It might also be a marker predicting subsequent development of invasive breast cancer. One of the well-studied functions of the HA and HAase system is the generation of angiogenic HA fragments. These angiogenic HA fragments have been shown to induce endothelial cell proliferation, migration, and adhesion. The secretion of HAase by tumor cells has been shown to induce angiogenesis. Angiogenic HA fragments are present in the urine of grade 2 and 3 bladder cancer patients, suggesting that the HA and HYAL1 system is active in bladder cancer. The HYAL1 and HYAL2 are widely distributed and degrade high MW HA in collaboration with CD44. We previously demonstrated that knockdown of HYAL1 expression in breast cancer cells resulted in decreased angiogenesis. In this study, we showed that upregulation of HYAL1 expression induced higher angiogenesis in vitro and in vivo. This was in accordance with previous reports that HYAL1 over-expression increased MVD in rat colon carcinoma xenografts, as well as the correlation of HYAL1 with MVD in bladder tumor. Which suggests that HYAL1 promotes tumor angiogenesis might be a general effect. Further studies characterizing this in other cancer models would be interest. At present, whether HAase is a tumor promoter or a repressor has been Z-VAD-FMK inhibitor controversial. The results presented in this study showed that forcing HYAL1 expression promoted tumor growth, invasion and angiogenesis supporting its role as a tumor promoter. HYAL1 levels in various cancers were associated with high-grade invasive tumors. However, Jacobson et al. found that the overexpression of HYAL1 by cDNA transfection in a rat colon carcinoma line decreased tumor growth, although the tumors were angiogenic. HYAL1 and HYAL2 have been identified to inhibit lung and renal carcinoma cell growth in vivo but not in vitro. Nykopp TK, et al found that HYAL1 and HYAL2 were coexpressed and significantly downregulated in endometrioid endometrial cancer and correlated with the accumulation of HA. The controversy surrounding HAase as a tumor promoter or a suppressor was recently explained by Lokeshwar et al. Selection of cells for expression of different HYAL1 levels showed that cells expressing amounts found in tumor tissues and cells promote tumor growth, invasion and angiogenesis. In contrast, cells with HAase levels exceeding 100 milliunits/106 cells, exhibit reduced tumor incidence and growth due to induction of apoptosis. Therefore, levels in genitourinary tumors are consistent with tumor cell derived HAase acting mainly as a tumor promoter.