24-hydroxycholesterol participates in pancreatic neuroendocrine tumor development

Matias Cristobal Soncini, Gianfranca Corna, Marta Moresco, Nadia Coltella, Umberto Restuccia, Daniela Maggioni, Laura Raccosta, Chin Yo Lin, Francesca Invernizzi, Roberto Crocchiolo, Claudio Doglioni, Catia Traversari, Angela Bachi, Rosa Bernardi, Claudio Bordignon, J. Å Gustafsson, Vincenzo Russo

Research output: Contribution to journalArticle

Abstract

Cells in the tumor microenvironment may be reprogrammed by tumor-derived metabolites. Cholesterol-oxidized products, namely oxysterols, have been shown to favor tumor growth directly by promoting tumor cell growth and indirectly by dampening antitumor immune responses. However, the cellular and molecular mechanisms governing oxysterol generation within tumor microenvironments remain elusive. We recently showed that tumorderived oxysterols recruit neutrophils endowed with protumoral activities, such as neoangiogenesis. Here, we show that hypoxia inducible factor-1a (HIF-1α) controls the overexpression of the enzyme Cyp46a1, which generates the oxysterol 24-hydroxycholesterol (24S-HC) in a pancreatic neuroendocrine tumor (pNET) model commonly used to study neoangiogenesis. The activation of the HIF-1α-24S-HC axis ultimately leads to the induction of the angiogenic switch through the positioning of proangiogenic neutrophils in proximity to Cyp46a1+islets. Pharmacologic blockade or genetic inactivation of oxysterols controls pNET tumorigenesis by dampening the 24S-HC-neutrophil axis. Finally, we show that in some human pNET samples Cyp46a1 transcripts are overexpressed, which correlate with the HIF-1α target VEGF and with tumor diameter. This study reveals a layer in the angiogenic switch of pNETs and identifies a therapeutic target for pNET patients.

Original languageEnglish
Pages (from-to)E6219-E6227
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number41
DOIs
Publication statusPublished - Oct 11 2016

Keywords

  • Angiogenic switch
  • Hif-1α
  • Neutrophils
  • Oxysterols
  • Pancreatic neuroendocrine tumors

ASJC Scopus subject areas

  • General

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  • Cite this

    Soncini, M. C., Corna, G., Moresco, M., Coltella, N., Restuccia, U., Maggioni, D., Raccosta, L., Lin, C. Y., Invernizzi, F., Crocchiolo, R., Doglioni, C., Traversari, C., Bachi, A., Bernardi, R., Bordignon, C., Gustafsson, J. Å., & Russo, V. (2016). 24-hydroxycholesterol participates in pancreatic neuroendocrine tumor development. Proceedings of the National Academy of Sciences of the United States of America, 113(41), E6219-E6227. https://doi.org/10.1073/pnas.1613332113