New link in the growth of Ewing’s sarcoma

To develop new therapeutic approaches to cancer, it is essential to understand the long and extremely complex process that underlies it, in other words the various stages of cancer development from the initial mutation to the tumor.

Having already identified the alteration that leads to Ewing’s sarcoma, a bone cancer which afflicts young people, an Inserm team at the Institut Curie has recently used a combination of novel techniques to show that there 86 deregulated genes in these tumors. One of these genes, a new “link” in the development of Ewing’s sarcoma, could be used as a therapeutic target.

These discoveries were published in the August 2004 issue of Molecular and Cellular Biology.

Cancer results from the proliferation of abnormal cells in the body. The trigger is an alteration in the genetic material of a single cell, in certain genes that regulate vital processes (division, differentiation, apoptosis, repair). However, a single mutation is not enough to transform a health cell into a cancer cell. Rather it is a succession of genetic accidents that results in uncontrolled cells that accumulate and lead to tumor formation.

Few cancers have a simple molecular signature – a specific mutation that leads to tumor growth. In Ewing’s sarcoma, a malignant tumor of the bone which affects children, teenagers and young adults, this molecular signature has been discovered thanks to a close collaboration between physicians and researchers at the Institut Curie, the internationally renowned reference center for the study and treatment of Ewing’s sarcoma.

Olivier Delattre and his group have identified and characterized this mutation: it arises from an accidental exchange of genetic material between two chromosomes. This leads to the formation of a mutated gene that produces an abnormal protein called EWS/FLI-1 (see box overleaf). To understand the growth of Ewing’s sarcoma, Delattre and colleagues are now studying the effects of EWS/FLI-1 on the cellular machinery. They use an original approach in which the technique of RNA interference is used to “switch off” the mutated gene. The abnormal protein is therefore no longer produced. Using DNA chips, they have studied how other genes are affected by the absence of the abnormal protein.

With this combination of innovative techniques, Delattre and colleagues have identified 86 genes whose expression is altered in the absence of the abnormal protein. They have paid particular attention to one of these genes – the IGFBP-3 gene – whose expression is greatly reduced in tumor cells but which is again expressed normally when the altered protein is absent.

The protein produced by the IGFBP-3 gene is known to block one of the most important cellular messengers, insulin-like growth factor 1. IGF-1 controls several fundamental mechanisms such as cellular proliferation and apoptosis (cell death). Overexpression of IGF-1 has, moreover, been implicated in certain cancers.

The Institut Curie researchers have thus shown in Ewing’s sarcoma that the altered protein prevents expression of the IGFBP-3 gene. As a consequence, IGF-1 is no longer "blocked" and so emits a continuous signal ordering the cells to proliferate. IGFBP-3 plays a role upstream in this signaling pathway and could be targeted therapeutically to block IGF-1-induced abnormal cellular proliferation.

Olivier Delattre and his team at the Institut Curie have therefore discovered a new “link” in the growth of Ewing’s sarcoma. Through better comprehension of the cascades of deregulations specific to each tumor, it will be possible to develop new therapeutic strategies that are better targeted and hence more effective.

Ewing’s sarcoma (sarcoma is a variety of cancer that develops in connective tissue), a malignant bone tumor, strikes children, teenagers and young adults (up to 30 years of age) at a frequency that peaks at puberty, between 10 and 20 years of age. In France, there are 50 to 100 new cases of Ewing’s sarcoma every year, making it the second most frequent bone tumor in the under-30s.

The tumor arises in the bone marrow, which explains why it is found mainly in flat bones and the diaphyseal portion of long bones. It has great metastatic potential and spreads above to the lungs and skeleton.

Early treatments of Ewing’s sarcoma were based essentially on radiotherapy, but much progress has been made over the last 30 years. Today, the therapeutic strategy used to overcome a localized tumor usually allies chemotherapy and surgery. Treatment is completed by post-operative chemotherapy, and sometimes radiotherapy.

The chromosomal anomaly responsible for this disease was discovered at the Institut Curie in 1984, and characterized in 1992. It is a translocation, in other words an abnormal exchange of genetic material between two chromosomes:

• In 85% of cases, the translocation occurs between chromosomes 11 and 22 and leads to the synthesis of an abnormal protein, EWS-FLI-1.
• In 10% of cases, it happens between chromosomes 22 and 21 and results in the production of an abnormal protein, EWS-ERG.

The discovery of these genetic alterations led to the development in 1994 at the Institut Curie of a diagnostic test for Ewing’s sarcoma.

Through close collaboration between physicians and research scientists, the Institut Curie has become an internationally renowned reference center for the clinical management of young patients with Ewing’s sarcoma and for the molecular analysis of these tumors.

http://www.curie.fr/