A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer.
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.
Joyce
Johanna A
JA
Department of Biochemistry and Biophysics, Diabetes and Comprehensive Cancer Centers, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0534, USA. joycej@mskcc.org.or
Freeman
Craig
C
Meyer-Morse
Nicole
N
Parish
Christopher R
CR
Hanahan
Douglas
D
D000595:Amino Acid Sequence; D000818:Animals; D002196:Capillaries / Q000502:physiology; D002417:Cattle; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism* / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010190:Pancreatic Neoplasms / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry; D016133:Polymerase Chain Reaction / Q000379:methods; D000099175:Heparanase
D005966:Glucuronidase; D006497:Heparan Sulfate; D010446:Peptide Fragments; D000099175:Heparanase