Parathyroid hormone-related Peptide expression in cartilaginous tumors.
ABSTRACT Parathyroid hormone-related peptide is one of the most important regulators of chondrocyte proliferation. Although cartilaginous neoplasms express different collagens, including Types II and X, the pathogenesis of these tumors has not been elucidated. The current study examined the hypothesis that parathyroid hormone-related peptide is expressed in cartilaginous neoplasms and its level of expression may correlate with the proliferative rate of cartilaginous neoplasms with higher levels in more malignant tumors and lower levels in benign lesions. Two hundred thirty-four biopsy and resection specimens of benign and malignant cartilage tumors from 179 patients were retrieved from surgical pathology archival material and analyzed immunohistochemically using an antibody to human parathyroid hormone-related peptide. Most cartilaginous neoplasms had some level of expression of parathyroid hormone-related peptide, and tumors with a more proliferative phenotype had higher levels of parathyroid hormone-related peptide. Although benign lesions such as enchondromas and osteochondromas had low levels of parathyroid hormone-related peptide, malignant neoplasms such as extraskeletal myxoid chondrosarcomas, dedifferentiated chondrosarcomas, and mesenchymal chondrosarcomas expressed high levels of parathyroid hormone-related peptide. Parathyroid hormone-related peptide expression correlated with grade of malignancy in chondrosarcoma. Although there were highly significant differences between Grade I chondrosarcoma versus Grade II and Grade III lesions, the difference between Grade II and Grade III chondrosarcomas approached significance. Parathyroid hormone-related peptide may represent a new tumor marker with potential diagnostic use in classifying cartilaginous neoplasms.
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ABSTRACT: The transcription factor glioma-associated oncogene 1 (Gli1) has been recognized as a very important nuclear executor at the distal end of the Hedgehog (Hh) signal pathway, which has crucial roles in regulating many developmental processes, such as pattern formation, differentiation, proliferation, and apoptosis. Overexpression of patched 1 protein and Gli1 or constitutively active Indian Hedgehog (IHh)-parathyroid hormone-related protein signal pathway may lead to musculoskeletal tumorigenesis. However, for chondrosarcoma few studies have paid close attention to the IHh-Gli1 signal transduction cascade and more work needs to be carried out to fully elucidate Gli1 protein functions. Here we show that the IHh signal pathway was activated in chondrosarcoma, and knocking down the expression of Gli1 attenuated the disturbed IHh signal pathway, which not only suppressed cell proliferation and promoted G2/M cell cycle arrest but also enhanced cell apoptosis by downregulating Bcl-2 and Bcl-xl expression. Furthermore, Gli1 downregulation, not cyclopamine, induced autophagy by regulating mTOR phosphorylation, and inhibition of autophagy prevented Gli1 small interfering RNA-mediated cell death. We also demonstrated that extracellular signal-regulated kinase 1/2 activity may mediate these antiproliferative events induced by Gli1 inhibition. These results indicate that Gli1 inhibition could ultimately provide a promising new approach for chondrosarcoma treatment.Cell Death & Disease 01/2014; 5(1):e979. DOI:10.1038/cddis.2013.497 · 5.18 Impact Factor
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ABSTRACT: Proefschrift Universiteit Leiden. Met samenvatting in het Nederlands.
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ABSTRACT: Osteochondroma is a cartilage capped benign bone tumour, arising at the external surface of bones preformed by endochondral ossification. A small percentage of osteochondromas can progress towards its malignant counterpart, secondary peripheral chondrosarcoma. About 15% of osteochondromas occur in the context of a rare hereditary syndrome, Multiple Osteochondromas for which two genes have been identified as causative genes, namely EXT1 and EXT2, which have been identified as tumor suppressor genes. However the vast majority of osteochondromas present as solitary lesions. We were able to demonstrate that similar to hereditary osteochondromas EXT1 also acts as a classical tumour suppressor gene in solitary osteochondroma. The EXT genes function as a complex in the biosynthesis of heparin sulphate proteoglycans (HSPGs), large multifunctional macromolecules that are involved in several growth signaling pathways. We showed that the loss of EXT1 and in hereditary cases also EXT2 is accompanied by intracellular accumulation of HSPGs, suggesting a disrupted EXT1/2 complex. The growth signalling pathways known from normal longitudinal bone growth are affected differently in osteochondromas and chondrosarcomas. The IHH signaling functions autonomously in osteochondromas and its activity decreases during malignant transformation and progression of chondrosarcomas, whereas the PTHLH and TFG-β signaling cascades seem to be re-activated.