Hepatocytes direct the formation of a pro-metastatic niche in the liver

Abstract

The liver is the most common site of metastatic disease1. While this metastatic tropism may reflect mechanical trapping of circulating tumor cells, liver metastasis is also dependent, at least in part, on formation of a “pro-metastatic” niche that supports tumor cell spread to the liver2,3. Mechanisms that direct formation of this niche, though, are poorly understood. Here, we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver, and in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. Early during pancreatic tumorigenesis, hepatocytes demonstrate activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling and increased production of serum amyloid A1 and A2 (SAA). Overexpression of SAA by hepatocytes also occurs in pancreatic and colorectal cancer patients with liver metastases, and many patients with locally advanced and metastatic disease display elevated levels of circulating SAA. STAT3 activation in hepatocytes and the subsequent production of SAA are dependent on interleukin 6 (IL-6) that is released into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6/STAT3/SAA signaling prevents establishment of a pro-metastatic niche and inhibits liver metastasis. Our data reveal an intercellular network underpinned by hepatocytes that forms the basis for a pro-metastatic niche in the liver and identify new therapeutic targets.

Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation

“…Moreover, CAFs secrete pro-inflammatory cytokines, such as IL-6 and IL-8 to promote tumor progression 29 . A recent study shows the crucial roles of IL-6 and hepatocytes in the formation of pre-metastatic niche in the liver 12 . The intercommunication between tumor cells and CAFs further elucidated the molecular mechanism of CRC metastatic growth in liver and lung, and explained why diverse types of CRC show different metastatic and growth abilities in the liver and lung.…”

“…Recent emerging evidence shows the existence of complex communicating mechanisms between primary tumors and remote metastasis [5][6][7] . Inflammatory cells, immune cells, and hepatocytes participate in the formation of metastatic niche to support metastatic tumor growth [8][9][10][11][12] . Extracellular vesicles (EVs) are tumor-derived vehicles to mediate molecular communications between primary tumors and metastases 13,14 .…”

Serum Amyloid A Proteins Induce Pathogenic TH17 Cells and Promote Inflammatory Disease

“…There is also evidence that SAAs, particularly SAA3, may form tetramers and associate with derivatives of vitamin A (Derebe et al, 2014). The anatomical distribution and cellular targets of SAAs in chronic disease are largely undefined, but the SAAs were recently implicated in conditioning the liver microenvironment to provide a niche for tumor metastases (Lee et al, 2019).…”

Serum amyloid a, a potential biomarker both in serum and tissue, correlates with ovarian cancer progression

“…Jae W. Lee, Meredith L. Stone and et al reported that in ammatory responses mounted by hepatocytes are critical to liver metastasis in pancreatic ductal adenocarcinoma. Mechanistically, hepatocytes orchestrate this process through activation of IL-6/STAT3/SAA signaling , which alters the immune and brotic microenvironment of the liver to establish a pro-metastatic niche [45]. Thus, we consider that SAA is involved in neoplastic progress and with immunosuppression and promotion of metastatic niches.…”