Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis
| Autor: | Sari Feld, Eviatar Nevo, Neta Ilan, Marina Weissmann, Netanel A. Horowitz, Israel Vlodavsky, Edward Hammond, Mary Ng, Yi Zhang, Gil Arvatz, Inna Naroditsky |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Lymphoma medicine.drug_class Angiogenesis Mice SCID Biology Monoclonal antibody Metastasis Extracellular matrix 03 medical and health sciences 0302 clinical medicine Mice Inbred NOD Tumor Microenvironment medicine Animals Humans Heparanase Neoplasm Metastasis Luciferases Cell Proliferation Glucuronidase Mice Inbred BALB C Tumor microenvironment Multidisciplinary Cell growth Antibodies Monoclonal Saponins Biological Sciences medicine.disease Antibodies Neutralizing Xenograft Model Antitumor Assays Recombinant Proteins Tumor Burden Raji cell Molecular Weight HEK293 Cells 030104 developmental biology 030220 oncology & carcinogenesis Cancer research |
| Zdroj: | Proceedings of the National Academy of Sciences. 113:704-709 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1519453113 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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