24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development

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.oxysterols | HIF-1α | pancreatic neuroendocrine tumors | angiogenic switch | neutrophils R ecent studies have highlighted the diversity of metabolic pathways altered between normal and tumor cells (1, 2). Activation of specific metabolic pathways within tumors is believed to derive from an intricate connection among intrinsic and extrinsic factors, such as oncogenic signaling, stromal-derived molecules, and hypoxia (3). Tumor hypoxia and hypoxia inducible factor-1a (HIF-1α) activation have been linked to increased glucose metabolism and cancer progression in a number of tumor types (4). Whether HIF-1α signaling regulates other metabolic products in tumor cells or during tumorigenesis remains only partially understood.The differential regulation of tumor metabolism and the relative abundance of some tumor-derived metabolites have also been shown to condition the tumor microenvironment, with particular emphasis on immune cell components (5). For example, metabolic products like pyruvic acid and lactic acid induce hypoxiaindependent stabilization of HIF-1α in tumor-associated macrophages (6). These products, especially lactic acid, are products of the so-called Warburg effect (aerobic glycolysis) (7) and mainly require the enzymatic activity of the pyruvate kinase M2 (PKM2), an isoform expressed by tumor cells and associated with the production of high amounts of pyruvate and lactate (8). More recently cholesterol metabolism, oxysterols, and liver X receptors (LXRs) have been shown to be important players in tumor metabolism (9, 10), due to their dual involvement in tumor and immune cell biology (11-13). This dual involvement makes the LXR/oxysterol axis an attractive ta...

Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy

“…Oxysterols have been reported to promote cancer cell proliferation (7), recruit pro-tumor neutrophils (8,9), which seem to play an important role in cancer progression (10), and facilitate metastasis (10,11). However, oxysterols can also suppress cancer cell proliferation acting as ligands of liver X receptors (LXRs) (12,13).…”

Amyloid aggregates accumulate in melanoma metastasis driving YAP mediated tumor progression

“…Oxysterols were prepared from melanoma cell lines using a modified version of the protocol described by Griffiths et al (Griffiths et al, 2013), consisting in an alcoholic extraction and a double round of reverse-phase (RP) solid-phase extraction (SPE) (Soncini et al, 2016). Briefly, melanoma cell pellets (2x10 6 cells) were sonicated for 5 min by adding 1. acetonitrile, and 0.1% formic acid.…”

The Role of Oxysterols in Human Cancer

“…The tumorigenesis of pNET is accompanied by high expression of the 24-HC forming enzyme CYP46A1 (OMIM: 604087), and 24-HC is suggested to recruit pro-tumor neutrophils and thus promote the angiogenesis [65]. Additionally, in various pancreatic cell lines, the expression of ORP5 has been associated with invasiveness and patients with the ORP5-expressing pancreatic tumors have poor prognosis [66].…”