title: Selective ablation of tumor-associated macrophages suppresses metastasis and angiogenesis.
abstract: Tumor-associated macrophages (TAM) play a critical role in promoting tumor development and metastasis. In the present study, we found that legumain, an asparaginyl endopeptidase, was highly expressed on the surface of TAM. A doxorubicin-based prodrug specifically activated by legumain selectively ablated TAM and resulted in a significant reduction of angiogenic factors and related tumor vessel growth. Treatment with the prodrug also suppressed circulating tumor cells and myeloid immune suppressor Gr-1+/CD11b+ cells in tumor-bearing animals. After selective ablation of TAM using the prodrug, tumor growth and metastases were greatly inhibited in murine tumor models. These results indicate that legumain-activated prodrugs targeting TAM in tumors might represent a novel anticancer strategy.
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Lin
authors.forename: Chongyang
authors.initials: C
authors.lastname: Wei
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Yongming
authors.initials: Y
authors.lastname: Qiu
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000099240:Asparaginyl Endopeptidase
chemical_list: D000970:Antineoplastic Agents; D003546:Cysteine Endopeptidases; D004317:Doxorubicin; D009842:Oligopeptides; D000099240:Asparaginyl Endopeptidase; C507748:LEG-3 prodrug