Heparanase, an endoglycosidase that cleaves heparan sulfate chains, is upregulated in many types of cancers and promotes an aggressive tumor phenotype. Heparanase is present in the bone marrow of myeloma patients where high levels of the enzyme correlate with enhanced angiogenesis and poor prognosis. Using in vivo models, we have shown that heparanase is a key driver of myeloma growth, osteolysis and metastasis. In order to explore the significance of heparanase in myeloma, we established an inducible model system in CAG human myeloma cells. In this system, heparanase gene expression is constantly repressed; gene induction is obtained following the addition of tetracycline (or its analog doxycycline; Dox) to the cell culture medium or drinking water of mice. To investigate alteration in gene expression associated with heparanase induction and tumor development, we applied gene array methodology. Consistently, we found that heparanase induction by Dox is associated with decreased levels of CXCL10, suggesting that this chemokine functions as a tumor suppressor. Indeed, recombinant CXCL10 attenuated proliferation of CAG, U266 and RPMI-8266 myeloma cells. Similarly, CXCL10 attenuated proliferation of human umbilical vein endothelial cells (HUVEC), implying that CXCL10 exhibits anti-angiogenic property. Likewise, CXCL10 over-expression by CAG cells resulted in reduced viability and decreased number and size of colonies in soft agar. Strikingly, tumor xenografts produced by CAG cells over-expressing CXCL10 was markedly reduced compared with control cells. Immunostaining of tumor specimens revealed lower proliferation rate (BrdU incorporation) and blood vessel density (CD31 staining) following CXCL10 over-expression. CXCL10 repression was not affected by heparanase inhibitors (i.e., heparin and heparin analogs), suggesting that CXCL10 repression is independent of heparanase enzymatic activity and thus represents a novel mechanism by which heparanase facilitates tumor progression.