title: Peripheral chondrosarcoma progression is accompanied by decreased Indian Hedgehog signalling.
abstract: Hedgehog (HH) signalling is important for specific developmental processes, and aberrant, increased activity has been described in various tumours. Disturbed HH signalling has also been implicated in the hereditary syndrome, Multiple Osteochondromas. Indian Hedgehog (IHH), together with parathyroid hormone-like hormone (PTHLH), participates in the organization of growth plates in long bones. PTHLH signalling is absent in osteochondromas, benign tumours arising adjacent to the growth plate, but is reactivated when these tumours undergo malignant transformation towards secondary peripheral chondrosarcoma. We describe a gradual decrease in the expression of Patched (PTCH) and glioma-associated oncogene homologue 1 (GLI1) (both transcribed upon IHH activity), and GLI2 with increasing malignancy, suggesting that IHH signalling is inactive and PTHLH signalling is IHH independent in secondary peripheral chondrosarcomas. cDNA expression profiling and immunohistochemical studies suggest that transforming growth factor-beta (TGF-beta)-mediated proliferative signalling is active in high-grade chondrosarcomas since TGF-beta downstream targets were upregulated in these tumours. This is accompanied by downregulation of energy metabolism-related genes and upregulation of the proto-oncogene jun B. Thus, the tight regulation of growth plate organization by IHH signalling is still seen in osteochondroma, but gradually lost during malignant transformation to secondary peripheral chondrosarcoma and subsequent progression. TGF-beta signalling is stimulated during secondary peripheral chondrosarcoma progression and could potentially regulate the retained activity of PTHLH.
authors.affiliation: Department of Pathology, Leiden University Medical Centre, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Hameetman
authors.forename: L B
authors.initials: LB
authors.lastname: Rozeman
authors.forename: M
authors.initials: M
authors.lastname: Lombaerts
authors.forename: J
authors.initials: J
authors.lastname: Oosting
authors.forename: A H M
authors.initials: AH
authors.lastname: Taminiau
authors.forename: A-M
authors.initials: AM
authors.lastname: Cleton-Jansen
authors.forename: J V M G
authors.initials: JV
authors.lastname: Bovée
authors.forename: P C W
authors.initials: PC
authors.lastname: Hogendoorn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016009:Chi-Square Distribution; D002648:Child; D002813:Chondrosarcoma / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006132:Growth Plate / Q000378:metabolism; D053823:Hedgehog Proteins; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics
chemical_list: C094538:GLIPR1 protein, human; C458481:GLIPR2 protein, human; D053823:Hedgehog Proteins; C509246:IHH protein, human; D036341:Intercellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D017395:Plasminogen Activator Inhibitor 1; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; C051321:SERPINE1 protein, human; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D051155:Wnt1 Protein; D051176:beta Catenin