IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

Abstract

Deregulation of the IGF system observed in human tumors indicates a role in malignant cell transformation and in tumor cell proliferation. Although overexpression of the IGF2 and IGF1R genes was described in adrenocortical tumors (ACTs), few studies reported their profiles in pediatric ACTs. In this study, the IGF2 and IGF1R expression was evaluated by RT-qPCR according to the patient's clinical/pathological features in 60 pediatric ACT samples, and IGF1R protein was investigated in 45 samples by immunohistochemistry (IHC). Whole transcriptome and functional assays were conducted after IGF1R inhibition with OSI-906 in NCI-H295A cell line. Significant IGF2 overexpression was found in tumor samples when compared with non-neoplastic samples (P < 0.001), significantly higher levels of IGF1R in patients with relapse/metastasis (P = 0.031) and moderate/strong IGF1R immunostaining in 62.2% of ACTs, but no other relationship with patient survival and clinical/pathological features was observed. OSI-906 treatment downregulated genes associated with MAPK activity, induced limited reduction of cell viability and increased the apoptosis rate. After 24 h, the treatment also decreased the expression of genes related to the steroid biosynthetic process, the protein levels of the steroidogenic acute regulatory protein (STAR), and androgen secretion in cell medium, supporting the role of IGF1R in steroidogenesis of adrenocortical carcinoma cells. Our data showed that the IGF1R overexpression could be indicative of aggressive ACTs in children. However, in vitro treatments with high concentrations of OSI-906 (>1 μM) showed limited reduction of cell viability, suggesting that OSI-906 alone could not be a suitable therapy to abolish carcinoma cell growth. 23:6Research R C P Lira et al.IGF1R in pediatric adrenocortical tumor IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

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

“…However, these encouraging findings have not been confirmed in clinical trials, although a small percentage of patients showed a partial response to treatment (24). In the present series, we confirmed IGF2 overexpression in 95% of cases, whereas IGF1R was down-regulated in 45% of cases, similarly as previously described (34). Of note, however, 37.5% of cases presented high CDK4 and normal or high IGF1R mRNA levels.…”

“…Of note, however, 37.5% of cases presented high CDK4 and normal or high IGF1R mRNA levels. On the other hand, an IGF1R overexpression is found in NCI-H295R cells in our and previous studies (33,34). Thus, with IGF1R being the main target of linsitinib, its low/absent expression in ACC might be one reason for the disappointing response rate in ACC patients (24) and pre-screening for IGF1R overexpression might then be useful to pre-select patients that may benefit from this treatment.…”

“…Cell viability was assessed by the water-soluble tetrazolium (WST-1) reagent according to manufacturer's instructions (Roche Diagnostics Deutschland GmbH, Mannheim, Germany). In addition, cells were treated with increasing concentrations of dual IGF1R/IR inhibitor linsitinib (OSI-906, Selleckchem, 0.125-4 µM), which effectively reduces cell viability in NCI-H295R cells (33,34). It is recognized IGF signaling may lead to activation of cyclin D by the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) pathway ( Figure 3C).…”

Challenges in surgical pathology of adrenocortical tumours

“…Many studies have found p53 expression to be frequent in malignant adrenocortical tumours . Insulin‐like growth factor 1 receptor overexpression, decreased expression of HLA‐DRA, HLA‐DPA1, and HLA‐DPB1, and major histocompatibility complex class II expression have also been suggested as a possible markers of aggressive disease in paediatric adrenocortical tumours …”

GLUT1 expression in pediatric adrenocortical tumors: a promising candidate to predict clinical behavior

“…However, overall, the findings point at the same direction, which is a metabolic reprogramming towards a glycolytic phenotype in adrenocortical malignant tumors. Previous studies focusing on the biological aspects behind malignancy in pediatric ACTs have identified the insulin-like growth factor (IGF) system, specifically the pair IGF2/IGF1 receptor (IGF1R), as one of the molecular mechanisms involved in the process of tumorigenesis [ 43 – 46 ]. Although some of the signaling proteins downstream of IGF1R, such as Akt, mTOR and AMP-activated protein kinase (AMPK), have a pivotal role in cancer cell metabolic reprogramming [ 42 , 47 , 48 ], the possible role of IGF1R as a mediator of the Warburg effect has not been clearly established.…”