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.

Increased expression of matrilin‐3 not only in osteoarthritic articular cartilage but also in cartilage‐forming tumors, and down‐regulation of SOX9 via epidermal growth factor domain 1–dependent signaling

“…Since MATN3 is believed to intervene in hedgehog regulation of chondrogenesis (10,31), overexpression of hedgehog signaling and overexpression of MATN3 might be functionally linked. In order to further explore this hypothesis, it will be interesting to study the MATN3 levels in secondary chondrosarcomas, in which hedgehog signaling has been previously found to be abrogated (32).…”

The role of noncartilage‐specific molecules in differentiation of cartilaginous tumors

“…This platform had been used successfully before and enabled a comparison with data previously published by our group. 10,11 It was chosen originally to overcome problems related to the low yield of RNA in cartilage tumors. 10,11,13 Slides were hybridized with labeled cDNAs (indocarbocyanine and indodicarbocyanine) that were synthesized from 1 lg of total RNA from the samples as well as from a reference panel that consisted of 15 different cell lines.…”

“…10,11 It was chosen originally to overcome problems related to the low yield of RNA in cartilage tumors. 10,11,13 Slides were hybridized with labeled cDNAs (indocarbocyanine and indodicarbocyanine) that were synthesized from 1 lg of total RNA from the samples as well as from a reference panel that consisted of 15 different cell lines. 10,11 The betweenspot correlation was used as a correction factor in the final model to find differentially expressed genes.…”

“…11 Briefly, an in-house, spotted cDNA array containing 8696 cDNA clones that were enriched for cartilage-specific genes was used. 10,11 All spots were printed in duplicate. This platform had been used successfully before and enabled a comparison with data previously published by our group.…”

“…Expression profiles were compared with those that had been obtained previously for OC and HGCCS. 10,11 …”