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, Geoffrey J. Faulkner, Gioacchino Natoli, Stefano Campaner, Bruno Amati

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The ST18 gene has been proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis has been lacking thus 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 messenger RNA (mRNA) and protein were detectable neither in normal liver nor in cultured hepatoblasts, but were readily expressed after 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 coculture 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 hepatoblasts. Finally, RNA sequencing of ST18-depleted tumors before involution revealed down-regulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa B-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. (Hepatology 2016).

Original languageEnglish
JournalHepatology
DOIs
Publication statusAccepted/In press - 2016

Fingerprint

Carcinogenesis
Epithelium
Macrophages
Liver
Neoplasms
Dependency (Psychology)
Maintenance
RNA Sequence Analysis
Pathologic Dilatations
Messenger RNA
Adoptive Transfer
NF-kappa B
Gastroenterology
Liver Neoplasms
Coculture Techniques
Oncogenes
Genes
Cues
Blood Vessels
Down-Regulation

ASJC Scopus subject areas

  • Hepatology

Cite this

Ravà, M., D'Andrea, A., Doni, M., Kress, T. R., Ostuni, R., Bianchi, V., ... Amati, B. (Accepted/In press). Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18. Hepatology. https://doi.org/10.1002/hep.28942

Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18. / Ravà, Micol; D'Andrea, Aleco; Doni, Mirko; Kress, Theresia R.; Ostuni, Renato; Bianchi, Valerio; Morelli, Marco J.; Collino, Agnese; Ghisletti, Serena; Nicoli, Paola; Recordati, Camilla; Iascone, Maria; Sonzogni, Aurelio; D'Antiga, Lorenzo; Shukla, Ruchi; Faulkner, Geoffrey J.; Natoli, Gioacchino; Campaner, Stefano; Amati, Bruno.

In: Hepatology, 2016.

Research output: Contribution to journalArticle

Ravà, M, D'Andrea, A, Doni, M, Kress, TR, Ostuni, R, Bianchi, V, Morelli, MJ, Collino, A, Ghisletti, S, Nicoli, P, Recordati, C, Iascone, M, Sonzogni, A, D'Antiga, L, Shukla, R, Faulkner, GJ, Natoli, G, Campaner, S & Amati, B 2016, 'Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18', Hepatology. https://doi.org/10.1002/hep.28942
Ravà, Micol ; D'Andrea, Aleco ; Doni, Mirko ; Kress, Theresia R. ; Ostuni, Renato ; Bianchi, Valerio ; Morelli, Marco J. ; Collino, Agnese ; Ghisletti, Serena ; Nicoli, Paola ; Recordati, Camilla ; Iascone, Maria ; Sonzogni, Aurelio ; D'Antiga, Lorenzo ; Shukla, Ruchi ; Faulkner, Geoffrey J. ; Natoli, Gioacchino ; Campaner, Stefano ; Amati, Bruno. / Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18. In: Hepatology. 2016.
@article{15f4947fbe0f41969885167fc1530246,
title = "Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18",
abstract = "The ST18 gene has been proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis has been lacking thus 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 messenger RNA (mRNA) and protein were detectable neither in normal liver nor in cultured hepatoblasts, but were readily expressed after 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 coculture 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 hepatoblasts. Finally, RNA sequencing of ST18-depleted tumors before involution revealed down-regulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa B-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. (Hepatology 2016).",
author = "Micol Rav{\`a} and Aleco D'Andrea and Mirko Doni and Kress, {Theresia R.} and Renato Ostuni and Valerio Bianchi and Morelli, {Marco J.} and Agnese Collino and Serena Ghisletti and Paola Nicoli and Camilla Recordati and Maria Iascone and Aurelio Sonzogni and Lorenzo D'Antiga and Ruchi Shukla and Faulkner, {Geoffrey J.} and Gioacchino Natoli and Stefano Campaner and Bruno Amati",
year = "2016",
doi = "10.1002/hep.28942",
language = "English",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Inc.",

}

TY - JOUR

T1 - Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18

AU - Ravà, Micol

AU - D'Andrea, Aleco

AU - Doni, Mirko

AU - Kress, Theresia R.

AU - Ostuni, Renato

AU - Bianchi, Valerio

AU - Morelli, Marco J.

AU - Collino, Agnese

AU - Ghisletti, Serena

AU - Nicoli, Paola

AU - Recordati, Camilla

AU - Iascone, Maria

AU - Sonzogni, Aurelio

AU - D'Antiga, Lorenzo

AU - Shukla, Ruchi

AU - Faulkner, Geoffrey J.

AU - Natoli, Gioacchino

AU - Campaner, Stefano

AU - Amati, Bruno

PY - 2016

Y1 - 2016

N2 - The ST18 gene has been proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis has been lacking thus 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 messenger RNA (mRNA) and protein were detectable neither in normal liver nor in cultured hepatoblasts, but were readily expressed after 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 coculture 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 hepatoblasts. Finally, RNA sequencing of ST18-depleted tumors before involution revealed down-regulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa B-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. (Hepatology 2016).

AB - The ST18 gene has been proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis has been lacking thus 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 messenger RNA (mRNA) and protein were detectable neither in normal liver nor in cultured hepatoblasts, but were readily expressed after 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 coculture 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 hepatoblasts. Finally, RNA sequencing of ST18-depleted tumors before involution revealed down-regulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa B-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. (Hepatology 2016).

UR - http://www.scopus.com/inward/record.url?scp=85007442882&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85007442882&partnerID=8YFLogxK

U2 - 10.1002/hep.28942

DO - 10.1002/hep.28942

M3 - Article

JO - Hepatology

JF - Hepatology

SN - 0270-9139

ER -