The role of insulin-like growth factor system in the adrenocortical tumors

Abstract

The different presentation of adrenocortical tumors in benign adenoma (aca) or adrenocortical carcinoma (acc) is related to the variability at the molecular level. The insulin-like growth factor (igF) system is one of the most frequently altered pathways in acc. in this review we will critically analyze the evidence regarding the pathogenic role of the igF system in adrenal tumorigenesis, focusing on acc. We will also examine the preclinical and clinical studies which investigated the targeting of the igF system as a therapeutic approach in acc. EVIDENCE ACQUISITION: The IGF system plays a crucial role in the embryogenesis of adrenal glands. No significant alterations of the igF system were observed in aca. in acc, the IGF2 overexpression is one of the most frequent molecular change presented in more than 85% of cases. However, IGF2 seems to be only a tumor progression factor which requires additional hits to trigger adrenal tumorigenesis. also, the igF1 receptor (igF1r) appears to be higher expressed in acc. Many igF1r target-drugs have been developed to inhibit the activation of the igF system. eVideNce SYNTHeSiS: Preclinical studies using antibody or tyrosine kinase which target the igF1r, or the dualtargeting of igF1r and insulin receptor (ir) reduced acc cells proliferation both in vitro and in vivo in mouse xenograft model. However, these promising results were not confirmed in clinical trials. coNclUSioNS: Nowadays, predictive markers for the response of target-igF therapy are missing and further studies which investigate new molecular markers and evaluate the entire igF receptors, including the ir, are urgently needed.

Targeted Gene Expression Profile Reveals CDK4 as Therapeutic Target for Selected Patients With Adrenocortical Carcinoma

“…IGF signaling is known to be activated in about 80-90% of cases (49,50) and the IGFR/IR inhibitor linsitinib has been demonstrated to be a promising targeted therapy for ACC by in vitro experiments (33). However, these encouraging findings have not been confirmed in clinical trials, although a small percentage of patients showed a partial response to treatment (24).…”

Screening and identification of key biomarkers in adrenocortical carcinoma based on bioinformatics analysis

“…ACC is associated with a poor prognosis, limited treatment options and high tumor recurrence rates (1–3). The pathogenetic mechanisms of ACC includes alterations of the Insulin-like Growth Factor system (35), Wnt/β-catenin pathway activation (36), TP53 mutations and prognostic molecular markers involved in cancer cell invasion properties and angiogenesis, appear to be very promising in elucidating of tumorigenesis and progression of ACC (37,38). However, the molecular mechanisms of ACC remain poorly understood.…”

The role of mTOR pathway as target for treatment in adrenocortical cancer

“…The relationship between the mTOR and the IGF pathways in ACCs has been scantly investigated (10). As the mTOR pathway mediates some of the IGF effects (10, 35, 36), it could be involved in mediating the pathogenic effects of IGFs in ACCs. Therefore it might be important to understand whether a differential expression of the main components of the IGF pathway could influence the in vitro sensitivity to mTOR inhibitors and whether there is a rational to combine drugs targeting the IGF and the mTOR pathways.…”

“…Therefore, the expression of the main components of the mTOR and the IGF pathways seem not to be strongly related, which raises the questions whether in ACCs there is a dissociation between the expression of IGF2 and the activation of the classical IGF stimulated intracellular pathways, and whether the role of IGF2 in the pathogenesis of adult ACCs may have been overestimated, in agreement with some other recent speculations (38). However, it should also be considered that the complexity of the IGF system may have been underestimated since ACC expresses other components of the IGF pathway as well, such as the insulin receptor subtype A and the IGF2R (31, 36). These components have been scantly considered up today.…”