title: Heparanase promotes lymphangiogenesis and tumor invasion in pancreatic neuroendocrine tumors.
abstract: Heparan sulfate proteoglycans are an important and abundant component of the extracellular matrix, which undergo substantial remodeling throughout tumorigenesis via the enzymatic activity of heparanase. Heparanase has been shown to be upregulated in many human cancers; however, its specific functions in human pancreatic neuroendocrine tumors (PanNETs) and spontaneous mouse models of cancer have not been evaluated. Here, we investigated the role of heparanase in PanNETs using patient samples and the RIP1-Tag2 (RT2) PanNET-transgenic mouse model. High heparanase expression significantly correlated with more advanced tumor stage, higher tumor grade and the presence of distant metastasis in PanNET patients. We genetically manipulated heparanase levels in the RT2 model using heparanase-transgenic mice, which constitutively overexpress heparanase, and heparanase-knockout mice. Heparanase was found to have a critical role in promoting tumor invasion, through both macrophage and cancer cell sources in the tumor microenvironment. In addition, elevated heparanase levels significantly increased peritumoral lymphangiogenesis in vivo and promoted the trans-differentiation of macrophages into lymphatic endothelial cell-like structures in culture. Conversely, we found that heparanase deletion led to increased angiogenesis and pericyte coverage. Together, these data identify important roles for heparanase in regulating several critical aspects of tumorigenesis, demonstrating that heparanase represents a potential therapeutic target for PanNET patients.
authors: 1] Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: K E
authors: KE
authors: Hunter
authors: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: C
authors: C
authors: Palermo
authors: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: J C
authors: JC
authors: Kester
authors: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: K
authors: K
authors: Simpson
authors: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors: J-P
authors: JP
authors: Li
authors: Pathology Department, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: L H
authors: LH
authors: Tang
authors: Pathology Department, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: D S
authors: DS
authors: Klimstra
authors: Cancer and Vascular Research Center, Rappaport Faculty of Medicine, Technion, Israel.
authors: I
authors: I
authors: Vlodavsky
authors: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: J A
authors: JA
authors: Joyce
mesh_terms: D000818:Animals; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D042583:Lymphangiogenesis / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D018358:Neuroendocrine Tumors / Q000201:enzymology* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D000099175:Heparanase
chemical_list: D020690:GTPase-Activating Proteins; D005966:Glucuronidase; D019812:Heparan Sulfate Proteoglycans; D000099175:Heparanase; C490620:Ralbp1 protein, mouse