Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4.
Ryan KolbPaige KluzZhen Wei TanNicholas BorcherdingNicholas BormannAjaykumar VishwakarmaLouis BalcziakPengcheng ZhuBrandon S J DaviesFrancoise GourroncLing-Zhi LiuXin GeBing-Hua JiangKatherine Gibson-CorleyAloysius KlingelhutzNguan Soon TanYuwen ZhuFayyaz S SutterwalaXian ShenWeizhou ZhangPublished in: Oncogene (2018)
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.
Keyphrases
- weight loss
- insulin resistance
- metabolic syndrome
- high fat diet induced
- obese patients
- bariatric surgery
- type diabetes
- adipose tissue
- weight gain
- endothelial cells
- roux en y gastric bypass
- gastric bypass
- poor prognosis
- vascular endothelial growth factor
- signaling pathway
- oxidative stress
- body mass index
- squamous cell
- gene expression
- squamous cell carcinoma
- cell proliferation
- lps induced
- inflammatory response
- young adults
- dengue virus
- nuclear factor
- physical activity
- living cells
- sensitive detection
- diabetic rats
- dna methylation
- combination therapy