Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18

Micol Ravà, Aleco D'Andrea, Mirko Doni, Theresia R Kress, Renato Ostuni, Valerio Bianchi, Marco J Morelli, Agnese Collino, Serena Ghisletti, Paola Nicoli, Camilla Recordati, Maria Iascone, Aurelio Sonzogni, Lorenzo D'Antiga, Ruchi Shukla, Geoff Faulkner, Gioacchino Natoli, Stefano Campaner, Bruno Amati

Research output: Contribution to journalArticlepeer-review

Abstract

The ST18 gene was proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis was missing so far. Here, we demonstrate that ST18 is critical for tumor progression and maintenance in a mouse model of liver cancer, based on oncogenic transformation and adoptive transfer of primary precursor cells (hepatoblasts). ST18 mRNA and protein were detectable neither in the normal liver nor in cultured hepatoblasts, but were readily expressed following subcutaneous engraftment and tumor growth. ST18 expression in liver cells was induced by inflammatory cues, including acute or chronic inflammation in vivo, as well as co-culture with macrophages in vitro. Knocking down the ST18 mRNA in transplanted hepatoblasts delayed tumor progression. Induction of ST18 knockdown in pre-established tumors, caused rapid tumor involution, associated with pervasive morphological changes, proliferative arrest and apoptosis in tumor cells, as well as depletion of tumor-associated macrophages, vascular ectasia and hemorrhage. Reciprocally, systemic depletion of macrophages in recipient animals had very similar phenotypic consequences, impairing either tumor development or maintenance, and suppressing ST18 expression in the hepatoblasts. Finally, RNA-seq profiling of ST18-depleted tumors prior to involution revealed down-regulation of inflammatory response genes, pointing to the suppression of NF-kB-dependent transcription.

CONCLUSION: ST18 expression in epithelial cells is induced by tumor-associated macrophages, contributing to the reciprocal feed-forward loop between both cell types in liver tumorigenesis. Our findings warrant the exploration of means to interfere with ST18-dependent epithelium-macrophage interactions in a therapeutic setting. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalHepatology
Early online date14 Nov 2016
DOIs
Publication statusE-pub ahead of print - 14 Nov 2016

Keywords

  • Hepatocellular carcinoma
  • Hepatoblastoma
  • Inflammation
  • Mouse models
  • Nuclear Factor kappa-B

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