Publications

Tumor-derived cyclooxygenase-2 fuels hypothalamic inflammation

Li, Xiaolin; Zhu, Xinxia; Diba, Parham; Shi, Xuan; Vrieling, Frank; Jansen, Fleur A.C.; Balvers, Michiel G.J.; de Bus, Ian; Levasseur, Peter R.; Sattler, Ariana; Arneson-Wissink, Paige C.; Poland, Mieke; Witkamp, Renger F.; van Norren, Klaske; Marks, Daniel L.

Summary

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.