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.
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 19 Jan 2016|
Bibliographical noteFunding Information:
I.V. received grant support from Sigma-Tau Research Switzerland. SST0001 is a proprietary drug of Sigma-Tau Research Switzerland. E.H. is an employee of Progen Pharmaceuticals. PG545 is a proprietary drug of Progen Pharmaceuticals. Y.Z. and M.N. are employees of Eli Lilly and Company. We thank Dr. Paul Kussie and Dr. Jacqueline Doody (Eli Lilly and Company) for supporting the development of the H1023 antiheparanase mAb. We thank Dr. Alessandro Noseda (Sigma-Tau Research Switzerland) for the kind gift of SST0001 and for his continuous help in supporting the heparanase research project. This study was supported by research grants awarded to I.V. by Sigma-Tau Research Switzerland; the Israel Science Foundation (Grant 601/14); the National Cancer Institute, NIH (Grant CA106456); the United States-Israel Binational Science Foundation; the Israel Cancer Research Fund; and the Rappaport Family Institute Fund. I.V. is a research professor at the Israel Cancer Research Fund.
- Neutralizing antibody
- Tumor growth
ASJC Scopus subject areas