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

DOI
Publisher DOI
PubMed ID
30021864
Abstract
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.
Date Issued
2018-12
Publication Type
Article
Subject(s)
Language(s)
en
Author(s)
Henfling, Mieke
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
Additional Credits
Journal
Endocrine-related cancer
Publisher
BioScientifica Ltd.
ISSN
1351-0088
Access(Rights)
open.access
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