The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis

Abstract

SUMMARY The contributions of the innate immune system to the development of pancreatic cancer are still ill-defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (ADM), which then give rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. We here demonstrate presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively-activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors such as IL-1ra and CCL2 to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly-decreased the accumulation of alternatively-activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.

KRAS mutation and epithelial–macrophage interplay in pancreatic neoplastic transformation

“…Recently, in a KRAS model of PDA, tumor-associated macrophages increased with ductal metaplasia and neoplastic transformation, effects that appeared to depend on IL-13 released from cancer cells. 47 On the other hand, several pathways have been proposed to mediate the effects of tumor-associated macrophages on cancerous epithelium. 10,13,29 Here we found that expression of PEDF, a tumor suppressor in PDA, decreases in the transforming epithelium not due to KRAS mutation but upon exposure to macrophages.…”

CD133 as a regulator of cancer metastasis through the cancer stem cells

“…Enrichment of DCLK1 and acetylated α-tubulin in the FACS-sorted CD133 + population of PDAC cells was reported (Bailey et al, 2014). Expression of CD133, DCLK1 and CD44 were present in PanIN cells of oncogenic Kras G12D mouse pancreas (Fig 2, (Bailey et al, 2014, Delgiorno et al, 2014, Liou et al, 2017)). However, these 3 CSC markers were expressed in different subpopulations of murine PanIN cells (Fig 2.…”

Metaplasia: tissue injury adaptation and a precursor to the dysplasia–cancer sequence

“…Macrophage-secreted inflammatory cytokines, such as tumour necrosis factor (TNF) and CC motif chemokine 5 (CCL5), play roles in pancreatic ADM, with contributions from macrophage-released matrix metalloproteinases (MMPs), such as MMP9, as well 131,132 . Recently, it was demonstrated that IL-13 alters macrophage populations from an inflammatory macrophage subpopulation to an alternatively activated macrophage subpopulation in ADM 133 . The development of Barrett-like metaplasia in the mouse requires the suppression of CD8 + T cell-dependent apoptosis of epithelial cells, which is probably mediated by CD11b + GR1 + immature myeloid cells or myeloid-derived suppressor cells 134 .…”