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Oncogene. 2018 Dec 5. doi: 10.1038/s41388-018-0592-6. [Epub ahead of print]

Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4.

Author information

1
Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA. ryankolb@ufl.edu.
2
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, 32610, USA. ryankolb@ufl.edu.
3
Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
4
Free Radical and Radiation Biology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
5
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, USA.
6
Medical Scientist Training Program, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
7
Cancer Biology Graduate Program, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
8
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
9
Interdisciplinary Neuroscience graduate program, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
10
Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center, and Obesity Research and Education Initiative, University of Iowa, Iowa City, IA, 52242, USA.
11
Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
12
Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Drive, Singapore, 639798, Singapore.
13
Institute of Molecular Cell Biology, 61 Biopolis Drive, Proteos, Agency for Science Technology & Research, Singapore, 138673, USA.
14
KK Research Centre, KK Women's and Children Hospital, 100 Bukit Timah Road, Singapore, 229899, Singapore.
15
Department of Surgery, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO, 80045, USA.
16
Department of Medicine, Cedars- Sinai Medical Center, Los Angeles, CA, 90048, USA.
17
Division of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Zhejiang, 325035, China. shenxian1120@126.com.
18
Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA. zhangw@ufl.edu.
19
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, 32610, USA. zhangw@ufl.edu.
20
Free Radical and Radiation Biology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA. zhangw@ufl.edu.
21
Medical Scientist Training Program, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA. zhangw@ufl.edu.
22
Cancer Biology Graduate Program, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA. zhangw@ufl.edu.

Abstract

Obesity is a risk factor for breast cancer and also predicts poor clinical outcomes regardless of menopausal status. Contributing to the poor clinical outcomes is the suboptimal efficacy of standard therapies due to dose limiting toxicities and obesity-related complications, highlighting the need to develop novel therapeutic approaches for treating obese patients. We recently found that obesity leads to an increase in tumor-infiltrating macrophages with activated NLRC4 inflammasome and increased interleukin (IL)-1β production. IL-1β, in turn, leads to increased angiogenesis and cancer progression. Using Next Generation RNA sequencing, we identified an NLRC4/IL-1β-dependent upregulation of angiopoietin-like 4 (ANGPTL4), a known angiogenic factor in cancer, in tumors from obese mice. ANGPTL4-deficiency by genetic knockout or treatment with a neutralizing antibody led to a significant reduction in obesity-induced angiogenesis and tumor growth. At a mechanistic level, ANGPTL4 expression is induced by IL-1β from primary adipocytes in a manner dependent on NF-κB- and MAP kinase-activation, which is further enhanced by hypoxia. This report shows that adipocyte-derived ANGPTL4 drives disease progression under obese conditions and is a potential therapeutic target for treating obese breast cancer patients.

PMID:
30518876
DOI:
10.1038/s41388-018-0592-6

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