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Insulin-like growth factor-1 receptor acts as a growth regulator in synovial sarcoma.
J Pathol. 2008 Dec; 216(4):428-39.JP

Abstract

Synovial sarcomas account for 5-10% of all soft tissue sarcomas and the majority of synovial sarcomas display characteristic t(X;18) translocations that result in enhanced transcription of the insulin-like growth factor-2 (IGF-2) gene. IGF-2 is an essential fetal mitogen involved in the pathogenesis of different tumours, leading to cellular proliferation and inhibition of apoptosis. Here we asked whether activation of IGF signalling is of functional importance in synovial sarcomas. We screened human synovial sarcomas for expression of IGF-2 and the phosphorylated IGF-1 receptor (IGF-1R), which mainly mediates the proliferative and anti-apoptotic effects of IGF-2. Since both the phosphatidylinositol 3'-kinase (PI3K)-AKT pathway and the MAPK signalling cascade are known to be involved in the transmission of IGF-1R signals, expression of phosphorylated (p)-AKT and p-p44/42 MAPK was additionally assessed. All tumours expressed IGF-2 and 78% showed an activated IGF-1R. All tumours were found to express p-AKT and 92% showed expression of activated p44/42 MAPK. To analyse the functional and potential therapeutic relevance of IGF-1R signalling, synovial sarcoma cell lines were treated with the IGF-1R inhibitor NVP-AEW541. Growth was impaired by the IGF-1R antagonist, which was consistently accompanied by a dose-dependent reduction of phosphorylation of AKT and p44/42 MAPK. Functionally, inhibition of the receptor led to increased apoptosis and diminished mitotic activity. Concurrent exposure of selected cells to NVP-AEW541 and conventional chemotherapeutic agents resulted in positive interactions. Finally, synovial sarcoma cell migration was found to be dependent on signals transmitted by the IGF-1R. In summary, our data show that the IGF-1R might represent a promising therapeutic target in synovial sarcomas.

Authors+Show Affiliations

Department of Pathology, University of Bonn Medical Centre, Bonn, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18855347

Citation

Friedrichs, N, et al. "Insulin-like Growth Factor-1 Receptor Acts as a Growth Regulator in Synovial Sarcoma." The Journal of Pathology, vol. 216, no. 4, 2008, pp. 428-39.
Friedrichs N, Küchler J, Endl E, et al. Insulin-like growth factor-1 receptor acts as a growth regulator in synovial sarcoma. J Pathol. 2008;216(4):428-39.
Friedrichs, N., Küchler, J., Endl, E., Koch, A., Czerwitzki, J., Wurst, P., Metzger, D., Schulte, J. H., Holst, M. I., Heukamp, L. C., Larsson, O., Tanaka, S., Kawai, A., Wardelmann, E., Buettner, R., Pietsch, T., & Hartmann, W. (2008). Insulin-like growth factor-1 receptor acts as a growth regulator in synovial sarcoma. The Journal of Pathology, 216(4), 428-39. https://doi.org/10.1002/path.2438
Friedrichs N, et al. Insulin-like Growth Factor-1 Receptor Acts as a Growth Regulator in Synovial Sarcoma. J Pathol. 2008;216(4):428-39. PubMed PMID: 18855347.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insulin-like growth factor-1 receptor acts as a growth regulator in synovial sarcoma. AU - Friedrichs,N, AU - Küchler,J, AU - Endl,E, AU - Koch,A, AU - Czerwitzki,J, AU - Wurst,P, AU - Metzger,D, AU - Schulte,J H, AU - Holst,M I, AU - Heukamp,L C, AU - Larsson,O, AU - Tanaka,S, AU - Kawai,A, AU - Wardelmann,E, AU - Buettner,R, AU - Pietsch,T, AU - Hartmann,W, PY - 2008/10/16/pubmed PY - 2008/12/25/medline PY - 2008/10/16/entrez SP - 428 EP - 39 JF - The Journal of pathology JO - J Pathol VL - 216 IS - 4 N2 - Synovial sarcomas account for 5-10% of all soft tissue sarcomas and the majority of synovial sarcomas display characteristic t(X;18) translocations that result in enhanced transcription of the insulin-like growth factor-2 (IGF-2) gene. IGF-2 is an essential fetal mitogen involved in the pathogenesis of different tumours, leading to cellular proliferation and inhibition of apoptosis. Here we asked whether activation of IGF signalling is of functional importance in synovial sarcomas. We screened human synovial sarcomas for expression of IGF-2 and the phosphorylated IGF-1 receptor (IGF-1R), which mainly mediates the proliferative and anti-apoptotic effects of IGF-2. Since both the phosphatidylinositol 3'-kinase (PI3K)-AKT pathway and the MAPK signalling cascade are known to be involved in the transmission of IGF-1R signals, expression of phosphorylated (p)-AKT and p-p44/42 MAPK was additionally assessed. All tumours expressed IGF-2 and 78% showed an activated IGF-1R. All tumours were found to express p-AKT and 92% showed expression of activated p44/42 MAPK. To analyse the functional and potential therapeutic relevance of IGF-1R signalling, synovial sarcoma cell lines were treated with the IGF-1R inhibitor NVP-AEW541. Growth was impaired by the IGF-1R antagonist, which was consistently accompanied by a dose-dependent reduction of phosphorylation of AKT and p44/42 MAPK. Functionally, inhibition of the receptor led to increased apoptosis and diminished mitotic activity. Concurrent exposure of selected cells to NVP-AEW541 and conventional chemotherapeutic agents resulted in positive interactions. Finally, synovial sarcoma cell migration was found to be dependent on signals transmitted by the IGF-1R. In summary, our data show that the IGF-1R might represent a promising therapeutic target in synovial sarcomas. SN - 1096-9896 UR - https://www.unboundmedicine.com/medline/citation/18855347/Insulin_like_growth_factor_1_receptor_acts_as_a_growth_regulator_in_synovial_sarcoma_ L2 - https://doi.org/10.1002/path.2438 DB - PRIME DP - Unbound Medicine ER -