The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development

M Howlett, AS Giraud, H Lescesen, CB Jackson… - Gastroenterology, 2009 - Elsevier
M Howlett, AS Giraud, H Lescesen, CB Jackson, A Kalantzis, IR Van Driel, L Robb…
Gastroenterology, 2009Elsevier
BACKGROUND & AIMS: Gastric cancer is the second most common cause of cancer-related
mortality worldwide, mainly as a result of late-stage detection. Interleukin (IL)-11 is a
multifunctional cytokine reported to be up-regulated in human gastric cancer. METHODS:
We investigated the importance of IL-11 in gastric cancer progression by examining its role
in a variety of mouse gastric tumor models, as well as in nonneoplastic and tumor tissues
taken from gastric cancer patients. We then determined the transcriptional and translational …
BACKGROUND & AIMS
Gastric cancer is the second most common cause of cancer-related mortality worldwide, mainly as a result of late-stage detection. Interleukin (IL)-11 is a multifunctional cytokine reported to be up-regulated in human gastric cancer.
METHODS
We investigated the importance of IL-11 in gastric cancer progression by examining its role in a variety of mouse gastric tumor models, as well as in nonneoplastic and tumor tissues taken from gastric cancer patients. We then determined the transcriptional and translational outcomes of IL-11 overexpression in normal gastric mucosa and identified a novel gene signature important early in the progression toward gastric tumorigenesis.
RESULTS
IL-11 was up-regulated significantly in 4 diverse mouse models of gastric pathology as well as in human biopsy specimens adjacent to and within gastric cancer. Removal of IL-11 co-receptor α significantly reduced HKβ-/- mouse fundic hyperplasia and ablated gp130757F/F mouse tumorigenesis. Exogenous IL-11 but not IL-6 activated oncogenic signal transducer and activator of transcription-3, and altered expression of novel proliferative and cytoprotective genes RegIII-β, RegIII-γ, gremlin-1, clusterin, and growth arrest specific-1 in wild-type gastric mucosa, a gene signature common in gp130757F/F and HKβ-/- tumors as well as nonneoplastic mucosa of gastric cancer patients. One week of chronic IL-11 administration in wild-type mice sustained the gene signature, causing pretumorigenic changes in both antrum and fundus.
CONCLUSIONS
Increased gastric IL-11 alters expression of proliferative and cytoprotective genes and promotes pretumorigenic cellular changes.
Elsevier