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      IGF2 Promotes Growth of Adrenocortical Carcinoma Cells, but Its Overexpression Does Not Modify Phenotypic and Molecular Features of Adrenocortical Carcinoma

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          Abstract

          Insulin-like growth factor 2 (IGF2) overexpression is an important molecular marker of adrenocortical carcinoma (ACC), which is a rare but devastating endocrine cancer. It is not clear whether IGF2 overexpression modifies the biology and growth of this cancer, thus more studies are required before IGF2 can be considered as a major therapeutic target. We compared the phenotypical, clinical, biological, and molecular characteristics of ACC with or without the overexpression of IGF2, to address these issues. We also carried out a similar analysis in an ACC cell line (H295R) in which IGF2 expression was knocked down with si- or shRNA. We found no significant differences in the clinical, biological and molecular (transcriptomic) traits between IGF2-high and IGF2-low ACC. The absence of IGF2 overexpression had little influence on the activation of tyrosine kinase pathways both in tumors and in H295 cells that express low levels of IGF2. In IGF2-low tumors, other growth factors (FGF9, PDGFA) are more expressed than in IGF2-high tumors, suggesting that they play a compensatory role in tumor progression. In addition, IGF2 knock-down in H295R cells substantially impaired growth (>50% inhibition), blocked cells in G1 phase, and promoted apoptosis (>2-fold). Finally, analysis of the 11p15 locus showed a paternal uniparental disomy in both IGF2-high and IGF2-low tumors, but low IGF2 expression could be explained in most IGF2-low ACC by an additional epigenetic modification at the 11p15 locus. Altogether, these observations confirm the active role of IGF2 in adrenocortical tumor growth, but also suggest that other growth promoting pathways may be involved in a subset of ACC with low IGF2 expression, which creates opportunities for the use of other targeted therapies.

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          Most cited references40

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          Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification.

          Adrenocortical carcinoma (ACC) is a rare malignancy, and it was only in 2004 that the International Union Against Cancer (UICC) defined TNM criteria and published the first staging classification. However, to date, the prognostic value of the proposed classification has not been evaluated. The German ACC Registry comprising 492 patients was searched for patients who were diagnosed between 1986 and 2007 with detailed information on primary diagnosis and a minimum follow-up of 6 months. Patients were assigned to UICC tumor stage, and disease-specific survival (DSS) was assessed. In addition, the contribution of potential risk factors for DSS was evaluated. In total, 416 patients with a mean follow-up of 36 months met the inclusion criteria (stage I, n=23 patients; stage II, n=176 patients; stage III, n=67 patients; stage IV, n=150 patients). Kaplan-Meier analysis revealed a stage-dependent DSS. However, DSS in patients with stage II ACC did not differ significantly from DSS in patients with stage III ACC (hazard ratio, 1.38; 95% confidence interval, 0.89-2.16). Furthermore, patients who had stage IV ACC without distant metastases had an improved DSS compared with patients who had metastatic disease (P=.004). An analysis of different potential risk factors for defining stage III ACC revealed important roles in DSS for tumor infiltration in surrounding tissue, venous tumor thrombus (VTT), and positive lymph nodes; whereas tumor invasion in adjacent organs carried a prognosis similar to that of infiltration in surrounding tissue only. The 2004 UICC staging classification for ACC has significant limitations. On the basis of the current analysis, a revised classification with superior prognostic accuracy is proposed (the European Network for the Study of Adrenal Tumors classification). In this system, stage III ACC is defined by the presence of positive lymph nodes, infiltration of surrounding tissue, or VTT; and stage IV ACC is restricted to patients with distant metastasis. Copyright (c) 2009 American Cancer Society.
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            Structural biology of insulin and IGF1 receptors: implications for drug design.

