Autophagy Flux is Induced in Gastroenteropancreatic Neuroendocrine Neoplasms - European Medical Journal

Autophagy Flux is Induced in Gastroenteropancreatic Neuroendocrine Neoplasms

2 Mins
Oncology
Authors:
*Ioanna Angelioudaki,1 Maria Theochari,2 Efthimios Koniaris,3 Agapi Kataki,4 Loukas Stoupis,1 Alexandros Mitrousias,1 Alexandros-Georgios Tzingounis,1 Nikolaos Dafnios,1 Georgios Zografos,2 Georgia Kifiri,3 Manousos M. Konstadoulakis1
Disclosure:

This study is part of NExT project which has received funding from the GSRT (Greece) within the Transcan-2 program ERA-NET ‘Translational research on rare cancers’. Angelioudaki has received Special Account for Research Grants of the National and Kapodistrian University of Athens, Greece. All other authors report no conflicts of interest.

Citation:
EMJ Oncol. ;10[1]:39-40. DOI/10.33590/emjoncol/10117618. https://doi.org/10.33590/emjoncol/10117618.
Keywords:
Autophagy, gastroenteropancreatic neuroendocrine neoplasms, neuroendocrine carcinomas, neuroendocrine tumours.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND AND AIMS

Neuroendocrine neoplasms (NEN) represent a rare heterogeneous group with an increasing incidence, consisting of neuroendocrine tumours (NET) and neuroendocrine carcinomas (NEC), mostly prevalent in the gastrointestinal tract. Cancer stage, tumour grade, mode of treatment, and mainly early diagnosis affect overall survival rate. Their classification is based on their differentiation, grade, mitotic rate, and Ki-67 index status, and according to the latest 2019 World Health Organization (WHO) definitions, NETs are well differentiated, whereas NECs are poorly differentiated.1 Genetic analysis of NENs deriving mostly from pancreatic cases recognises differences in the mutational profiles between NETs and NECs, but there is still limited understanding on the molecular pathogenesis of the disease.2 The molecular mechanism of autophagy is crucial for the survival of cells. However, it holds a dual role in the progression of cancer, as it can either promote tumour survival by ameliorating stress, recycling unwanted proteins, and generation of energy; or suppress tumour survival through apoptosis, necrosis, and inflammation.3 Various molecules participating in the initiation, nucleation, elongation, or fusion of autophagosome with lysosome, are targeted to study autophagy. The LC3B protein, part of the elongation of the dynamic membrane structure of the autophagosome, is the most characteristic and widely-used autophagy marker, especially in association with the adaptor protein p62/sequestrome 1. Their interaction facilitates autophagic degradation of ubiquitinated protein aggregates in lysosomes.4,5

MATERIALS AND METHODS

In this study, autophagy flux was assessed by means of p62 and LC3B protein expression in various GEP-NENs derived from pancreas (n=19), stomach (n=2), small intestine (n=2), and oesophagus (n=1), where existing data are limited. The study was approved by the ethics committee of the Hippokration General Hospital of Athens, Greece. The patient cohort consisted of nine patients with NECs (six male, three females; mean age: 55±7; six pancreas, one stomach, one small intestine, one oesophagus), and 16 patients with NETs (11 male, five female; mean age: 58.69±3.7; 13 pancreas, one stomach, two small intestine). Immunohistochemistry was performed on 5 μm sections of formalin-fixed paraffin-embedded tissue from lesions and normal adjacent tissue. Staining intensity (negative to high: 0–3) was multiplied with the immunoreactive score (0–10%=1; 11–50%=2; 51–80%=3; 81–100%=4) to obtain the final score. Epithelial and stromal cell populations were assessed separately.

RESULTS

Results were statistically analysed using IBM SPSS Statistics 28.0 (Armonk, New York, USA). Both cytoplasmic and nuclear p62 expression were observed. Expression, mainly cytoplasmic, was higher in NEN lesions compared to their corresponding NA epithelium (0.92±0.4 versus 0.0; p=0.017), in which nuclear expression was prominent (p=0.047). LC3B expression was also induced in lesions compared to NA epithelium, but this difference was not statistically significant (p=0.1), probably due to the limited number of patients. Nevertheless, LC3B protein expression was mainly detected in NENs lesions’ epithelium with limited expression in stroma (5.67±0.9 versus 0.47; p<0.001). The difference between epithelium and stroma was more prevalent in NEC lesions (NECs: 7.25±1.5 versus 0.62±0.3; p=0.018) versus NETs (4.67±1.3 versus 0.58±0.3; p=0.016 [hl]Figure 1[/hl]).

Figure 1: Representative immunohistochemical detection of LC3B and p62.
LC3B and p62 in stomach samples (A–D) and pancreas samples (E–H): p62 cytoplasmic expression is prominent in NEC lesions (D and H), while LC3B protein expression is significantly increased (A–C and E–G) in lesions’ epithelium compared to their corresponding stroma (epithelium versus stroma [red arrow]; p<0.001). This pattern is more prominent in NEC lesions (NECs: p=0.018 versus NETs: p=0.016). Magnification: 20x.
NA: normal adjacent epithelium; NET: neuroendocrine tumour; NEC: neuroendocrine carcinoma.

CONCLUSION

An apparent induction in autophagy was also detected in this study, which includes NENs from various organs of the gastrointestinal tract, and further supports existing data derived from pancreatic NENs.6,7 However, more data are required, as the number of patients in this cohort was limited. Still, the observed prevalence of autophagy in epithelium compared to stroma in NECs versus NETs might be related to their distinct clinical phenotype, making autophagy a potential candidate for introducing new therapeutic strategies for patients with GEP-NENs.

References
Nagtegaal ID et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76(2):182-8. Melone V et al. Identification of functional pathways and molecular signatures in neuroendocrine neoplasms by multi-omics analysis. J Transl Med. 2022;20(1):306. Yoshii SR, Mizushima N. Monitoring and measuring autophagy. Int J Mol Sci. 2017;18(9):1865. Liu J-L et al. Prognostic significance of p62/SQSTM1 subcellular localization and LC3B in oral squamous cell carcinoma. Br J Cancer. 2014;111(5):944-54. Kim J-W et al. Prognostic value of LC3B and p62 expression in small intestinal adenocarcinoma. J Clin Med. 2021;10(22):5398. Weckman A et al. Autophagy in endocrine tumors. Endocr Relat Cancer. 2015;22(4):R205-18. Daskalakis K et al. Increased autophagy/mitophagy levels in primary tumours of patients with pancreatic neuroendocrine neoplasms. Endocrine. 2020;68:438-47.

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