Metabolic changes in neuroendocrine neoplasms

Abstract

Neuroendocrine neoplasms (NENs) are a group of highly heterogeneous neoplasms originating from neuroendocrine cells with a gradually increased incidence. Metabolic change is one of the recognized markers of tumor progression, which has been extensively and systematically studied in other malignant tumors. However, metabolic change in NENs has been relatively poorly studied, and systematic reviews are lacking. We reviewed the relationship between metabolic changes and NENs from the aspects of glucose metabolism, lipid metabolism, metabolic syndrome, amino acid metabolism and metabolomics, and discussed the potential therapeutic strategies of metabolic changes for NENs.

Keywords: Metabolic changes; Metabolite; Neuroendocrine neoplasm.

Fig. 1

Schematic overview of metabolic pathways in NENs. PI3K/AKT/mTOR pathway plays an important role in the glycometabolism, lipid, and amino acid metabolism processes of NENs

Fig. 2

Lipid metabolism changes in NENs. The expression of ACSS2 is up-regulated by HIF-1α under hypoxia, which regulates lipid metabolism through the PI3K/AKT/mTOR pathway to promote the progression of NENs. FASN, a key enzyme in the fatty acid synthesis pathway, is up-regulated in NEN. FABP5 interacts with FASN to regulate the expression of FASN through the ubiquitin-proteasome pathway, promote lipid droplet deposition and activate Wnt/β-catenin signaling pathway to promote the progression of NEN. However, the FASN inhibitor orlistat could reverse this process. ALKBH5, an m6A demethylase, is up-regulated in NENs, which increases the expression of FABP5 in an m6A-IGF2BP2-dependent manner, activates PI3K/Akt/mTOR signaling pathway, and leads to lipid metabolism disorders and promotes the progression of NENs. HIF-1α regulates the overexpression of Cyp46a1 enzyme in NENs to produce 24 S-HC, and activation of the HIF-1α/ 24 S-HC axis induces neovascularization

Fig. 3

Schematic diagram of amino acid metabolism in NENs. (A) GCGR knockout mice exhibit elevated plasma amino acids and activation of mTOR signaling, driving the proliferation of mouse SLC38A5 + embryonic progenior-like α cell population, which drives tumor initiation when the inducing signal is prolonged. (B) TPH1 converts tryptophan to 5-HTP, which is then decarboxylated by AAAD to synthesize serotonin. Carbidopa and MFMD, inhibitors of AAAD, and Telotristat, a novel inhibitor of TPH, inhibit serotonin synthesis and ameliorate the carcinoid syndrome

Fig. 4

Metabolomics study in NENs. (A) The flow chart of metabolomics is shown in the upper left panel. (B) NENs cause metabolic alterations and environmental factors can in turn affect the progression of NENs by affecting metabolism. (C) In addition to providing energy for tumor cells, metabolism can also cause epigenetic changes through metabolites and affect signaling pathways, thereby regulating tumor progression. (D) MMA, a serum metabolite, up-regulates the expression of INHBA through transcription factor FOXA2, which affects the downstream signaling pathways and regulates the progression of NENs