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

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.

Aggressive versus indolent insulinomas: new clinicopathological insights

“…Interestingly, aggressive insulinomas often only have sporadic or focal insulin expression, and some studies have reported cases lacking immunohistochemical insulin expression, although this might be a sampling effect in larger tumors (de Sa et al 2007, Yu et al 2017, Andreassen et al 2019. In line with these findings, decreased INS mRNA expression (relative to normal betacells) was seen in aggressive vs indolent insulinomas (Henfling et al 2018). Aggressive insulinomas are multihormonal in 50% of cases compared to 25% of indolent insulinomas (Kapran et al 2006), and glucagon is expressed more often in aggressive cases (de Sa et al 2007, Andreassen et al 2019.…”

“…In contrast to non-functioning PanNETs, tumor grade based on mitosis count per high power field or Ki-67 staining index is not univocally associated with aggressive behavior (Alkatout et al 2015, Yu et al 2017, Henfling et al 2018, Andreassen et al 2019, Sada et al 2021. Importantly, even grade 1 tumors may show aggressive behavior (Wild et al 2011, Hackeng et al 2020; therefore, tumor grade cannot reliably be used clinically for excluding aggressive behavior.…”

“…The most consistent indicator of insulinoma behavior is pathological tumor size (Raffel et al 2010, Alkatout et al 2015, Yu et al 2017, Camara-de-Souza et al 2018, Henfling et al 2018, Andreassen et al 2019, Hackeng et al 2020, Sada et al 2021. Although cut-off values (if used) differ per study, virtually all indolent tumors are smaller than 3 cm, while aggressive tumors are often larger at diagnosis.…”

Whole-exome sequencing as a tool for searching for genetic background modifiers in MEN1 patients with neuroendocrine pancreatic tumours, including insulinomas

“…Henfling et al found decreased expression of EGFR and mTOR pathway components, and increased expression of IGF2 in insulinoma cells [72]. Again, however, because those results were compared to normal pancreatic islets, it was not possible to determine whether this was associated with the tumour state or specifically with insulinomas.…”

Interplay Between Diabetes and Pancreatic Ductal Adenocarcinoma and Insulinoma: The Role of Aging, Genetic Factors, and Obesity

“…Moreover, in a mouse model of multistage carcinogenesis induced by the SV40 large T antigen in pancreatic beta-cells, IGF2 was increased and contributed to insulinoma development (103). Recently, studies have shown that the IGF pathway is activated in insulinoma (104). Glutamine can also stimulate biosynthesis and secretion of IGF2 in mouse insulinoma cells, which regulate beta-cell mass and function in an autocrine manner (105).…”