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BMC Cancer (2)
Cleton-Jansen, Anne-Marie (2)
Boeuf, Stephane (1)
Bovée, Judith VMG (1)
Briaire-de Bruijn, Inge H (1)
Hassan, A Bassim (1)
Hogendoorn, Pancras CW (1)
Kuijjer, Marieke L (1)
Lehner, Burkhard (1)
Meza-Zepeda, Leonardo A (1)
Myklebost, Ola (1)
Peterse, Elisabeth FP (1)
Richter, Wiltrud (1)
Serra, Massimo (1)
van Ruler, Maayke (1)
van den Akker, Brendy (1)
van den Akker, Brendy EWM (1)
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IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma
Kuijjer, Marieke L
Peterse, Elisabeth FP
Briaire-de Bruijn, Inge H
Meza-Zepeda, Leonardo A
Hassan, A Bassim
Hogendoorn, Pancras CW
High-grade osteosarcoma is an aggressive tumor most often developing in the long bones of adolescents, with a second peak in the 5th decade of life. Better knowledge on cellular signaling in this tumor may identify new possibilities for targeted treatment.
We performed gene set analysis on previously published genome-wide gene expression data of osteosarcoma cell lines (n=19) and pretreatment biopsies (n=84). We characterized overexpression of the insulin-like growth factor receptor (IGF1R) signaling pathways in human osteosarcoma as compared with osteoblasts and with the hypothesized progenitor cells of osteosarcoma – mesenchymal stem cells. This pathway plays a key role in the growth and development of bone. Since most profound differences in mRNA expression were found at and upstream of the receptor of this pathway, we set out to inhibit IR/IGF1R using OSI-906, a dual inhibitor for IR/IGF1R, on four osteosarcoma cell lines. Inhibitory effects of this drug were measured by Western blotting and cell proliferation assays.
OSI-906 had a strong inhibitory effect on proliferation of 3 of 4 osteosarcoma cell lines, with IC50s below 100 nM at 72 hrs of treatment. Phosphorylation of IRS-1, a direct downstream target of IGF1R signaling, was inhibited in the responsive osteosarcoma cell lines.
This study provides an in vitro rationale for using IR/IGF1R inhibitors in preclinical studies of osteosarcoma.
Osteosarcoma; IGF1R signaling; Signal transduction; IGF1R; OSI-906; Bone neoplasm; Sarcoma
BMP and TGFbeta pathways in human central chondrosarcoma: enhanced endoglin and Smad 1 signaling in high grade tumors
Bovée, Judith VMG
van Ruler, Maayke
As major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor β (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma. In order to uncover their possible implication, the aim of this study was to perform a systematic quantitative study of the expression of BMPs, TGFBs and their receptors and to assess activity of the corresponding pathways in central chondrosarcoma.
Gene expression analysis was performed by quantitative RT-PCR in 26 central chondrosarcoma and 6 healthy articular cartilage samples. Expression of endoglin and nuclear localization of phosphorylated Smad1/5/8 and Smad2 was assessed by immunohistochemical analysis.
The expression of TGFB3 and of the activin receptor-like kinase ALK2 was found to be significantly higher in grade III compared to grade I chondrosarcoma. Nuclear phosphorylated Smad1/5/8 and Smad2 were found in all tumors analyzed and the activity of both signaling pathways was confirmed by functional reporter assays in 2 chondrosarcoma cell lines. Immunohistochemical analysis furthermore revealed that phosphorylated Smad1/5/8 and endoglin expression were significantly higher in high-grade compared to low-grade chondrosarcoma and correlated to each other.
The BMP and TGFβ signaling pathways were found to be active in central chondrosarcoma cells. The correlation of Smad1/5/8 activity to endoglin expression suggests that, as described in other cell types, endoglin could enhance Smad1/5/8 signaling in high-grade chondrosarcoma cells. Endoglin expression coupled to Smad1/5/8 activation could thus represent a functionally important signaling axis for the progression of chondrosarcoma and a regulator of the undifferentiated phenotype of high-grade tumor cells.
Conventional central chondrosarcoma; Bone tumor; Chondrogenic differentiation; Bone morphogenic proteins; Transforming growth factor β
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