Hepatocyte-mediated inflammatory signaling is critical for liver metastasis.
Major finding: Hepatocyte-mediated inflammatory signaling is critical for liver metastasis.
Mechanism: IL6–STAT3 signaling produces SAA in the liver microenvironment to establish a prometastatic niche.
Impact: Therapeutically targeting inflammatory signaling in hepatocytes might prevent liver metastasis.
Although the tendency of many cancers to metastasize to the liver may be due to tropism inherent to tumor cells, liver metastasis is also partially dependent upon establishment of a prometastatic niche that promotes the deposition of circulating tumor cells within the liver. Lee and colleagues showed that hepatocytes drive accumulation of myeloid cells and liver fibrosis to increase the susceptibility of the liver to metastatic seeding and outgrowth. Livers from a Kras-mutant;Trp53-mutant mouse model of pancreatic ductal adenocarcinoma (PDAC) contained increased myeloid cells and expressed increased levels of fibronectin and type I collagen compared with control mice, resulting in a higher metastatic tumor burden in the liver. Hepatocytes exhibited increased STAT3 activation and subsequent upregulation of serum amyloid A1 and A2 (SAA). Deletion of interleukin 6 (Il6) or blockade of the IL6 receptor decreased STAT3 activation and SAA production in hepatocytes and reduced myeloid cell accumulation and extracellular matrix deposition in the liver, effectively inhibiting formation of the prometastatic niche; hepatocyte-specific deletion of either Stat3 or Saa1 and Saa2 elicited similar effects on prometastatic niche formation. Patients with PDAC and non–small cell lung cancer with liver metastases displayed elevated levels of circulating SAA, which correlated with poor outcome, and overexpression of SAA and phospho-STAT3 was observed in several patients with PDAC with liver metastasis. Taken together, these results depart from previous observations that tumor-intrinsic factors influence metastatic spread. Instead, hepatocytes mount an inflammatory response that mediates formation of a prometastatic niche within the liver via an IL6–STAT3–SAA signaling axis. Targeting this axis in hepatocytes may help improve outcomes in patients with cancers prone to liver metastasis.
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