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Discovery of the cellular origin of Ewing’s sarcoma

Inserm researchers at the Institut Curie have identified the cells that cause Ewing’s sarcoma. They are cells of the mesenchyme, the connective tissue that supports other tissues. The Institut Curie is the reference center in France for Ewing’s sarcoma, a bone tumor of children, adolescents, and young adults.

The researchers have also succeeded “to make” the tumor cells to become virtually normal mesenchymal cells again. These results, published in Cancer Cell on 7 May 2007, open up new therapeutic possibilities for blocking the development of Ewing’s sarcoma in young patients.

Ewing’s sarcoma (1) is the second most frequent malignant bone tumor in France, with 50 to 100 new cases a year. It occurs in children, teenagers, and young adults (up to 30 years of age), at a frequency that peaks around puberty, between 10 and 20 years of age. This bone tumor essentially grows in the pelvis, ribs, femur, fibula, and tibia. It is highly invasive and metastases are common, especially in the lungs and skeleton.

Treatment of Ewing’s sarcoma, has progressed greatly in the last thirty years. Nowadays, the therapeutic strategy used in most cases combines chemotherapy, radiotherapy and surgery. The Institut Curie is the reference center for Ewing’s sarcoma in France, and is internationally renowned both for clinical management of patients and research into this disease.

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New therapeutic leads

Cancers rarely have a simple molecular signature—a specific mutation that causes tumor growth. In the case of Ewing’s sarcoma, a molecular signature was identified and characterized in 1992 by Olivier Delattre’s Inserm team at the Institut Curie. It is an accidental change of genetic material between two chromosomes, which results in the formation of a mutant gene, which codes for an abnormal protein called EWS/FLI-1. This discovery led on to the development of a diagnostic test for Ewing’s sarcoma in 1994. Yet until now, the nature of the cell in which this mutation occurs was unknown.

The group of Olivier Delattre, the Director of Inserm Unit 830 “Genetics and Biology of Cancer” at the Institut Curie, and the team of Pierre Charbord, the Director of Inserm Laboratory ERI5 “Microenvironment of Hematopoiesis and Stem Cells” in Tours, have now discovered that Ewing’s sarcoma are caused by cells of the mesenchyme, a connective tissue that supports other tissues. They have shown that the profile of the transcriptome (2) of Ewing’s sarcoma ressemble that of mesenchymal cells, particularly mesenchymal stem cells, when EWS/FLI-1 is inhibited.

By inhibiting the abnormal protein EWS/FLI-1 that causes Ewing’s sarcoma, the researchers also “forced” the tumor cells to return to their original status of mesenchymal stem cells, which can then differentiate normally into bone or fat cells. This approach opens up new therapeutic prospects, since by forcing the cells to resume their original function it may be possible in the future to make them less aggressive and prevent their proliferation. As long as the tumor cells are still able to fulfill their function, they generally proliferate slowly, and the prognosis is good; once they lose this capacity, however, the tumor cells become highly aggressive.

This discovery could allow Delattre, Charbord and colleagues to produce an animal model of Ewing’s sarcoma, an essential stage in the development of new treatments.

These results, published in the May 7 issue of Cancer Cell, show once more that the close collaboration at the Institut Curie between physicians and researchers is vital to advances in treatments of Ewing’s sarcoma.

Catherine Goupillon | alfa
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