Bladder Cancer Cells Maintain Paracrine IL-1 Signaling and IL-1Ra Sensitivity Following Chronic IL-1 Exposure

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• The tumor microenvironment (TME) contains proinflammatory cytokines like interleukin-1 (IL-1).
• IL-1 promotes tumor growth, angiogenesis, and metastasis.
• Cancer cells can produce IL-1, contributing to autocrine and paracrine signaling within the TME.

Purpose of the Study:

• To investigate the consequences of sustained amplified IL-1 signaling on cancer cell regulation, function, and therapeutic response.
• To explore whether chronic exposure to exogenous IL-1 affects cancer cell sensitivity to IL-1 and IL-1 receptor antagonist (IL-1Ra).

Main Methods:

• Generated chronic IL-1 sublines from the 5637 bladder cancer (BlCa) cell line by prolonged exposure to IL-1α or IL-1β.
• Assessed acute IL-1 sensitivity, paracrine signaling, and response to IL-1Ra in established sublines.

Main Results:

• Chronic exposure to elevated exogenous IL-1 did not alter the acute IL-1 sensitivity of 5637 BlCa cells.
• These cells retained sensitivity to IL-1Ra, and IL-1-dependent endothelial cell activation was reversible with IL-1Ra.
• Sustained extrinsic IL-1 exposure did not dampen IL-1 or IL-1Ra sensitivity in cancer cells with intrinsic IL-1 signaling.

Conclusions:

• For cancer cells with cell-autonomous IL-1 signaling, sustained extrinsic IL-1 exposure does not diminish sensitivity to IL-1 or IL-1Ra.
• IL-1 antagonists can be rationally used as therapeutics in both acute and chronic inflammatory TMEs.
• Findings support the context-dependent application of IL-1Ra in cancer therapy.