title: The cardioprotective protein apolipoprotein A1 promotes potent anti-tumorigenic effects.
abstract: Here, we show that apolipoprotein A1 (apoA1), the major protein component of high density lipoprotein (HDL), through both innate and adaptive immune processes, potently suppresses tumor growth and metastasis in multiple animal tumor models, including the aggressive B16F10L murine malignant melanoma model. Mice expressing the human apoA1 transgene (A1Tg) exhibited increased infiltration of CD11b(+) F4/80(+) macrophages with M1, anti-tumor phenotype, reduced tumor burden and metastasis, and enhanced survival. In contrast, apoA1-deficient (A1KO) mice showed markedly heightened tumor growth and reduced survival. Injection of human apoA1 into A1KO mice inoculated with tumor cells remarkably reduced both tumor growth and metastasis, enhanced survival, and promoted regression of both tumor and metastasis burden when administered following palpable tumor formation and metastasis development. Studies with apolipoprotein A2 revealed the anti-cancer therapeutic effect was specific to apoA1. In vitro studies ruled out substantial direct suppressive effects by apoA1 or HDL on tumor cells. Animal models defective in different aspects of immunity revealed both innate and adaptive arms of immunity contribute to complete apoA1 anti-tumor activity. This study reveals a potent immunomodulatory role for apoA1 in the tumor microenvironment, altering tumor-associated macrophages from a pro-tumor M2 to an anti-tumor M1 phenotype. Use of apoA1 to redirect in vivo elicited tumor-infiltrating macrophages toward tumor rejection may hold benefit as a potential cancer therapeutic.
authors.affiliation: From the Department of Cellular and Molecular Medicine,; Center for Cardiovascular Diagnostics and Prevention.
authors.forename: Maryam
authors.initials: M
authors.lastname: Zamanian-Daryoush
authors.affiliation: Taussig Cancer Center.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindner
authors.affiliation: From the Department of Cellular and Molecular Medicine,; Center for Cardiovascular Diagnostics and Prevention.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Tallant
authors.affiliation: From the Department of Cellular and Molecular Medicine,; Center for Cardiovascular Diagnostics and Prevention.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: From the Department of Cellular and Molecular Medicine,; Center for Cardiovascular Diagnostics and Prevention.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Buffa
authors.affiliation: From the Department of Cellular and Molecular Medicine,; Center for Cardiovascular Diagnostics and Prevention.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Klipfell
authors.affiliation: Taussig Cancer Center.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Parker
authors.affiliation: Imaging Core, and.
authors.forename: Denise
authors.initials: D
authors.lastname: Hatala
authors.affiliation: the John H. Glenn Research Center, National Aeronautics and Space Administration, Cleveland, Ohio 44135, and.
authors.forename: Patricia
authors.initials: P
authors.lastname: Parsons-Wingerter
authors.affiliation: Departments of Immunology and.
authors.forename: Pat
authors.initials: P
authors.lastname: Rayman
authors.affiliation: From the Department of Cellular and Molecular Medicine.
authors.forename: Mohamed Sharif S
authors.initials: MSS
authors.lastname: Yusufishaq
authors.affiliation: the Department of Cell Biology and the Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York 10016.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: From the Department of Cellular and Molecular Medicine,; Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Departments of Immunology and.
authors.forename: Jim
authors.initials: J
authors.lastname: Finke
authors.affiliation: From the Department of Cellular and Molecular Medicine,; Center for Cardiovascular Diagnostics and Prevention.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DiDonato
authors.affiliation: From the Department of Cellular and Molecular Medicine,; Center for Cardiovascular Diagnostics and Prevention,; Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195,. Electronic address: hazens@ccf.org.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016632:Apolipoprotein A-I / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D016633:Apolipoprotein A-II / Q000494:pharmacology; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007121:Immunocompetence / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000378:metabolism; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D012074:Remission Induction; D016019:Survival Analysis; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D002316:Cardiotonic Agents; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D020780:Matrix Metalloproteinase 9; C032881:lysophosphatidic acid
keywords: Adaptive Immunity; Apolipoprotein A1 Therapy; Cancer; Cancer Biology; Cancer Therapy; High Density Lipoprotein (HDL); Innate Immunity; Matrix Metalloproteinase 9 (MMP-9); Melanoma; Tumor-suppressive Infiltrating Leukocytes