‘Big’-Insulin-Like Growth Factor–II Signaling Is an Autocrine Survival Pathway in Gastrointestinal Stromal Tumors
| Autor: | Winette T. A. van der Graaf, Coby Meijer, Gert Jan Meersma, Ed Schuuring, Jaap van Doorn, Bart Rikhof, Steven de Jong, Albert J. H. Suurmeijer, Patricia J. T. A. Groenen |
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| Přispěvatelé: | Guided Treatment in Optimal Selected Cancer Patients (GUTS), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON) |
| Rok vydání: | 2012 |
| Předmět: |
Male
INDUCED HYPOGLYCEMIA Piperazines Receptor IGF Type 1 Tumor Cells Cultured SARCOMA Aged 80 and over Cell Death Age-related aspects of cancer Quality of hospital and integrated care [ONCOL 2] Middle Aged Neoplasm Proteins Autocrine Communication Benzamides Imatinib Mesylate Female INSULIN-LIKE-GROWTH-FACTOR-1-RECEPTOR Tyrosine kinase medicine.drug Adult EXPRESSION medicine.medical_specialty Translational research Renal disorder [ONCOL 3] Stromal cell Cell Survival Gastrointestinal Stromal Tumors KIT ONCOPROTEIN Down-Regulation Antineoplastic Agents Biology IMATINIB Pathology and Forensic Medicine Young Adult RECEPTOR ISOFORM Growth factor receptor Insulin-Like Growth Factor II Translational research [ONCOL 3] Internal medicine medicine Humans Protein Precursors CANCER-CELLS IGF-II Autocrine signalling Protein kinase B Aged THERAPEUTIC TARGET Imatinib Receptor Insulin Insulin receptor Pyrimidines Endocrinology Cancer cell Cancer research biology.protein |
| Zdroj: | American Journal of Pathology, 181, 303-12 American Journal of Pathology, 181, 1, pp. 303-12 American Journal of Pathology, 181(1), 303-312. ELSEVIER SCIENCE INC |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2012.03.028 |
| Popis: | Contains fulltext : 109924.pdf (Publisher’s version ) (Closed access) New treatment targets need to be identified in gastrointestinal stromal tumors (GISTs) to extend the treatment options for patients experiencing failure with small-molecule tyrosine kinase inhibitors, such as imatinib. Insulin-like growth factor (IGF)-II acts as an autocrine factor in several tumor types by binding to IGF receptor type 1 (IGF-1R) and/or the insulin receptor (IR) isoform A. The aim of the present study was to investigate the putative role of unprocessed pro-IGF-II, called 'big'-IGF-II, in GISTs. The imatinib-sensitive GIST882 and imatinib-resistant GIST48 cell lines secrete high levels of big-IGF-II as demonstrated by ELISA and Western blotting analyses. IR isoform A mRNA and protein expression, but not that of IGF-1R, was found in these KIT mutant cell lines and in KIT and platelet-derived growth factor receptor alpha-mutant GIST specimens. Down-regulation of either big-IGF-II or IR affected AKT and MAPK signaling and reduced survival in both cell lines. Disruption of big-IGF-II signaling in combination with imatinib had additive cytotoxic effects on GIST882 cells. IGF-II mRNA as determined by in situ hybridization was present in 91% of 60 primary GISTs. Immunohistochemical analysis of big-IGF-II protein expression was associated with moderate- to high-risk tumors compared with tumors with a lower risk classification (P < 0.028). Our data put forth the big-IGF-II/IR isoform A axis as an autocrine survival pathway and potential therapeutic target in GISTs. 01 juli 2012 |
| Databáze: | OpenAIRE |
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