Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2021
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/146661 |
| _version_ | 1811678276673863680 |
|---|---|
| author | Kolb, Ryan Kluz, Paige Tan, Zhen Wei Borcherding, Nicholas Bormann, Nicholas Vishwakarma, Ajaykumar Balcziak, Louis Zhu, Pengcheng Davies, Brandon S. J. Gourronc, Francoise Liu, Ling-Zhi Ge, Xin Jiang, Bing-Hua Gibson-Corley, Katherine Klingelhutz, Aloysius Tan, Nguan Soon Zhu, Yuwen Sutterwala, Fayyaz S. Shen, Xian Zhang, Weizhou |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Kolb, Ryan Kluz, Paige Tan, Zhen Wei Borcherding, Nicholas Bormann, Nicholas Vishwakarma, Ajaykumar Balcziak, Louis Zhu, Pengcheng Davies, Brandon S. J. Gourronc, Francoise Liu, Ling-Zhi Ge, Xin Jiang, Bing-Hua Gibson-Corley, Katherine Klingelhutz, Aloysius Tan, Nguan Soon Zhu, Yuwen Sutterwala, Fayyaz S. Shen, Xian Zhang, Weizhou |
| author_sort | Kolb, Ryan |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T02:50:42Z |
| format | Journal Article |
| id | ntu-10356/146661 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:50:42Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1466612023-02-28T17:08:29Z Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4 Kolb, Ryan Kluz, Paige Tan, Zhen Wei Borcherding, Nicholas Bormann, Nicholas Vishwakarma, Ajaykumar Balcziak, Louis Zhu, Pengcheng Davies, Brandon S. J. Gourronc, Francoise Liu, Ling-Zhi Ge, Xin Jiang, Bing-Hua Gibson-Corley, Katherine Klingelhutz, Aloysius Tan, Nguan Soon Zhu, Yuwen Sutterwala, Fayyaz S. Shen, Xian Zhang, Weizhou Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences Science::Medicine Breast Cancer Inflammation 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. Ministry of Education (MOE) Accepted version 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 R01AI118719. 2021-03-04T06:36:15Z 2021-03-04T06:36:15Z 2018 Journal Article Kolb, R., Kluz, P., Tan, Z. W., Borcherding, N., Bormann, N., Vishwakarma, A., . . . Zhang, W. (2019). Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4. Oncogene, 38(13), 2351-2363. doi:10.1038/s41388-018-0592-6 0950-9232 https://hdl.handle.net/10356/146661 10.1038/s41388-018-0592-6 30518876 13 38 2351 2363 en MOE2014-T2-1-012 Oncogene © 2018 Springer Nature Limited. All rights reserved. This paper was published in Oncogene and is made available with permission of Springer Nature Limited. application/pdf |
| spellingShingle | Science::Medicine Breast Cancer Inflammation Kolb, Ryan Kluz, Paige Tan, Zhen Wei Borcherding, Nicholas Bormann, Nicholas Vishwakarma, Ajaykumar Balcziak, Louis Zhu, Pengcheng Davies, Brandon S. J. Gourronc, Francoise Liu, Ling-Zhi Ge, Xin Jiang, Bing-Hua Gibson-Corley, Katherine Klingelhutz, Aloysius Tan, Nguan Soon Zhu, Yuwen Sutterwala, Fayyaz S. Shen, Xian Zhang, Weizhou Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4 |
| title | Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4 |
| title_full | Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4 |
| title_fullStr | Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4 |
| title_full_unstemmed | Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4 |
| title_short | Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4 |
| title_sort | obesity associated inflammation promotes angiogenesis and breast cancer via angiopoietin like 4 |
| topic | Science::Medicine Breast Cancer Inflammation |
| url | https://hdl.handle.net/10356/146661 |
| work_keys_str_mv | AT kolbryan obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT kluzpaige obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT tanzhenwei obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT borcherdingnicholas obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT bormannnicholas obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT vishwakarmaajaykumar obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT balcziaklouis obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT zhupengcheng obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT daviesbrandonsj obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT gourroncfrancoise obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT liulingzhi obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT gexin obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT jiangbinghua obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT gibsoncorleykatherine obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT klingelhutzaloysius obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT tannguansoon obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT zhuyuwen obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT sutterwalafayyazs obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT shenxian obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 AT zhangweizhou obesityassociatedinflammationpromotesangiogenesisandbreastcancerviaangiopoietinlike4 |