Tumor-derived cyclooxygenase-2 fuels hypothalamic inflammation
2025
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.
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.
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