Insulin-like growth factor (IGF) 1 and 2 help to predict disease outcome in GIST patients

Braconi, Chiara; Bracci, R.; Bearzi, Italo; Bianchi, Francesca; Sabato, Silvana; Mandolesi, Alessandra; Belvederesi, L.; Cascinu, Stefano; Valeri, Nicola; Cellerino, R

doi:10.1093/annonc/mdn040

Cited by 75 publications

(59 citation statements)

References 37 publications

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“…29 Similarly, previous studies have suggested that both adult and pediatric WT GISTs may share alterations in IGF-1 pathway. [30][31][32][33] By merging copy number and gene expression data, we observed a high level of correlation between CNAs and the correspondent gene expression profile. This was especially true on chromosome 14, in the q23.1-qter region, which harbors several possible target genes (DAAM1, RTN1, PPM1A, DACT1, MPP5, SNW1, FOXN3, PPM1A and PTPN21).…”

Section: Discussionmentioning

confidence: 98%

A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number

Astolfi

Nannini

Pantaleo

et al. 2010

Laboratory Investigation

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In addition to KIT and PDGFRA mutations, sequential accumulation of other genetic events is involved in the development and progression of gastrointestinal stromal tumors (GISTs). Until recently, the significance of these other alterations has not been thoroughly investigated. We report the first study that integrates gene expression profiling and high-resolution genomic copy number analyses in GIST. Fresh tissue specimens from 25 patients with GIST were collected, and gene expression profiling and high-resolution genomic copy number analyses were performed, using Affymetrix U133Plus and SNP array 6.0. We found that all 21 mutant GIST patients showed both macroscopic cytogenetic alterations and cryptic microdeletions or amplifications, whereas 75% (three of four) of wild-type patients with GIST did not show genomic imbalances. The most frequently observed chromosomal alterations in patients with mutant GIST included 14q complete or partial deletion (17 of 25), 1p deletion (14 of 25) and 22q deletion (10 of 25). Genetic targets of the chromosomal aberrations were selected by integrated analysis of copy number and gene expression data. We detected the involvement of known oncogenes and tumor suppressors including KRAS in chr 12p amplification and KIF1B, PPM1A, NF2 in chr 1p, 14q and 22p deletions, respectively. The genomic segment most frequently altered in mutated samples was the 14q23.1 region, which contains potentially novel tumor suppressors, including DAAM1, RTN1 and DACT1. siRNA-mediated RTN1 downregulation showed evidence for the potential role in GIST pathogenesis. The combination of gene expression profiling and high-resolution genomic copy number analysis offers a detailed molecular portrait of GISTs, providing an essential comprehensive knowledge necessary to guide the discovery of novel target genes involved in tumor development and progression.

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Section: Discussionmentioning

confidence: 98%

A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number

Astolfi

Nannini

Pantaleo

et al. 2010

Laboratory Investigation

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“…It is therefore interesting to find downregulated IGF1 expression in SKP2-silenced myxofibrosarcoma cells. Actually, the ligand binding of IGF1 to IGF1 receptor has been shown to activate signaling cascades in several soft tissue sarcomas, thereby contributing to their tumorigenesis (35,36). Notably, SKP2 knockdown also negatively regulated expression of ENAH gene encoding the hMENA protein, a member of enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) family.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Gene Amplification–Driven SKP2 Overexpression in Myxofibrosarcoma: Potential Implications in Tumor Progression and Therapeutics

Wang

Kang

et al. 2012

Clinical Cancer Research

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Purpose: Myxofibrosarcoma remains obscure in molecular determinants of clinical aggressiveness, for which we elucidated implications of SKP2 amplification.Experimental Design: Array comparative genomic hybridization was applied on samples and cell lines (NMFH-1 to OH931) to search causal genes of tumor progression. SKP2 gene dosage was determined in 82 independent tumors for clinical correlates. Stable SKP2 knockdown was achieved in myxofibrosarcoma cells to assess its oncogenic attributes and candidate mediators in prometastatic function. Pharmacologic assays were evaluated in vitro and in vivo for the therapeutic relevance of bortezomib.Results: DNA gains frequently involved 5p in which three amplicons were differentially overrepresented in samples behaving unfavorably, encompassing mRNA-upregulated TRIO, SKP2, and AMACR genes. Detected in NMFH-1 cells and 38% of tumors, SKP2 amplification was associated with SKP2 immunoexpression and adverse prognosticators and independently predictive of worse outcomes. Nevertheless, SKP2-expressing OH931 cells and 14% of such tumors lacked gene amplification. Knockdown of SKP2 suppressed proliferation, anchorage-independent growth, migration, and invasion of sarcoma cells and downregulated motility-promoting genes, including ITGB2, ACTN1, IGF1, and ENAH. In vitro, bortezomib downregulated SKP2 expression at the mRNA level with p27 kip1 accumulation, induced caspase activation, and decreased cell viability in myxofibrosarcoma cells but not in fibroblasts. In vivo, bortezomib inhibited growth of NMFH-1 xenografts, the cells of which displayed decreased SKP2 expression but increased p27 kip1 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Conclusions: As a predominant mechanism driving protein overexpression, SKP2 amplification confers tumor aggressiveness in myxofibrosarcoma. The sensitivity of myxofibrosarcoma cells to bortezomib with SKP2-repressing effect indicates the potentiality of ubiquitin-proteasome pathway as a therapeutic target.

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“…Expression arrays and Western blots have identified adult sarcomas subtypes that have the greatest relative amount of IGFs at the mRNA or protein level. [114][115][116][117][118][119][120] For example, as a surrogate for IGF1R signaling, those sarcomas with highest IGF2 expression by immunohistochemistry include SFT/HPC, malignant peripheral-nerve sheath tumor, GIST, and synovial sarcoma (Fig 2). 120 Although consistent expression would not foreordain a good response to agents that block the target, subtypes can be eliminated for testing that lack expression of the target of interest, understanding that our screening tests may be insensitive for assessing expression of a relevant protein.…”

Section: Igf1r and Sarcomas More Commonly Observed In Adultsmentioning

confidence: 99%

Small Is Beautiful: Insulin-Like Growth Factors and Their Role in Growth, Development, and Cancer

Maki

2010

JCO

187

140

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A B S T R A C TInsulin-like growth factors were discovered more than 50 years ago as mediators of growth hormone that effect growth and differentiation of bone and skeletal muscle. Interest of the role of insulin-like growth factors in cancer reached a peak in the 1990s, and then waned until the availability in the past 5 years of monoclonal antibodies and small molecules that block the insulin-like growth factor 1 receptor. In this article, we review the history of insulin-like growth factors and their role in growth, development, organism survival, and in cancer, both epithelial cancers and sarcomas. Recent developments regarding phase I to II clinical trials of such agents are discussed, as well as potential studies to consider in the future, given the lack of efficacy of one such monoclonal antibody in combination with cytotoxic chemotherapy in a first-line study in metastatic non-small-cell lung adenocarcinoma. Greater success with these agents clinically is expected when combining the agents with inhibitors of other cell signaling pathways in which cross-resistance has been observed.

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Insulin-like growth factor (IGF) 1 and 2 help to predict disease outcome in GIST patients

Abstract: The expression of IGF1 and IGF2 seems to predict relapse in GIST patients.

Cited by 75 publications

References 37 publications

A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number

A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number

Characterization of Gene Amplification–Driven SKP2 Overexpression in Myxofibrosarcoma: Potential Implications in Tumor Progression and Therapeutics

Small Is Beautiful: Insulin-Like Growth Factors and Their Role in Growth, Development, and Cancer

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