Relationship Between Chronic Inflammation and Cancer: Interleukin-1β Overexpression Induces Pancreatic Ductal Adenocarcinoma in Oncogenic Kras Mice

Macchini, Marina (2016) Relationship Between Chronic Inflammation and Cancer: Interleukin-1β Overexpression Induces Pancreatic Ductal Adenocarcinoma in Oncogenic Kras Mice, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Oncologia e patologia sperimentale, 28 Ciclo. DOI 10.6092/unibo/amsdottorato/7316.
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Chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC) development. Polymorphisms in the pro-inflammatory cytokine gene interleukin 1β (IL-1β), as well as high IL-1β or low IL-1 receptor antagonist (IL-1RA) serum levels, are associated to worse prognosis in PDAC patients. To characterize the role of IL-1β in pancreatic tumorigenesis, we generated a transgenic mouse model bearing KRASG12D mutation combined to chronic inflammation induced by pancreatic overexpression of human IL-1β (KC-IL-1β). We found that IL-1β overexpression induced PDAC onset in 6 out of 13 KRASG12D bearing animals (46%), with a median overall survival of 10.5 months, compared to only 1 out of 13 mice carrying KRASG12D mutation alone (KC)(7.7% p= 0.02). In primary pancreatic KRASG12D organoid cultures, IL-1β exposure increased the number of spheroids and induced gene expression changes consistent with epithelial to mesenchymal transition (EMT), as shown by increased expression of vimentin, Zeb1, Snail. All these changes were counteracted using a recombinant human IL-1receptor antagonist (IL1-RA). Consistently, immuno-histochemical analysis confirmed that in KC-IL-1β tumor epithelial cells and metastasis were strongly positive for vimentin. The relevance of these findings was confirmed in human PDAC, showing higher IL-1 receptor I (IL1-RI) and vimentin expression in tumor tissue compared with adjacent normal pancreas. Regarding the mechanism involved in EMT activation, IL-1β exposure was found to induce an up-regulation of ribosome biogenesis rate, with consequent down-regulation of p53 protein expression which has been shown to be responsible for EMT changes. The finding that IL-1β/IL1-RI inflammatory pathway stimulates acinar cell proliferation and promotes EMT provides the rationale for a therapeutic strategy based on IL-1β receptor blockade to counteract inflammation-induced pancreatic tumorigenesis

Tipologia del documento
Tesi di dottorato
Macchini, Marina
Dottorato di ricerca
Scuola di dottorato
Scienze biologiche, biomediche e biotecnologiche
Settore disciplinare
Settore concorsuale
Parole chiave
chronic inflammation, pancreatic cancer
Data di discussione
9 Maggio 2016

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