            Type 2 diabetes mellitus -- in which the body produces insufficient amounts of insulin or the insulin that is produced does not function properly to control blood glucose -- is an increasingly common disorder. Prospective clinical studies have proven the benefits of tighter glucose control in reducing the frequency and severity of complications of the disease, leading to the advocation of earlier and more aggressive use of insulin therapy. Given the reluctance of patients with type 2 diabetes to inject themselves with insulin, orally active insulin mimetics would be a major therapeutic advance. Here, we discuss recent progress in understanding the structure-function relationships of the insulin and insulin-like growth factor 1 (IGF1) receptors, their mechanism of activation and their implications for the design of insulin-receptor agonists for diabetes therapy and IGF1-receptor antagonists for cancer therapy.
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              Pathologic features of prognostic significance in adrenocortical carcinoma.

              There are currently no well-established pathologic prognostic factors helpful in distinguishing low versus high grade adrenocortical carcinomas. The effect of 11 pathologic parameters on survival was investigated in 42 cases of adrenocortical carcinoma. Only one variable, mitotic rate, had a strong statistical association with patient outcome. The 21 patients with carcinomas with greater than 20 mitoses per 50 high power fields (hpf) had a median survival of 14 months, whereas the 21 patients with carcinomas with less than or equal to 20 mitoses had a median survival of 58 months (p less than 0.02). The presence of atypical mitoses, capsular invasion, tumor weight greater than 250 g, and size greater than 10 cm each showed a marginal statistical association with poor survival (p less than 0.06), whereas other features assessed, such as nuclear grade, presence of necrosis or of venous or sinusoidal invasion, character of the tumor cell cytoplasm, or architectural pattern, showed no statistical significance in predicting survival. It is proposed that adrenal cortical carcinomas with greater than 20 mitoses be designated high grade, whereas tumors with less than or equal to 20 mitoses be designated low grade.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                4 August 2014
                : 9
                : 8
                : e103744
                Affiliations
                [1 ]Paris Cardiovascular Center, Institut National de la Santé et de la Recherche Médicale U970, Université Paris Descartes, Paris, France
                [2 ]Département de Biologie Hormonale, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
                [3 ]Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Paris, France
                [4 ]Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
                [5 ]Département d'Endocrinologie, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
                [6 ]Institut National de la Santé et de la Recherche Médicale U938, Université Pierre et Marie Curie, Paris, France
                [7 ]Laboratoire d'explorations fonctionnelles endocriniennes, Assistance Publique Hôpitaux de Paris, Hôpital Armand Trousseau, Paris, France
                [8 ]Service d'Anatomie Pathologique, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Université Pierre et Marie Curie, Paris, France
                [9 ]Département de Biologie et Pathologie Médicales, Institut Gustave Roussy, Villejuif, France
                [10 ]Département d'Imagerie Médicale, Médecine nucléaire, Institut Gustave Roussy, Villejuif, France
                Columbia University, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MGB EC YLB JB GA XB EB. Performed the experiments: MGB BR CC IF OB VS JG FT MRR FRC. Analyzed the data: MGB AdR BR FT OB GA YLB JB EC. Contributed reagents/materials/analysis tools: AAG EB JB. Wrote the paper: MGB AdR XB GA BR YLB JB EC.

                Article
                PONE-D-14-07646
                10.1371/journal.pone.0103744
                4121173
                25089899
                b7e32631-a336-415f-8623-2d22d77bda16
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 18 February 2014
                : 1 July 2014
                Page count
                Pages: 14
                Funding
                INSERM; Assistance Publique Hôpitaux de Paris. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Endocrine System
                Adrenal Cortex
                Cell Biology
                Cell Processes
                Cell Growth
                Molecular Cell Biology
                Signal Transduction
                Computational Biology
                Genome Analysis
                Transcriptome Analysis
                Genome Expression Analysis
                Genetics
                Cancer Genetics
                Gene Expression
                Genomics
                Medicine and Health Sciences
                Endocrinology
                Oncology
                Basic Cancer Research
                Cancer Detection and Diagnosis

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                Uncategorized

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