The loss of function of a gene called FOXO1a plays an important role inthe development of the most common cancer of soft tissues in children,and restoring the function of that gene in cancer cells suppresses thatcancer, according to investigators at St. Jude Children's ResearchHospital. The cancer, called alveolar rhabdomyosarcoma (ARMS), arisesfrom immature skeletal muscle cells that remain partiallydifferentiated (do not acquire all the characteristics of a maturemuscle cell).
The St. Jude team found that the expression of FOXO1a is suppressedin ARMS and that the gene potently suppresses tumor activity whenre-introduced into ARMS tumor cells in the laboratory. Therefore, theinvestigators theorize that the observed loss of FOXO1a activity is apivotal step in the ARMS development. The FOXO1a gene produces theprotein FOXO1a. Gene expression refers to the production of the proteincoded for by a particular gene. A report on these findings appears inthe September 12 issue of Journal of Cell Biology.
FOXO1a kills ARMS cells by activating the gene that produces aprotein called caspase-3. Caspase-3 is a key player in the signalingpathway that triggers programmed cell death (apoptosis). Althoughcaspase-3 triggers apoptosis in abnormal cells, normal myoblasts(immature muscle cells) also depend on caspase-3 activity in order todifferentiate into mature muscle cells.
"Our study shows that suppression of FOXO1a is necessary forARMS cells to survive and avoid caspase-3-mediated apoptosis, even inthe more aggressive secondary tumors that are highly resistant toirradiation and chemotherapy, said Gerard Grosveld, Ph.D., chair ofgenetics and tumor cell biology at St. Jude. Grosveld is senior authorof the paper. His team previously reported that FOXO1a (also calledFKHR) is the master regulator that controls the differentiation ofmyoblasts into muscle cells (EMBO Journal 22:1147-1157; 2003).
The investigators also showed that the loss of FOXO1aexpression works in combination with another mutation in ARMS.Specifically, muscle cells first acquire a mutation called achromosomal translocation. Translocation occurs when two chromosomesbreak and exchange the pieces of DNA that break off. Because thechromosome breaks occur within genes, a piece of a gene from onechromosome is able to combine with the remaining piece of gene on theother chromosome. When two broken normal genes combine, the outcome isan abnormal gene called a fusion gene. In ARMS, the two possible fusiongenes that arise by translocation are called PAX3-FOXO1a andPAX7-FOXO1a. Translocation destroys one of the two copies of FOXO1a,Grosveld noted.
If the remaining FOXO1a gene then fails to produce FOXO1aprotein, the combination of the absence of FOXO1a with the genetranslocation causes ARMS.
The finding suggests that drugs aimed at restoring orincreasing the activity of FOXO1a in ARMS might successfully treat thiscancer in children by forcing the abnormal cells to undergo apoptosis.Furthermore, the mutations that cause ARMS do not occur in the relatedbut different muscle cancer ERMS (embryonal rhabdomyosarcoma), theresearchers reported. Therefore, forcing the expression of FOXO1a inthese cancer cells does not cause them to undergo apoptosis.
The proteins made by the PAX3 and PAX7 genes play criticalroles in the development and differentiation of muscle cells, and thetranslocations disrupt their important functions, according toGrosveld. "So it's not surprising that ARMS cells look like skeletalmuscle cells that only partially differentiated," Grosveld said. "Andin the absence of FOXO1a protein, these abnormal cells simply continueto grow and multiply and cause ARMS."
"Our findings emphasize that ARMS and ERMS are different formsof rhabdomyosarcoma that arise by independent mutations," said PhilppeR. J. Bois, Ph.D., the postdoctoral fellow who did most of this work."Therefore, different strategies will be required to improve treatmentoutcomes for each of these tumors." Bois is first author of the paper.
Other authors of this paper include Kamel Izeradjene, Peter J. Houghton, John L. Cleveland and Janet A. Houghton.
This work was supported inpart by the National Cancer Institute, a Cancer Center Support grant,the Van Vleet Foundation of Memphis (Philippe Bois) and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized forits pioneering work in finding cures and saving children with cancerand other catastrophic diseases. Founded by late entertainer DannyThomas and based in Memphis, Tenn., St. Jude freely shares itsdiscoveries with scientific and medical communities around the world.No family ever pays for treatments not covered by insurance, andfamilies without insurance are never asked to pay. St. Jude isfinancially supported by ALSAC, its fund-raising organization. For moreinformation, please visit www.stjude.org.
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