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

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.

Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis

“…Consistent with this idea, depletion of macrophages in obese mice resulted in significant decreases in endothelial cells and enhanced tumor necrosis. Within adipose tissue, adipocytes have also been shown to regulate angiogenesis through the secretion of adipokines [43], and adipokine secretion, including leptin, has been implicated in tumor angiogenesis in the context of obesity [44,45]. Although we observed increased tumor cell invasion into surrounding obese adipose tissue, we did not observe elevated numbers of adipocytes within the tumor mass.…”

Prognostic Inflammasome‐Related Signature Construction in Kidney Renal Clear Cell Carcinoma Based on a Pan‐Cancer Landscape

“…Accumulating evidence has revealed that inflammasomes are involved in the pathological processes of different tumors [14,30,31], but the specific molecular mechanisms remained incompletely elucidated. In this study, we identified different expression patterns and prognostic characteristics of IRGs among 10 cancers.…”

“…Recent studies have demonstrated that the functions of inflammasomes in tumor, to a certain extent, are determined by the different types of cells and tissues [12][13][14]. However, there is still no systematic molecular profile of inflammasome-related genes (IRGs) across diverse human cancers until now.…”

The Roles of ANGPTL Families in Cancer Progression

“…Along with cancer progression, hypoxia and undernutrition occur in cancer tissues due to rapid cancer proliferation [42]. Angiopoietin-like protein 4 (ANG-PTL4) is known to be induced by hypoxia and undernutrition [43], and is induced by IL-1β in a manner dependent on NF-κB-and MAPK-activation to promote angiogenesis and progression in breast cancer [44]. In oral cancer, ANGPTL4 enhances the tumorigenesis and poor prognosis based on the clinical tumor tissues [45].…”