Impact of Heparanase and the Tumor Microenvironment on Cancer Metastasis and Angiogenesis: Basic Aspects and Clinical Applications

摘要

Heparanase is an endo-β-D-glucuronidase that cleaves heparan sulfate (HS) side chains at a limited number of sites, activity that is strongly implicated with cell invasion associated with cancer metastasis, a consequence of structural modification that loosens the extracellular matrix barrier. Heparanase activity is also implicated in neovascularization, inflammation, and autoimmunity, involving migration of vascular endothelial cells and activated cells of the immune system. The cloning of a single human heparanase cDNA 10 years ago enabled researchers to critically approve the notion that HS cleavage by heparanase is required for structural remodeling of the extracellular matrix (ECM), thereby facilitating cell invasion. Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an invasive phenotype in experimental animals. The enzyme also releases angiogenic factors residing in the tumor microenvironment and thereby induces an angiogenic response in vivo. Heparanase up-regulation correlates with increased tumor vascularity and poor postoperative survival of cancer patients. These observations, the anticancerous effect of heparanase gene silencing and of heparanase-inhibiting molecules, as well as the unexpected identification of a single functional heparanase suggest that the enzyme is a promising target for anticancer drug development. Progress in the field expanded the scope of heparanase function and its significance in tumor progression and other pathologies such as inflammatory bowel disease and diabetic nephropathy. Notably, while heparanase inhibitors attenuated tumor progression and metastasis in several experimental systems, other studies revealed that heparanase also functions in an enzymatic activity-independent manner. Thus, point-mutated inactive heparanase was noted to promote phosphorylation of signaling molecules such as Akt and Src, facilitating gene transcription (i.e. VEGF) and phosphorylation of selected Src substrates (i.e. EGF receptor). The concept of enzymatic activity-independent function of heparanase gained substantial support by elucidation of the heparanase C-terminus domain as the molecular determinant behind its signaling capacity and the identification of a human heparanase splice variant (T5) devoid of enzymatic activity, yet endowed with protumorigenic characteristics. Resolving the heparanase crystal structure will accelerate rational design of effective inhibitory molecules and neutralizing antibodies, paving the way for advanced clinical trials in patients with cancer and other diseases involving heparanase.Keywords: Heparanase, heparan sulfate, extracellular matrix, angiogenesis, metastasis, inflammation, myeloma, signaling, C-domain, matrix metalloproteinasePREFACEThe extracellular matrix (ECM) is a heterogeneous mixture of proteins and polysaccharides that surrounds cells, providing physical support for cellular organization into tissue and organs. Traditionally, the ECM was regarded as an inert scaffold providing a structural framework for cells to form tissues and organs. Specifically, our research focuses on heparan sulfate (HS) glycosaminoglycan (GAG), one of the most important subsets of the ECM and cell surface molecules, shown to have a pronounced effect on fundamental biological processes, ranging from development and formation of blood vessels to cell invasion and viral infection. While 4 and 20 building-blocks make nucleic acids and proteins, respectively, 32 disaccharide building-blocks make up these complex, highly acidic, and information-dense biopolymers. The chemical heterogeneity and structural complexity of GAGs make investigations of these molecules most challenging, with fundamental questions arising as to how topological positioning and function of cells and tissues are regulated by GAGs.Back in 1979, we were among the first to realize that the ECM plays an active role in orchestrating cellular responses to both normal an