Identification of a novel IL-5 signaling pathway in chronic pancreatitis and crosstalk with pancreatic tumor cells

Abstract

Background: While inflammation is associated with pancreatic cancer, the underlying mechanisms leading to cancer initiation are still being delineated. Eosinophils may promote or inhibit tumor growth, although the specific role in pancreatic cancer has yet to be determined. Eosinophil-supporting cytokine interleukin-5 and receptor are likely to have a role, but the significance in the pancreatic cancer microenvironment is unknown. Methods: Genetically engineered Akt1 Myr /KRas G12D and KRas G12D mice were used to model changes induced by chronic inflammation. Tissue samples were collected to analyze the tumor microenvironment and infiltration of immune cells, whereas serum was collected to analyze cytokine and amylase activity in the inflammatory model. The expression of IL-5R and the effects of IL-5 were analyzed in human and murine tumor cells. Results: Compound Akt1 Myr /KRas G12D mice, compared to single KRas G12D or Akt1 Myr mice, exhibited increased tissue damage after repeat inductions of inflammation, and had accelerated tumor development and metastasis. M2 macrophages and newly identified eosinophils co-localized with fibrotic regions rather than infiltrating into tumors, consistent with immune cell privilege. The majority of eosinophils found in the pancreas of Akt1 Myr / KRas G12D mice with chronic inflammation lacked the cytotoxic NKG2D marker. IL-5 expression was upregulated in pancreatic cells in response to inflammation, and then diminished in advanced lesions. Although not previously described in pancreatic tumors, IL-5Rα was increased during mouse pancreatic tumor progression and expressed in human pancreatic ductal adenocarcinomas (7 of 7 by immunohistochemistry). IL-5 stimulated tumor cell migration and activation through STAT5 signaling, thereby suggesting an unreported tumor-promoting role for IL-5Rα in pancreatic cancer. Conclusions: Chronic inflammation induces increased pancreatic cancer progression and immune cells such as eosinophils are attracted to areas of fibrosis. Results suggest that IL-5 in the pancreatic compartment stimulates increased IL-5Rα on ductal tumor cells to increase pancreatic tumor motility. Collectively, IL-5/IL-5Rα signaling in the mouse and human pancreatic tumors microenvironment is a novel mechanism to facilitate tumor progression.

Prognostic value of circulating proteins in patients undergoing surgery for pancreatic cancer

“…The fact that IL‐6 is included in several of our indices, identified through use of two different statistical methods, speaks for the validity of our results. Few other proteins overlapped between our indices, and they can be grouped as immune stimulating (CD40 and CD40L 43 ), angiogenic and tumor promoting (CXCL1 44 and PTN 45 ), and immune suppressing (IL‐4 46 and IL‐5 47 ).…”

Soy-tomato enriched diet reduces inflammation and disease severity in a pre-clinical model of chronic pancreatitis

“…Eosinophilia can occur in patients with chronic pancreatitis and have an active role in tissue remodeling by activating fibroblasts, which increase collagen and fibrosis 33 , 34 . Eosinophils can be a potential source of inflammation-driven IL-5 production in patients with CP 35 , 36 . Tomato metabolites such as lycopene and β-carotene have previously been observed to reduce IL-5 and to suppress eosinophil function in other inflammatory conditions 37 , 38 .…”

Benefits and Pitfalls of a Glycosylation Inhibitor Tunicamycin in the Therapeutic Implication of Cancers

“…In pancreatic cancer progression, IL-5/IL-5Rα roles are possibly a double-edged sword, with both pro- and antitumor activities recently discovered [ 80 , 122 , 123 , 124 ]. However, the mechanistic roles of IL-5 are still unclear.…”