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

Oncogene volume 38, pages 2351–2363 (2019)Cite this article

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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.

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Data Availability:

The processed RNA-sequencing data shown as fragments per kilobase of transcript per million mapped reads (FPKM) and their original FASTQ files are currently being submitted to GEO data sets.

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Acknowledgements

We would like to thank the Comparative Histopathology Core in the Department of Pathology, University of Iowa for the processing of fixed tissue and CD31 immunohistochemistry. We thank Dr. Mikhail Kolonin (UT health science center at Houston) and Dr. Leslie Ellies (UCSD) for sharing E0771 and Py8119 cells, respectively.

Financial Support:

RK: NIH T32 AI007260; WZ: NIH R01 grants CA200673 and CA203834, Oberley Award (National Cancer Institute Award P30CA086862) from Holden Comprehensive Cancer Center at the University of Iowa; NB: NIH F30 CA206255; AK: Mark Stinski Developmental Grant from the Department of Microbiology, University of Iowa; BD: NIH R01HL130146; NST: grant from Ministry of Education, Singapore (MOE2014-T2-1-012); FSS: NIH R01 AI118719.

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Authors and Affiliations

  1. Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    Ryan Kolb, Paige Kluz, Nicholas Borcherding, Ajaykumar Vishwakarma, Ling-Zhi Liu, Xin Ge, Bing-Hua Jiang, Katherine Gibson-Corley & Weizhou Zhang

  2. Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, 32610, USA

    Ryan Kolb & Weizhou Zhang

  3. Free Radical and Radiation Biology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    Paige Kluz & Weizhou Zhang

  4. School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, USA

    Zhen Wei Tan, Pengcheng Zhu & Nguan Soon Tan

  5. Medical Scientist Training Program, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    Nicholas Borcherding & Weizhou Zhang

  6. Cancer Biology Graduate Program, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    Nicholas Borcherding, Ajaykumar Vishwakarma & Weizhou Zhang

  7. Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    Nicholas Bormann

  8. Interdisciplinary Neuroscience graduate program, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    Louis Balcziak

  9. Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center, and Obesity Research and Education Initiative, University of Iowa, Iowa City, IA, 52242, USA

    Brandon SJ. Davies

  10. Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    Francoise Gourronc & Aloysius Klingelhutz

  11. Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Drive, Singapore, 639798, Singapore

    Nguan Soon Tan

  12. Institute of Molecular Cell Biology, 61 Biopolis Drive, Proteos, Agency for Science Technology & Research, Singapore, 138673, USA

    Nguan Soon Tan

  13. KK Research Centre, KK Women’s and Children Hospital, 100 Bukit Timah Road, Singapore, 229899, Singapore

    Nguan Soon Tan

  14. Department of Surgery, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO, 80045, USA

    Yuwen Zhu

  15. Department of Medicine, Cedars- Sinai Medical Center, Los Angeles, CA, 90048, USA

    Fayyaz S. Sutterwala

  16. Division of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Zhejiang, 325035, China

    Xian Shen

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Correspondence to Ryan Kolb, Xian Shen or Weizhou Zhang.

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Kolb, R., Kluz, P., Tan, Z.W. et al. Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4. Oncogene 38, 2351–2363 (2019). https://doi.org/10.1038/s41388-018-0592-6

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