A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer

• Published in: Oncogene Vol. 24; no. 25; pp. 4037 - 4051
• Main Authors: JOYCE, Johanna A, FREEMAN, Craig, MEYER-MORSE, Nicole, PARISH, Christopher R, HANAHAN, Douglas
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 09.06.2005; Nature Publishing Group
• Subjects: Amino Acid Sequence; Angiogenesis; Animals; Apoptosis; Biological and medical sciences; Capillaries - physiology; Carcinogenesis; Carcinoma; Cattle; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chemokines; Disease Models, Animal; Endothelium; Endothelium, Vascular - physiology; Extracellular matrix; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Gene Expression Regulation, Neoplastic; Glucuronidase - genetics; Glucuronidase - metabolism; Growth factors; Heparan sulfate; Heparan sulfate proteoglycans; Heparitin Sulfate - metabolism; Heparitin Sulfate - pharmacology; Invasiveness; Islets of Langerhans - blood supply; Islets of Langerhans - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Mammalian cells; Medical sciences; Mice; Molecular and cellular biology; Molecular Sequence Data; mRNA; Neovascularization, Pathologic - physiopathology; Oligosaccharides; Pancreatic cancer; Pancreatic Neoplasms - genetics; Peptide Fragments - chemistry; Polymerase Chain Reaction - methods; Proteoglycans; Sulfates; Tumorigenesis; Tumors; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; Animal model; mouse model; heparan sulfate-binding proteins; Rodentia; heparanase; Malignant tumor; Sulfates; Carcinogenesis; Angiogenesis; Binding protein; Vertebrata; Mammalia; Mouse; invasion; Pancreas cancer; pancreatic neuroendocrine cancer; Digestive diseases; Pancreatic disease
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1208602

Heparan sulfate proteoglycans are integral components of the extracellular matrix that surrounds all mammalian cells. In addition to providing structural integrity, they act as a storage depot for a variety of heparan sulfate (HS)-binding proteins, including growth factors and chemokines. Heparanase is a matrix-degrading enzyme that cleaves heparan sulfate side chains from the core proteoglycans, thus liberating such HS-binding proteins, as well as potentially contributing to extracellular matrix degradation. Here, we report that heparanase mRNA and protein expression are increased in the neoplastic stages progressively unfolding in a mouse model of multistage pancreatic islet carcinogenesis. Notably, heparanase is delivered to the neoplastic lesions in large part by infiltrating Gr1+/Mac1+ innate immune cells. A sulfated oligosaccharide mimetic of heparan sulfate, PI-88, was used to inhibit simultaneously both heparanase activity and HS effector functions. PI-88 had significant effects at distinct stages of tumorigenesis, producing a reduction in the number of early progenitor lesions and an impairment of tumor growth at later stages. These responses were associated with decreased cell proliferation, increased apoptosis, impaired angiogenesis, and a substantive reduction in the number of invasive carcinomas. In addition, we show that the reduction in tumor angiogenesis is correlated with a reduced association of VEGF-A with its receptor VEGF-R2 on the tumor endothelium, implicating heparanase in the mobilization of matrix-associated VEGF. These data encourage clinical applications of inhibitors such as PI-88 for the many human cancers where heparanase expression is elevated or mobilization of HS-binding regulatory factors is implicated.