In contrast, progression of tumors produced by TIM-barrel-transfected cells appeared comparable with control mock transfected cells.67 These results show that in some tumor systems

(i.e. glioma) heparanase facilitates primary tumor progression regardless of its find more Enzymatic activity, while in others (i.e. myeloma) heparanase enzymatic activity dominates (see below). Enzymatic activity-independent function of heparanase is further supported by the recent identification Inhibitors,research,lifescience,medical of T5, a functional human splice variant of heparanase.70 The emerging signaling capacity of heparanase should not come as a surprise. Enzymatic activity-independent function has been described for diverse classes of enzymes including, among others, caspases,71 cathepsins,72 plasminogen activator,73 matrix metalloproteinases (MMPs),10 and even telomerase.74 MMPs are a family of 23 zinc-dependent mammalian metalloenzymes which, after processing

to their active form, are able to cleave Inhibitors,research,lifescience,medical all known ECM components. ECM degradation by MMPs has long been implicated in cellular invasion and metastasis, yet MMPs inhibitors failed as anticancer therapeutics.75 The reason behind this disappointing conclusion combines several considerations,75 among which is the increasing awareness of a non-proteolytic function of MMPs which is not affected by MMP inhibitors.10 It is now Inhibitors,research,lifescience,medical evident that Inhibitors,research,lifescience,medical MMP function is not restricted to cleavage of ECM constituents but rather MMPs are also engaged in multiple signaling pathways that affect the tumor cells and the tumor microenvironment. Non-proteolytic function of MMPs is thought to be executed primarily by their C-terminal, hemopexin-like domain. For example, the hemopexin domain of MMP-9 but not its proteolytic activity is necessary for enhanced epithelial cell migration, mediated by the PI3-kinase pathway.76 Likewise, the hemopexin domain of MMP-9 attenuated apoptosis Inhibitors,research,lifescience,medical of leukemia cells in a Src-dependent manner. Thus, apart from their well characterized enzymatic activity function in cancer metastasis and angiogenesis, the status of heparanase and MMP research

parallels in terms of concept (enzymatic activity-independent function), methodology (i.e. transfection of catalytically inactive mutants), cellular consequences (i.e. increased cell adhesion and migration). For both 4-Aminobutyrate aminotransferase MMPs and heparanase the underlying molecular mechanism (i.e. PI3-kinase and Src activation) is executed by the C-terminus domains (hemopexin and C-domain, respectively).67 This and other examples71,72 suggest that enzyme function exceeds beyond the enzymatic aspect, thus significantly expanding the scope of the functional proteome. HEPARANASE INHIBITION STRATEGIES Attempts to inhibit heparanase enzymatic activity were initiated already in the early days of heparanase research, in parallel with the emerging clinical relevance of this activity.