Heparanase enhances myeloma progression via CXCL10 downregulation.
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.
Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
U
U
Barash
Department of Immunology, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Y
Y
Zohar
Department of Immunology, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
G
G
Wildbaum
Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel.
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K
Beider
Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel.
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A
Nagler
Department of Immunology, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
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N
Karin
Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
N
N
Ilan
Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
I
I
Vlodavsky
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D049109:Cell Proliferation; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D000099175:Heparanase
D000900:Anti-Bacterial Agents; D054357:Chemokine CXCL10; D004318:Doxycycline; D005966:Glucuronidase; D000099175:Heparanase; C114753:CXCL10 protein, human; C485433:Cxcl10 protein, mouse