Lipocalin-2 promotes pancreatic ductal adenocarcinoma by regulating inflammation in the tumor microenvironment

Sobeyda B. Gomez-Chou, Agnieszka Katarzyna Swidnicka-Siergiejko, Niharika Badi, Myrriah Chavez-Tomar, Gregory B. Lesinski, Tanios Bekaii-Saab, Matthew R. Farren, Thomas A. Mace, Carl Schmidt, Yan Liu, Defeng Deng, Rosa F. Hwang, Liran Zhou, Todd Moore, Deyali Chatterjee, Huamin Wang, Xiaohong Leng, Ralph B. Arlinghaus, Craig D. Logsdon, Zobeida Cruz-Monserrate

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Lipocalin-2 (LCN2) promotes malignant development in many cancer types. LCN2 is upregulated in patients with pancreatic ductal adenocarcinoma (PDAC) and in obese individuals, but whether it contributes to PDAC development is unclear. In this study, we investigated the effects of Lcn2 depletion on dietinduced obesity, inflammation, and PDAC development. Mice with acinar cell-specific expression of KrasG12D were crossed with Lcn2-depleted animals and fed isocaloric diets with varying amounts of fat content. Pancreas were collected and analyzed for inflammation, pancreatic intraepithelial neoplasia (PanIN), and PDAC. We also used a syngeneic orthotopic PDAC mouse model to study tumor growth in the presence or absence of Lcn2 expression. In addition, to understand the mechanistic role of how LCN2 could be mediating PDAC, we studied LCN2 and its specific receptor solute carrier family 22 member 17 (SLC22A17) in human pancreatic cancer stellate cells (PSC), key mediators of the PDAC stroma. Depletion of Lcn2 diminished extracellular matrix deposition, immune cell infiltration, PanIN formation, and tumor growth. Notably, it also increased survival in both obesity-driven and syngeneic orthotopic PDAC mouse models. LCN2 modulated the secretion of proinflammatory cytokines in PSC of the PDAC tumor microenvironment, whereas downregulation of LCN2-specific receptor SLC22A17 blocked these effects. Our results reveal how LCN2 acts in the tumor microenvironment links obesity, inflammation, and PDAC development.

Original languageEnglish (US)
Pages (from-to)2647-2660
Number of pages14
JournalCancer research
Volume77
Issue number10
DOIs
StatePublished - May 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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