[From bench to bedside for new treatment paradigms in chordomas: An update]. / Depuis la recherche translationnelle jusqu'aux nouveaux paradigmes thérapeutiques : mise à jour des données dans les chordomes.

Chordomas are rare malignant tumours, which typically occur in the axial skeleton and skull base. They arise from embryonic remnants of the notochord. They constitute less than 5 % of primary bone tumours. They are characterised by their locally aggressive potential with high frequency of recurrences and a median overall survival of 6 years. The initial therapeutic strategy must be discussed in an expert centre and may involve surgery, preoperative radiotherapy, exclusive radiotherapy or therapeutic abstention. Despite this, more than 50 % of patients will be facing recurrences with few therapeutic options available at this advanced stage. This review aims to outline current treatment options available in chordomas, as well as discussing potentiality of new therapeutic approaches through their molecular characterization and the comprehension of their immunological environment.

EWS-FLI1 causes neuroepithelial defects and abrogates emigration of neural crest stem cells.

The most frequently occurring chromosomal translocation that gives rise to the Ewing's sarcoma family of tumors (ESFT) is the chimeric fusion gene EWS-FLI1 that encodes an oncogenic protein composed of the N terminus of EWS and the C terminus of FLI1. Although the genetic basis of ESFT is fairly well understood, its putative cellular origin remains to be determined. Previous work has proposed that neural crest progenitor cells may be the causative cell type responsible for ESFT. However, surprisingly little is known about the expression pattern or role of either wild-type EWS or wild-type FLI1 in this cell population during early embryonic development. Using the developing chick embryo as a model system, we identified EWS expression in emigrating and migratory neural crest stem cells, whereas FLI1 transcripts were found to be absent in these populations and were restricted to developing endothelial cells. By ectopically expressing EWS-FLI1 or wild-type FLI1 in the developing embryo, we have been able to study the cellular transformations that ensue in the context of an in vivo model system. Our results reveal that misexpression of the chimeric EWS-FLI1 fusion gene, or wild-type FLI1, in the developing neural crest stem cell population leads to significant aberrations in neural crest development. An intriguing possibility is that misexpression of the EWS-FLI1 oncogene in neural crest-derived stem cells may be an initiating event in ESFT genesis.

EGFR and VEGFR2 protein expressions in bone metastases of clear cell renal cancer.

BACKGROUND: EGFR and VEGFR2 protein expressions are hallmarks of clear cell renal cancer (RCC) with questionable prognostic impact. The skeletal system is one of the most common metastatic sites of RCC. Unfortunately, there are no data for EGFR and VEGFR2 protein expression in such lesions. MATERIALS AND METHODS: Twenty cases of bone metastatic clear cell RCC were analyzed. EGFR and VEGFR2 proteins were detected by immunohistochemistry and analyzed by morphometry scoring both % positivity and the intensity. RESULTS: EGFR protein scores were significantly reduced in bone metastases of RCC due to the reduction of EGFR protein expression in about one third of the cases (7/20). The VEGFR2 protein-positive phenotype of clear cell RCC was relatively frequent (7/20, 35%), but was lost in bone metastases (2/20, 10%). CONCLUSION: These data suggest a phenotypic/genotypic change of clear cell RCC during the progression to bones and warrant further investigation.

Brachyury and chordoma: the chondroid-chordoid dilemma resolved?

Chordoma, and its relationship to the notochord, has intrigued many researchers over the last two centuries. In particular, the morphological overlap with cartilaginous tumours is striking, and developmental biology has shown a tight relationship between cartilage and the notochord. This is reflected in the expression of common genes in chordoid and chondroid tumours. Wide gene expression analyses have led to the identification of key molecules that might play a crucial role in the pathogenesis of chordoma. Brachyury, a key factor in notochord fate, is significantly differentially expressed in chordoma. This not only gives insight into the histogenesis of this tumour but may also point towards new diagnostic tools in the differential diagnosis between chordoid and chondroid tumours.

Three-dimensional reconstruction of human embryonic notochords: clue to the pathogenesis of chordoma.

Three-dimensional reconstruction experiments performed on serial sections of human embryos showed that the anatomy of the caudal and rostral ends of the notochord was complex. Forking of the ends, with separate fragments of chordal tissue, was demonstrated and these provide a way by which notochordal cell rests could be left behind in the basicranial and sacral regions when the notochord involutes elsewhere. Assuming the histogenesis of chordomas from notochordal cell rests, this would furnish an explanation for the observed skeletal distribution of chordomas.

Osteoclast origin of giant cells in giant cell tumors of bone: ultrastructural and cytochemical study of six cases.

To clarify the histogenesis of giant cells appearing in giant cell tumors of bone (GCTB), an ultrastructural and cytochemical study of six cases was performed with both acid phosphatase (ACPase) and tartrate-resistant acid phosphatase (TRACPase) as marker enzymes. TRACPase is considered a specific marker for osteoclasts. ACPase was demonstrated in the macrophagelike stromal cells, the multinucleated giant cells, and the infiltrating macrophages. The enzyme reaction was localized in lysosomal dense bodies and Golgi areas. Intense TRACPase activity was demonstrated in the multinucleated giant cells, whereas a weak reaction was found in the macrophagelike stromal cells. The multinucleated giant cells and macrophagelike stromal cells resembled osteoclasts with regard to the subcellular localization of TRACPase. The present results suggest that the giant cells in GCTB are indeed derived from osteoclasts.