The IGF pathway is activated in insulinomas but downregulated in metastatic disease.

Henfling, Mieke; Perren, Aurel; Schmitt, Anja Maria; Saddig, Christiane M; Starke, Achim A; Riedl, Robert G; Versleijen-Jonkers, Yvonne M H; Sprij-Mooij, Diane M; Ramaekers, Frans C S; Hofland, Leo; Speel, Ernst-Jan M (2018). The IGF pathway is activated in insulinomas but downregulated in metastatic disease. (In Press). Endocrine-related cancer BioScientifica Ltd. 10.1530/ERC-18-0222

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Clinical and molecular studies have implicated epidermal growth factor receptor (EGFR), insulin-like growth factor (IGF) and target of rapamycin (mTOR) signaling pathways in the regulation of pancreatic neuroendocrine tumor (PanNET) growth. Interpretation and comparison of these studies is complex due to clinical and molecular tumor heterogeneity. We therefore focused in this study on insulinomas, which we examined for mRNA and protein expression of EGFR, IGF and mTOR signaling pathway components by quantitative real-time PCR (n=48) and immunohistochemistry (n=86). Findings were compared with normal pancreatic islets and correlated with histopathological data and clinical outcome. Insulinomas showed low EGFR and high IGF2 expression. IGFBP2, IGFBP3 and IGFBP6 mRNA levels were 2-4 folds higher than in islets. High protein expression of IGF2, IGF1R and INSR (in 51-92% of the tumors) and low to moderate expression of mTORC1 pathway proteins p-PS6k and p-4EBP1 (7-28% of the tumors) were observed. Correlations were found between 1) ERK1 mRNA expression and that of numerous IGF pathway genes, 2) p-ERK and IGF1R protein expression and 3) decrease of IGF pathway components and both metastatic disease and shorter 10 years disease free survival. In conclusion, our observations suggest that high expression of IGF signaling pathway components is a hallmark of insulinomas, but does not necessarily lead to increased mTOR signaling. Reduced expression of IGF pathway components may be an adverse prognostic factor in insulinomas.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Perren, Aurel and Schmitt Kurrer, Anja

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1351-0088

Publisher:

BioScientifica Ltd.

Language:

English

Submitter:

Aurel Perren

Date Deposited:

30 Aug 2018 09:54

Last Modified:

28 Oct 2019 16:16

Publisher DOI:

10.1530/ERC-18-0222

PubMed ID:

30021864

BORIS DOI:

10.7892/boris.119686

URI:

https://boris.unibe.ch/id/eprint/119686

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