Tumor-derived cyclooxygenase-2 fuels hypothalamic inflammation
Xiaolin Li, Xinxia Zhu, Parham Diba, Xuan Shi, Frank Vrieling, Fleur A. C. Jansen, Michiel G.J. Balvers, Ian de Bus, Peter R. Levasseur, Ariana Sattler, Paige C. Arneson‐Wissink, Mieke Poland, Renger F. Witkamp, Klaske van Norren, Daniel L. Marks
Abstract
• Tumor-derived Prostaglandin E2, produced via COX-2, and host gut-originated LPS synergistically amplify hypothalamic inflammation both in vitro and in vivo . • Prostaglandin E2 directly exerts hypothalamic inflammation through EP4 receptor, while also augmenting hypothalamic inflammation via NF-κB pathways in the presence of host gut-derived pathogen-associated molecular patterns (PAMPs). • Tumor-specific COX-2 knockout attenuates hypothalamic inflammation and improves survival during cancer. Hypothalamic inflammation often coincides with cancer and cachexia-anorexia. Prior work established the significance of tumor-derived inflammatory factors in triggering hypothalamic inflammation, yet the precise mechanisms remained elusive. Here, we demonstrate that prostaglandin E2 (PGE2), produced in the tumor via cyclooxygenase-2 (COX-2), plays a pivotal role in this context. PGE2 itself directly exerts pro-inflammatory effects on the hypothalamus through the EP4 receptor, while also augmenting hypothalamic inflammation via NF-κB pathways in the presence of host gut-derived pathogen-associated molecular patterns (PAMPs). In tumor-bearing mice, we confirm this synergistic interaction between tumor-derived COX-2/PGE2 and host-derived lipopolysaccharide (LPS) in amplifying hypothalamic inflammation. Supporting this mechanism we find that the tumor-specific knockout of COX-2 attenuates hypothalamic inflammation and improves survival in mice. Together, these findings highlight the mechanisms of tumor-associated COX-2 in fuelling hypothalamic inflammation. They also emphasize the potential of tumor-specific COX-2 inhibition and targeting gut permeability as a novel therapeutic strategy for improving clinical outcomes in cancer patients.