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标题：Heparanase is required for activation and function of macrophages
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作者：Lilach Gutter-Kapon ; Dror Alishekevitz ; Yuval Shaked 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：48
页码：E7808-E7817
DOI：10.1073/pnas.1611380113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe tumor microenvironment is now considered to play a major role in cancer growth and metastasis. Heparanase is the only enzyme in mammals capable of cleaving heparan sulfate, an activity that is highly implicated in tumor growth, metastasis, and inflammation. Here we provide evidence that heparanase is critically required for the activation and function of macrophages, an important constituent of the tumor microenvironment. 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. 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., TNF, IL1-{beta}) 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.
关键词：heparanase ; macrophage ; tumor growth ; cytokine expression ; knockout mice