Editors' ChoiceCancer

MIF: A harbinger of evil

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Science Translational Medicine  17 Jun 2015:
Vol. 7, Issue 292, pp. 292ec102
DOI: 10.1126/scitranslmed.aac7157

The majority of patients with cancer die of metastatic disease, and there is a major effort to understand and formulate effective ways to treat cancer metastasis. Pancreatic ductal adenocarcinoma (PDAC) is a particularly deadly cancer, with a high metastatic potential and a median survival of only 6 months. Exosomes are secreted membrane vesicles that mediate intercellular communication between cancer cells and their microenvironment. Although exosomes have previously been implicated in the formation of premetastatic niches in target organs, the mechanism for this phenomenon was unclear. Now, Costa-Silva et al. present evidence that PDAC-derived exosomal macrophage migration inhibitory factor (MIF) promotes the formation of premetastatic niches in the liver through induction of transforming growth factor–β (TGF-β) release by Kupffer cells (KCs).

When PDAC-derived exosomes were administered to mice prior to tumor cell injection, liver metastatic burden increased. Fluorescently labeled tumor exosomes were preferentially taken up by KCs, and in vitro “education” of KCs by PDAC-derived exosomes up-regulated soluble factors associated with liver fibrosis, including TGF-β. Examination of exosome-educated livers showed a marked increase in extracellular fibronectin deposited by hepatic stellate cells (hStCs), followed by an influx of bone marrow–derived macrophages. Moreover, injected PDAC cells were shown to localize adjacent to KCs. Treatment with a TGF-β type I receptor inhibitor (A83-01) during exosome education decreased hStCs, fibronectin deposition, and macrophage migration to the liver. Furthermore, knocking out fibronectin or depleting recruited macrophages caused a reversion of the prometastatic phenotype. Mass spectrometry of PDAC-derived exosomes revealed high expression of MIF. Knockdown of MIF in exosomes resulted in pronounced reduction in TGF-β, fibronectin deposition, macrophage recruitment, and liver metastatic burden, without affecting exosome binding to KCs. Baseline exosomal MIF concentrations were markedly higher in patients with subsequent progressive disease compared with patients without progression, confirming the importance of this process in human disease. Last, in a genetic model of PDAC, an increase in exosomal MIF and TGF-β expression by liver KCs was observed in the early pretumoral stage and increased in correlation with disease progression.

This study demonstrates the importance of PDAC-derived exosomal MIF in premetastatic niche formation and efficient liver metastasis, which correlates with patient outcomes. These findings suggest that exosomal MIF can potentially serve as both a therapeutic target and a prognostic marker for PDAC.

B. Costa-Silva et al., Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015). [Abstract]

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