Proteomic analysis of small intestinal neuroendocrine tumors and mesenteric fibrosis

in Endocrine-Related Cancer
Authors:
Anela Blažević Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Anand M Iyer Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Marie-Louise F van Velthuysen Department of Pathology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Johannes Hofland Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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https://orcid.org/0000-0003-0679-6209
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Gaston J H Franssen Department of Surgery, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Richard A Feelders Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Marina Zajec Laboratory of Neuro-Oncology/Clinical & Cancer Proteomics, Department of Neurology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Theo M Luider Laboratory of Neuro-Oncology/Clinical & Cancer Proteomics, Department of Neurology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Wouter W de Herder Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Leo J Hofland Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Correspondence should be addressed to A Blažević: a.blazevic.1@erasmusmc.nl
DOI:
https://doi.org/10.1530/ERC-22-0237
Volume/Issue:
Volume 30: Issue 6
Article Type:
Research Article
Article ID:
e220237
Online Publication Date:
11 May 2023
Copyright:
© the author(s) 2023
Restricted access
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Mesenteric metastases in small intestinal neuroendocrine tumors (SI-NETs) are associated with mesenteric fibrosis (MF) in a proportion of patients. MF can induce severe abdominal complications, and an effective preventive treatment is lacking. To elucidate possible novel therapeutic targets, we performed a proteomics-based analysis of MF. The tumor cell and stromal compartment of primary tumors and paired mesenteric metastases of SI-NET patients with MF (n = 6) and without MF (n = 6) was analyzed by liquid chromatography-mass spectrometry-based proteomics. Analysis of differential protein abundance was performed. Collagen alpha-1(XII) (COL12A1) and complement component C9 (C9) expression was evaluated by immunohistochemistry (IHC) in mesenteric metastases. A total of 2988 proteins were identified. Unsupervised hierarchical clustering showed close clustering of paired primary and mesenteric tumor cell samples. Comparing MF to non-MF samples, we detected differentially protein abundance solely in the mesenteric metastasis stroma group. There was no differential abundance of proteins in tumor cell samples or primary tumor stroma samples. Analysis of the differentially abundant proteins (n = 36) revealed higher abundance in MF samples of C9, various collagens and proteoglycans associated with profibrotic extracellular matrix dysregulation and signaling pathways. Proteins involved in fatty acid oxidation showed a lower abundance. COL12A1 and C9 were confirmed by IHC to have significantly higher expression in MF mesenteric metastases compared to non-MF. In conclusion, proteome profiles of SI-NETs with and without MF differ primarily in the stromal compartment of mesenteric metastases. Analysis of differentially abundant proteins revealed possible new signaling pathways involved in MF development. In conclusion, proteome profiles of SI-NETs with and without MF differ primarily in the stromal compartment of mesenteric metastases. Analysis of differentially abundant proteins revealed possible new signaling pathways involved in MF development.

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© the author(s) 2023
Article ID:
e220237
Received Date:
07 Dec 2023
Accepted Date:
23 Mar 2023
Print Publication Date:
01 Jun 2023
Online Publication Date:
11 May 2023
Keywords:
neuroendocrine tumor; mesenteric fibrosis; proteomics; immunohistochemistry; extracellular matrix; collagens; proteoglycans; fatty acid oxidation; complement system

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