2. Academic Validation
  3. 24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development

24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development

  • Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6219-E6227. doi: 10.1073/pnas.1613332113.
Matias Soncini 1,  Gianfranca Corna 2,  Marta Moresco 2,  Nadia Coltella 3,  Umberto Restuccia 4,  Daniela Maggioni 2,  Laura Raccosta 2,  Chin-Yo Lin 5,  Francesca Invernizzi 6,  Roberto Crocchiolo 7,  Claudio Doglioni 8,  Catia Traversari 7,  Angela Bachi 4,  Rosa Bernardi 3,  Claudio Bordignon 9,  Jan-Åke Gustafsson 10,  Vincenzo Russo 1
Affiliations

Affiliations

  • 1 Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan 20132, Italy; soncini.matias@gmail.com bordignon.claudio@hsr.it jgustafsson@uh.edu russo.vincenzo@hsr.it.
  • 2 Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan 20132, Italy.
  • 3 Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Milan 20132, Italy.
  • 4 Functional Proteomics Program, Istituto FIRC di Oncologia Molecolare (IFOM), Milan 20132, Italy.
  • 5 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77004.
  • 6 Department of Pathology, Scientific Institute San Raffaele, Milan 20132, Italy.
  • 7 MolMed S.p.A., Milan 20132, Italy.
  • 8 Department of Pathology, Scientific Institute San Raffaele, Milan 20132, Italy; Università Vita-Salute San Raffaele, Milan 20132, Italy.
  • 9 MolMed S.p.A., Milan 20132, Italy; Università Vita-Salute San Raffaele, Milan 20132, Italy soncini.matias@gmail.com bordignon.claudio@hsr.it jgustafsson@uh.edu russo.vincenzo@hsr.it.
  • 10 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77004; soncini.matias@gmail.com bordignon.claudio@hsr.it jgustafsson@uh.edu russo.vincenzo@hsr.it.
PMID: 27671648 DOI: 10.1073/pnas.1613332113
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 tumor-derived 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.

Keywords

HIF-1α; angiogenic switch; neutrophils; oxysterols; pancreatic neuroendocrine tumors.

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