Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

By B. Costa-Silva, Nicole M. Aiello, A. Ocean, Swarnima Singh, Haiying Zhang, B. K. Thakur, A. Becker, Ayuko Hoshino, M. T. Mark, H. Molina and 27 more. Nature Cell Biology, 2015

2,472 citations recorded by the source corpus.

Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.

Subfields: Immunology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/02627bf2f2f6333495a1115393ced243b3847b77

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In Immunology

In Pharmacology

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Citations in the corpus

Roles of the immune system in cancer: from tumor initiation to metastatic progression (2018, background): “This is followed by subsequent arrest of bone marrow-derived macrophages and neutrophils in the liver, resulting in a prometastatic effect, reversible by macrophage ablation (Costa-Silva et al. 2015).”
Revisiting the hallmarks of cancer. (2017, neutral): “Growing evidence also supports a role for exosomes in the process [137, 138].”
Systems Biology of Cancer Metastasis (2019, background): “Exosomes: Microvesicles secreted by cancer cells bearing microRNA and other components, which could prepare niches in other tissues for micrometastases (Costa-Silva et al., 2015; Hoshino et al., 2015).”
Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression (2018, background): “It has also been shown that pancreatic tumor-derived EVs are taken up by Kupffer cells in the liver, which leads to recruitment of bone marrow-derived macrophages through increased FN production by hepatic stellate cells (26).”
Exosomes in cancer development, metastasis, and immunity (2019, background): “Pancreatic cancer cell-derived exosomes deliver macrophage-inhibitory factor (MIF) that made Kupffer cells release more TGFβ, which in turn increased fibronectin production and recruited bone marrow–derived macrophages for liver pre-metastatic niche formation [103].”
The biology, function, and biomedical applications of exosomes (2020, neutral): “The recruitment of bone marrow progenitor cells and macrophages to metastatic sites by cancer cell–derived exosomeshas been reported inmelanoma (154) and pancreatic cancer (155) and implicated inmetastasis.”
The biology and function of exosomes in cancer. (2016, background): “(35) reported that macrophage migration inhibitory factor (MIF) is elevated in circulating exosomes of PDAC patients with disease progression after diagnosis when compared with healthy control subjects or PDAC patients with no evidence of disease 5 years after diagnosis and treatment.”