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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2017

Open Access 01-12-2017 | Research

MIF/CD74 axis is a target for novel therapies in colon carcinomatosis

Authors: Fabio Bozzi, Angela Mogavero, Luca Varinelli, Antonino Belfiore, Giacomo Manenti, Claudio Caccia, Chiara C. Volpi, Galina V. Beznoussenko, Massimo Milione, Valerio Leoni, Annunziata Gloghini, Alexandre A. Mironov, Ermanno Leo, Silvana Pilotti, Marco A. Pierotti, Italia Bongarzone, Manuela Gariboldi

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

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Abstract

Background

Strategies aimed at obtaining a complete cytoreduction are needed to improve long-term survival for patients with colorectal cancer peritoneal carcinomatosis (CRC-pc).

Methods

We established organoid models from peritoneal metastases of two naïve CRC patients. A standard paraffin inclusion was conducted to compare their 3D structure and immunohistochemical profile with that of the corresponding surgical samples. RNA expression levels of the CRC stem cell marker LGR5 was measured by in situ hybridization. The secretome of organoids was profiled by mass spectrometry. Energy homeostasis of organoids was interfered with 4-IPP and metformin. Biochemical and metabolic changes after drug treatments were investigated by western blot and mass spectrometry. Mitochondria impairment was evaluated by electron microscopy and mitotraker staining.

Results

The two organoids recapitulated their corresponding clinical samples in terms of 3D structure and immmunoistochemical profile and were positive for the cancer stem cells marker LGR5. Proteomic analyses of organoids highlighted their strong dependence on energy producing pathways, which suggest that their targeting could be an effective therapeutic approach.
To test this hypothesis, we treated organoids with two drugs that target metabolism acting on AMP-activated protein kinase (AMPK), the main regulator of cellular energy homeostasis, which may act as metabolic tumour suppressor in CRC. Organoids were treated with 4-IPP, an inhibitor of MIF/CD74 signalling axis which activates AMPK function, or metformin that inhibits mitochondrial respiratory chain complex I.
As a new finding we observed that treatment with 4-IPP downregulated AMPK signalling activity, reduced AKT phosphorylation and activated a JNK-mediated stress-signalling response, thus generating mitochondrial impairment and cell death. Metformin treatment enhanced AMPK activation, decreasing the activity of the anabolic factors ribosomal protein S6 and p4EBP-1 and inducing mitochondrial depolarization.

Conclusion

We provide evidence that the modulation of AMPK activity may be a strategy for targeting metabolism of CRC-pc organoids.
Appendix
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Metadata
Title
MIF/CD74 axis is a target for novel therapies in colon carcinomatosis
Authors
Fabio Bozzi
Angela Mogavero
Luca Varinelli
Antonino Belfiore
Giacomo Manenti
Claudio Caccia
Chiara C. Volpi
Galina V. Beznoussenko
Massimo Milione
Valerio Leoni
Annunziata Gloghini
Alexandre A. Mironov
Ermanno Leo
Silvana Pilotti
Marco A. Pierotti
Italia Bongarzone
Manuela Gariboldi
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-016-0475-z

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