In addition, activated macrophages secrete cathepsin L – a cysteine protease responsible for proteolytic activation of latent heparanase enzyme. Altogether, our
results identify heparanase as a key factor in pathogenesis of colitis-associated cancer and attest the inhibition of heparanase as a promising mean to disrupt the vicious cycle that fuels chronic colitis and the associated tumorigenesis. O96 The Role of Heparanase in Promoting Multistage Pancreatic Islet Tumorigenesis Karen Hunter 1 , Carmela STI571 order Palermo1, Karoline Dubin1, Israel Vlodavsky2, Johanna Joyce1 1 Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 2 The Cancer and RG 7204 Vascular Biology Research Center, Technion – Israel Institute of Technology, Haifa, Israel Heparanase is a matrix-degrading enzyme whose increased expression is significantly associated with malignant progression in many human cancers. We have previously shown that heparanase expression increases during tumorigenesis in the RIP1-Tag2 (RT2) transgenic mouse model of pancreatic islet carcinogenesis. Moreover, we have found that heparanase
is expressed in human pancreatic neuroendocrine tumors and its increased expression is correlated with metastases. However, the exact molecular and cellular mechanisms by which this enzyme functions in pancreatic tumorigenesis remain to be elucidated. To study the role of heparanase in RT2 tumorigenesis,
we crossed transgenic mice that constitutively overexpress heparanase (hpa-Tg) to RT2 mice to generate the hpa-Tg RT2 line. Hpa-Tg RT2 mice exhibit increased tumor invasion, angiogenesis and lymphangiogenesis. To further investigate heparanase function in RT2 tumorigenesis, heparanase knockout mice have been crossed to RT2 mice. These mice are currently being analyzed for multiple parameters of tumorigenesis. check details Additionally, a heparanase-overexpressing β-tumor cell line (Hpa-βTC) was derived from a hpa-Tg RT2 tumor and utilized in in vitro approaches to dissect the mechanisms by which heparanase promotes tumor progression. The Hpa-βTC line was found to be highly invasive in Matrigel invasion assays when compared to a wildtype βTC line (WT-βTC). Furthermore increased heparanase expression renders the Hpa-βTC line highly motile when tested in cell migration assays. Interestingly, the WT βTC line has a very low intrinsic migration ability that can be significantly enhanced by factors secreted by the Hpa-βTC line in co-culture assays. Efforts are currently underway to identify the precise factors that are secreted by heparanase overexpressing cells in the tumor microenvironment to promote malignant tumor progression.