Heparanase; C557899:PG 545
keywords: heparanase; lymphoma; metastasis; neutralizing antibody; tumor growth