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  • Original Article
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Heparanase enhances myeloma progression via CXCL10 downregulation

Abstract

In order to explore the mechanism(s) underlying the pro-tumorigenic capacity of heparanase, we established an inducible Tet-on system. Heparanase expression was markedly increased following addition of doxycycline (Dox) to the culture medium of CAG human myeloma cells infected with the inducible heparanase gene construct, resulting in increased colony number and size in soft agar. Moreover, tumor xenografts produced by CAG-heparanase cells were markedly increased in mice supplemented with Dox in their drinking water compared with control mice maintained without Dox. Consistently, we found that heparanase induction is associated with decreased levels of CXCL10, suggesting that this chemokine exerts tumor-suppressor properties in myeloma. Indeed, recombinant CXCL10 attenuated the proliferation of CAG, U266 and RPMI-8266 myeloma cells. Similarly, CXCL10 attenuated the proliferation of human umbilical vein endothelial cells, implying that CXCL10 exhibits anti-angiogenic capacity. Strikingly, development of tumor xenografts produced by CAG-heparanase cells overexpressing CXCL10 was markedly reduced compared with control cells. Moreover, tumor growth was significantly attenuated in mice inoculated with human or mouse myeloma cells and treated with CXCL10–Ig fusion protein, indicating that CXCL10 functions as a potent anti-myeloma cytokine.

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Acknowledgements

We acknowledge the devoted help of Dr Liat Linde and Dr Boaz Kigel (Rappaport Faculty of Medicine) in performing the gene array methodology and purification of the CXCL10–Ig fusion protein, respectively. This study was supported (in part) by research funding from the Israel Science Foundation (grant 593/10); National Cancer Institute, NIH (grant CA106456); the Israel Cancer Research Fund (ICRF); and the Rappaport Family Institute Fund to I Vlodavsky. I Vlodavsky is a research professor of the ICRF.

Author contributions

UB, GW and KB designed and performed experiments, analyzed and interpreted data; YZ, NK and AN provided valuable reagents, designed, analyzed and interpreted data; NI co-directed the study, designed, analyzed and interpreted data and wrote the manuscript; IV directed the study, designed, analyzed and interpreted data and co-wrote the manuscript.

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Correspondence to I Vlodavsky.

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Barash, U., Zohar, Y., Wildbaum, G. et al. Heparanase enhances myeloma progression via CXCL10 downregulation. Leukemia 28, 2178–2187 (2014). https://doi.org/10.1038/leu.2014.121

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