Background Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of... Show moreBackground Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was therefore explored in this study. Methods Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot. The effect of activation and inhibition of IGF1R signalling on downstream targets was assessed by western blot. Ten chondrosarcoma cell lines were treated with OSI-906 (IGF1R and IR dual inhibitor) after which cell proliferation and migration were determined by a viability assay and the xCELLigence system, respectively. In addition, four chondrosarcoma cell lines were treated with a combination of doxorubicin and OSI-906. By immunohistochemistry, IGF1R expression levels were determined in tissue microarrays of 187 cartilage tumours and ten paraffin embedded cell lines. Results Mediators of IGF1R signalling are heterogeneously expressed and phosphorylated IRS1 was detected in 67 % of the tested chondrosarcoma cell lines, suggesting that IGF1R signalling is active in a subset of chondrosarcoma cell lines. In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity. In line with these findings, treatment with IGF1R/IR inhibitors did not impact proliferation or migration in any of the chondrosarcoma cell lines, even upon stimulation with IGF1. Although synergistic effects of IGF1R/IR inhibition with doxorubicin are described for other cancers, our results demonstrate that this was not the case for chondrosarcoma. In addition, we found minimal IGF1R expression in primary tumours in contrast to the high expression detected in chondrosarcoma cell lines, even if both were derived from the same tumour, suggesting that in vitro culturing upregulates IGF1R expression. Conclusions The results from this study indicate that the IGF pathway is not essential for chondrosarcoma growth, migration or chemoresistance. Furthermore, IGF1R is only minimally expressed in chondrosarcoma primary tumours. Therefore, the IGF pathway is not expected to be an effective therapeutic target for chondrosarcoma of bone. Show less
Clinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) varies strikingly, both in terms of symptoms and outcome. An understanding of the basic biology unique to GEP-NETs is... Show moreClinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) varies strikingly, both in terms of symptoms and outcome. An understanding of the basic biology unique to GEP-NETs is necessary for optimum management of patients with these complex tumors. Although markers for GEP-NETs exist, sensitive and specific markers that predict tumor growth and behaviour are lacking. The general purpose of the studies described in this thesis was to investigate the epidemiology, diagnosis and pathogenesis of GEP-NETs in The Netherlands, to reveal insights in the pathological mechanisms contributing to the development and progression of these tumors. Not only worldwide but also in The Netherlands, the incidence of these tumors is increasing. The diverse studies contribute to a better understanding of the role of angiogenesis, neuropeptides and matrix metallo-proteinases in neuroendocrine tumors of the digestive tract and pancreas. Additional studies and further research will possible lead to new diagnostic and therapeutic implications of endoglin, bombesin and MMPs in patients with gastroenteropancreatic neuroendocrine tumors. Show less
