title: 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 24h, 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 (>1μM) showed limited reduction of cell viability, suggesting that OSI-906 alone could not be a suitable therapy to abolish carcinoma cell growth.
authors.affiliation: Department of PediatricsRibeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil.
authors.forename: Régia Caroline
authors.initials: RC
authors.lastname: Peixoto Lira
authors.affiliation: Department of PediatricsRibeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil.
authors.forename: Paola Fernanda
authors.initials: PF
authors.lastname: Fedatto
authors.affiliation: Department of Research and DevelopmentFleury Group, Sao Paulo, São Paulo, Brazil.
authors.forename: David Santos
authors.initials: DS
authors.lastname: Marco Antonio
authors.affiliation: Department of PediatricsRibeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil.
authors.forename: Letícia Ferro
authors.initials: LF
authors.lastname: Leal
authors.affiliation: Department of PediatricsRibeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil.
authors.forename: Carlos Eduardo
authors.initials: CE
authors.lastname: Martinelli
authors.affiliation: Department of Internal MedicineRibeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil.
authors.forename: Margaret
authors.initials: M
authors.lastname: de Castro
authors.affiliation: Department of SurgeryRibeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil.
authors.forename: Silvio
authors.initials: S
authors.lastname: Tucci
authors.affiliation: Department of PathologyRibeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil.
authors.forename: Luciano
authors.initials: L
authors.lastname: Neder
authors.affiliation: Department of PathologyRibeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil.
authors.forename: Leandra
authors.initials: L
authors.lastname: Ramalho
authors.affiliation: Boldrini Children CenterState University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: Ana Luiza
authors.initials: AL
authors.lastname: Seidinger
authors.affiliation: Boldrini Children CenterState University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: Izilda
authors.initials: I
authors.lastname: Cardinalli
authors.affiliation: Boldrini Children CenterState University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Mastellaro
authors.affiliation: Boldrini Children CenterState University of Campinas (UNICAMP), Campinas, São Paulo, Brazil State University of Campinas (UNICAMP)CampinasSão Paulo, Brazil.
authors.forename: José Andres
authors.initials: JA
authors.lastname: Yunes
authors.affiliation: Boldrini Children CenterState University of Campinas (UNICAMP), Campinas, São Paulo, Brazil State University of Campinas (UNICAMP)CampinasSão Paulo, Brazil.
authors.forename: Silvia Regina
authors.initials: SR
authors.lastname: Brandalise
authors.affiliation: Department of PediatricsRibeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil.
authors.forename: Luiz Gonzaga
authors.initials: LG
authors.lastname: Tone
authors.affiliation: Department of PediatricsRibeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil.
authors.forename: Sonir Roberto
authors.initials: SR
authors.lastname: Rauber Antonini
authors.affiliation: Department of PediatricsRibeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil scrideli@fmrp.usp.br.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Scrideli
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000728:Androgens / Q000378:metabolism; D000735:Androstenedione / Q000378:metabolism; D017209:Apoptosis; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007223:Infant; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D009364:Neoplasm Recurrence, Local; D010750:Phosphoproteins / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D000728:Androgens; C000597236:IGF1R protein, human; C035170:IGF2 protein, human; D007093:Imidazoles; D010750:Phosphoproteins; D011719:Pyrazines; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D000098682:Steroidogenic Acute Regulatory Protein; D013739:Testosterone; D000735:Androstenedione; D019314:Dehydroepiandrosterone Sulfate; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1
keywords: IGF1R; IGF2; OSI-906; adrenocortical tumor; childhood