Insulin‐like growth factor‐1 receptor acts as a growth regulator in synovial sarcoma

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.

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

“…26 In brief, fibroblasts were seeded using DMEM supplemented with 10% FBS followed by a 48 h interval of low serum conditions. Subsequently, TGF-b1 ligand (2 ng/ml) was added to fibroblast culture for 72 h. In all, 100 000 cells in medium containing 0.5% FBS were added into the upper chambers of transwells of 6.5 mm diameter and 8.0 mm pore size (Corning Costar Corporation, Bodenheim, Germany).…”

Expression of insulin-like growth factor 2 in mesenchymal neoplasms

“…This could In synovial sarcoma, in vitro studies have found that the SS18-SSX oncogene induces IGF2 expression which seems critical to convey tumorigenic properties. [48][49][50] IGF2 expression was associated with both the ÀSSX1 and ÀSSX2 translocation subtypes. 48 In this study, we present evidence that in primary synovial sarcoma tumor specimens, IGF2 is highly expressed at the protein level, supporting translational relevance to patients of these experimental findings, and attempts to target this pathway in patients using IGF signaling inhibitors.…”

The type 1 insulin-like growth factor receptor signalling system and targeted tyrosine kinase inhibition in cancer

“…78 Preclinical studies are ongoing, but its antitumour activity has been demonstrated in musculoskeletal tumours, 79 hepatocellular carcinoma, 80 NET, 76 malignant mesothelioma, 81 HNSCC, 77 colorectal cancer, 82 neuroblastoma, 83 Ewing's sarcoma, 84 multiple myeloma, 85 pancreatic cancer, 86 gastrointestinal stromal tumour, 87 gastrointestinal cancer, 88 breast cancer 89 and synovial sarcoma. 65 As expected for a specific IGF1R kinase inhibitor, NVP-AEW541 abrogated IGF1-mediated survival, inhibited the proliferation of cultured tumour cell lines by inducing apoptosis and cell cycle arrest in vitro, and significantly inhibited the growth of tumour xenografts in vivo. 65,76,77,[79][80][81][82][83][84][85][86][87][88][89] Accumulating evidence suggests that NVP-AEW541 represents a potential therapeutic strategy for the treatment of tumour types in which IGF1R-mediated signalling is required for driving/ survival.…”

“…Treatment of synovial sarcoma cell lines with the IGF1R antagonist NVP-AEW541 led to increased apoptosis, and impaired growth, mitotic activity and cell migration. 65 IGF1R did not enhance motility in LCC6-DN cells (a breast cancer cell line with dominant negative IGF1R), in contrast to increased motility in wild-type LCC6 cells, suggesting that metastasis is inhibited by truncated IGF1R. 66 The injection of mice with LCC6, but not LCC6-DN, cells resulted in the formation of lung metastases, indicating that IGF1R regulates metastasis independently from tumour growth.…”