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: Maryam Zamanian-Daryoush, Daniel Lindner, Thomas C Tallant, Zeneng Wang, Jennifer Buffa, Elizabeth Klipfell, Yvonne Parker, Denise Hatala, Patricia Parsons-Wingerter, Pat Rayman, Mohamed Sharif S Yusufishaq, Edward A Fisher, Jonathan D Smith, Jim Finke, Joseph A DiDonato, Stanley L Hazen
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 29 Pg. 21237-21252 (Jul 19 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23720750 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Apolipoprotein A-I
• Apolipoprotein A-II
• Cardiotonic Agents
• Lipoproteins, HDL
• Lysophospholipids
• Matrix Metalloproteinase 9
• lysophosphatidic acid

Topics

• Animals
• Antigen Presentation (drug effects)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apolipoprotein A-I (deficiency, metabolism, pharmacology)
• Apolipoprotein A-II (pharmacology)
• Carcinogenesis (metabolism, pathology)
• Cardiotonic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dendritic Cells (drug effects, metabolism)
• Female
• Humans
• Immunity (drug effects)
• Immunocompetence (drug effects)
• Lipoproteins, HDL (metabolism)
• Lysophospholipids (blood, metabolism)
• Macrophages (drug effects, metabolism)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Neoplasm Metastasis
• Neoplasms (blood supply, drug therapy, immunology, pathology)
• Neovascularization, Pathologic (metabolism, pathology)
• Remission Induction
• Survival Analysis
• Tumor Microenvironment (drug effects)