Myeloid-specific genetic ablation of ATP-binding cassette transporter ABCA1 is protective against cancer
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Maryam Zamanian-Daryoush1, Daniel J. Lindner2, Joseph A. DiDonato1, Matthew Wagner1, Jennifer Buffa1, Patricia Rayman3, John S. Parks4, Marit Westerterp5, Alan R. Tall5 and Stanley L. Hazen1,6
1Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
2Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
3Department of Immunology, Cleveland Clinic, Cleveland, OH 44195, USA
4Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
5Department of Medicine, Columbia University, College of Physicians and Surgeons 8-401, New York, NY 10032, USA
6Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
Stanley L. Hazen, email: [email protected]
Keywords: cancer, apolipoprotein, myeloid cell, cholesterol, ABC transporter
Received: March 18, 2016 Accepted: May 23, 2017 Published: June 27, 2017
Increased circulating levels of apolipoprotein A-I (apoA-I), the major protein of high-density lipoprotein (HDL), by genetic manipulation or infusion, protects against melanoma growth and metastasis. Herein, we explored potential roles in melanoma tumorigenesis for host scavenger receptor class B, type 1 (SR-B1), and ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1), all mediators of apoA-I and HDL sterol and lipid transport function. In a syngeneic murine melanoma tumor model, B16F10, mice with global deletion of SR-B1 expression exhibited increased plasma HDL cholesterol (HDLc) levels and decreased tumor volume, indicating host SR-B1 does not directly contribute to HDL-associated anti-tumor activity. In mice with myeloid-specific loss of ABCA1 (Abca1-M/-M; A1-M/-M), tumor growth was inhibited by ~4.8-fold relative to wild type (WT) animals. Abcg1-M/-M (G1-M/-M) animals were also protected by 2.5-fold relative to WT, with no further inhibition of tumor growth in Abca1/Abcg1 myeloid-specific double knockout animals (DKO). Analyses of tumor-infiltrating immune cells revealed a correlation between tumor protection and decreased presence of the immune suppressive myeloid-derived suppressor cell (MDSC) subsets, Ly-6G+Ly-6CLo and Ly-6GnegLy-6CHi cells. The growth of the syngeneic MB49 murine bladder cancer cells was also inhibited in A1-M/-M mice. Collectively, our studies provide further evidence for an immune modulatory role for cholesterol homeostasis pathways in cancer.
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