Neuroendocrine Neoplasms: Identification of Novel Metabolic Circuits of Potential Diagnostic Utility

Abstract

The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (1H-NMR) for NEN in a prospective cohort of patients through a single-centre, prospective controlled observational study. Urine samples of 34 treatment-naïve NEN patients (median age: 59.3 years, range: 36–85): 18 had pancreatic (Pan) NEN, of which seven were functioning; 16 had small bowel (SB) NEN; 20 age- and sex-matched healthy control individuals were analysed using a 600 MHz Bruker 1H-NMR spectrometer. Orthogonal partial-least-squares-discriminant analysis models were able to discriminate both PanNEN and SBNEN patients from healthy control (Healthy vs. PanNEN: AUC = 0.90, Healthy vs. SBNEN: AUC = 0.90). Secondary metabolites of tryptophan, such as trigonelline and a niacin-related metabolite were also identified to be universally decreased in NEN patients, while upstream metabolites, such as kynurenine, were elevated in SBNEN. Hippurate, a gut-derived metabolite, was reduced in all patients, whereas other gut microbial co-metabolites, trimethylamine-N-oxide, 4-hydroxyphenylacetate and phenylacetylglutamine, were elevated in those with SBNEN. These findings suggest the existence of a new systems-based neuroendocrine circuit, regulated in part by cancer metabolism, neuroendocrine signalling molecules and gut microbial co-metabolism. Metabonomic profiling of NEN has diagnostic potential and could be used for discovering biomarkers for these tumours. These preliminary data require confirmation in a larger cohort.

Inovações adotadas no diagnóstico de tumores neuroendócrinos do intestino delgado

“…Trata-se de uma proteína que participa da composição do aparelho celular neuroendócrino. Sua sensibilidade gira em torno de 60% a 90% uma vez que um TNE já tenha sido identificado, todavia não é indicado o seu uso como ferramenta inicial, pois tem baixa precisão diagnóstica e prognóstica (Jiménez et al, 2021). O desenvolvimento de biomarcadores com adequados valores de sensibilidade e especificidade são imprescindíveis para que a investigação clínica seja mais acurada e que possibilite precocemente a terapêutica pertinente.…”

FOXA2-initiated transcriptional activation of INHBA induced by methylmalonic acid promotes pancreatic neuroendocrine neoplasm progression

“…Several clinical studies have reported the stratified metabolic phenotype of various neuroendocrine neoplasmas to identify novel biomarkers for diagnosis and prognosis based on metabolic profiling of urine samples [ 35 ], tissue samples [ 36 ], and plasma samples [ 37 ]. It has been revealed that cell metabolism possessed heterogeneous characteristics and varied depending on the site and origin of tumors [ 15 ].…”

An update on the diagnosis of gastroenteropancreatic neuroendocrine neoplasms

“…Multianalyte analysis of neuroendocrine metabolites has also been explored as a diagnostic strategy for GEP-NENs. A 2021 study from Jiménez et al [ 85 ] used nuclear magnetic resonance to compare urine samples from patients with GEP-NENs and healthy controls and generated a model that could accurately discriminate between the two groups. The study suggests that nuclear magnetic resonance could be a useful clinical tool for diagnosing GEP-NENs[ 85 ].…”

“…A 2021 study from Jiménez et al [ 85 ] used nuclear magnetic resonance to compare urine samples from patients with GEP-NENs and healthy controls and generated a model that could accurately discriminate between the two groups. The study suggests that nuclear magnetic resonance could be a useful clinical tool for diagnosing GEP-NENs[ 85 ]. They identified several metabolites that were either increased or decreased in GEP-NENs, including kynurenine, hippurate, and phenylacetylglutamine[ 85 ].…”

“…The study suggests that nuclear magnetic resonance could be a useful clinical tool for diagnosing GEP-NENs[ 85 ]. They identified several metabolites that were either increased or decreased in GEP-NENs, including kynurenine, hippurate, and phenylacetylglutamine[ 85 ]. These novel biomarkers represent areas of future study and suggest that a multianalyte test involving multiple metabolites that are altered in GEP-NENs could be more effective than monoanalyte tests.…”