24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development.
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.
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.
Matias
M
Soncini
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.
Gianfranca
G
Corna
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.
Marta
M
Moresco
Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Milan 20132, Italy.
Nadia
N
Coltella
Functional Proteomics Program, Istituto FIRC di Oncologia Molecolare (IFOM), Milan 20132, Italy.
Umberto
U
Restuccia
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.
Daniela
D
Maggioni
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.
Laura
L
Raccosta
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77004.
Chin-Yo
CY
Lin
Department of Pathology, Scientific Institute San Raffaele, Milan 20132, Italy.
Francesca
F
Invernizzi
MolMed S.p.A., Milan 20132, Italy.
Roberto
R
Crocchiolo
Department of Pathology, Scientific Institute San Raffaele, Milan 20132, Italy; Università Vita-Salute San Raffaele, Milan 20132, Italy.
Claudio
C
Doglioni
MolMed S.p.A., Milan 20132, Italy.
Catia
C
Traversari
Functional Proteomics Program, Istituto FIRC di Oncologia Molecolare (IFOM), Milan 20132, Italy.
Angela
A
Bachi
Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Milan 20132, Italy.
Rosa
R
Bernardi
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.
Claudio
C
Bordignon
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.
Jan-Åke
JÅ
Gustafsson
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.
Vincenzo
V
Russo
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism; D000072556:Cholesterol 24-Hydroxylase; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D005455:Fluorescent Antibody Technique; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006888:Hydroxycholesterols / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics; D018358:Neuroendocrine Tumors / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D020690:GTPase-Activating Proteins; D006888:Hydroxycholesterols; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C490620:Ralbp1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C044563:24-hydroxycholesterol; D000072556:Cholesterol 24-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase
HIF-1α; angiogenic switch; neutrophils; oxysterols; pancreatic neuroendocrine tumors
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