title: Heparanase is required for activation and function of macrophages.
abstract: The emerging role of heparanase in tumor initiation, growth, metastasis, and chemoresistance is well recognized and is encouraging the development of heparanase inhibitors as anticancer drugs. Unlike the function of heparanase in cancer cells, very little attention has been given to heparanase contributed by cells composing the tumor microenvironment. Here we used a genetic approach and examined the behavior and function of macrophages isolated from wild-type (WT) and heparanase-knockout (Hpa-KO) mice. Hpa-KO macrophages express lower levels of cytokines (e.g., TNFα, IL1-β) and exhibit lower motility and phagocytic capacities. Intriguingly, inoculation of control monocytes together with Lewis lung carcinoma (LLC) cells into Hpa-KO mice resulted in nearly complete inhibition of tumor growth. In striking contrast, inoculating LLC cells together with monocytes isolated from Hpa-KO mice did not affect tumor growth, indicating that heparanase is critically required for activation and function of macrophages. Mechanistically, we describe a linear cascade by which heparanase activates Erk, p38, and JNK signaling in macrophages, leading to increased c-Fos levels and induction of cytokine expression in a manner that apparently does not require heparanase enzymatic activity. These results identify heparanase as a key mediator of macrophage activation and function in tumorigenesis and cross-talk with the tumor microenvironment.
authors.affiliation: Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Lilach
authors.initials: L
authors.lastname: Gutter-Kapon
authors.affiliation: Department of Cell Biology and Cancer Science, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Alishekevitz
authors.affiliation: Department of Cell Biology and Cancer Science, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.affiliation: Department of Medical Biochemistry and Microbiology, University of Uppsala, SE-751 05 Uppsala, Sweden.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
authors.affiliation: Department of Molecular Genetics, the Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Ami
authors.initials: A
authors.lastname: Aronheim
authors.affiliation: Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.affiliation: Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel; vlodavsk@mail.huji.ac.il.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000502:physiology*; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D047368:Tumor Burden; D059016:Tumor Microenvironment; D000099175:Heparanase
chemical_list: D016207:Cytokines; D005966:Glucuronidase; D014157:Transcription Factors; D000099175:Heparanase
keywords: cytokine expression; heparanase; knockout mice; macrophage; tumor growth