Inflammatory cytokine IL-8/CXCL8 promotes tumour escape from hepatocyte-induced dormancy

Background: Breast cancers can recur after a long latency period following 'successful' primary treatments. Chronic inflammation significantly correlates with reduced diseased-free survival in breast cancer patients and could be a point of intervention to prevent recurrence. Liver is among the main sites of breast cancer recurrence. Thus, we hypothesise that inflammatory signals from hepatic stellate cells, the major inflammatory regulators in the sinusoid, could stimulate dormant cancer cells to emerge. Methods: We utilise in vitro co-culture of breast cancer cells with stellate cells and an ex vivo 3D human liver micro-physiologic system to identify stellate cells-derived factors that mediate tumour emergence. Results: Activated, but not quiescent, hepatic stellate cells secreted soluble factors to induce the proliferation of MCF7 and MDA-MB231 cancer cells. IL-8 and MCP-1 were highly secreted by the activated stellate cells and primary human non-parenchymal cells. IL-8 significantly reduced serum-starvation growth arrest on MDA-MB231 cells in vitro and increased cancer proliferation ex vivo. Blocking IL-8Rb/CXCR2 reduced IL-8-induced cancer growth and proliferation. Conclusions: Activated stellate cells can induce breast cancer emergence from dormancy in the liver by secreting inflammatory cytokines. Preventing liver inflammation or disrupting the subsequent key cytokines may prevent metastatic outgrowth.