Oncotarget

Research Papers:

Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis

Veronica De Simone, Giulia Ronchetti, Eleonora Franzè, Alfredo Colantoni, Angela Ortenzi, Massimo C. Fantini, Angelamaria Rizzo, Giuseppe S. Sica, Pierpaolo Sileri, Piero Rossi, Thomas T. MacDonald, Francesco Pallone, Giovanni Monteleone and Carmine Stolfi _

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Oncotarget. 2015; 6:9908-9923. https://doi.org/10.18632/oncotarget.3532

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Abstract

Veronica De Simone1, Giulia Ronchetti1, Eleonora Franzè1, Alfredo Colantoni1, Angela Ortenzi1, Massimo C. Fantini1, Angelamaria Rizzo1, Giuseppe S. Sica2, Pierpaolo Sileri2, Piero Rossi2, Thomas T. MacDonald3, Francesco Pallone1, Giovanni Monteleone1 and Carmine Stolfi1

1 Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy

2 Department of Surgery, University of Rome “Tor Vergata”, Rome, Italy

3 Centre for Immunology and Infectious Disease, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, UK

Correspondence to:

Carmine Stolfi, email:

Keywords: Apcmin/+ mice, STAT3, COX-2/PGE2, VEGF

Received: September 22, 2014 Accepted: February 17, 2015 Published: March 12, 2015

Abstract

Interleukin (IL)-21 triggers inflammatory signals that contribute to the growth of neoplastic cells in mouse models of colitis-associated colorectal cancer (CRC). Because most CRCs are sporadic and arise in the absence of overt inflammation we have investigated the role of IL-21 in these tumors in mouse and man. IL-21 was highly expressed in human sporadic CRC and produced mostly by IFN-γ-expressing T-bet/RORγt double-positive CD3+CD8- cells. Stimulation of human CRC cell lines with IL-21 did not directly activate the oncogenic transcription factors STAT3 and NF-kB and did not affect CRC cell proliferation and survival. In contrast, IL-21 modulated the production of protumorigenic factors by human tumor infiltrating T cells. IL-21 was upregulated in the neoplastic areas, as compared with non-tumor mucosa, of Apcmin/+ mice, and genetic ablation of IL-21 in such mice resulted in a marked decrease of both tumor incidence and size. IL-21 deficiency was associated with reduced STAT3/NF-kB activation in both immune cells and neoplastic cells, diminished synthesis of protumorigenic cytokines (that is, IL-17A, IL-22, TNF-α and IL-6), downregulation of COX-2/PGE2 pathway and decreased angiogenesis in the lesions of Apcmin/+ mice. Altogether, data suggest that IL-21 promotes a protumorigenic inflammatory circuit that ultimately sustains the development of sporadic CRC.


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