Limits...
Targeted therapy in Ewing sarcoma.

Lissat A, Chao MM, Kontny U - ISRN Oncol (2012)

Bottom Line: The particular biologic feature of ES, the fusion of the EWS gene with a member of the ETS family of genes, is present in >95% of cases.The EWS-ETS chimeric protein leads to aberrant transcription that promotes tumor initiation and propagation via prosurvival and antiapoptotic pathways.Recent research has identified cooperating mutations important for ES tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, University Medical Center Freiburg, 79106 Freiburg, Germany.

ABSTRACT
Despite marked improvement in the prognosis of patients with nonmetastatic Ewing sarcoma (ES), the outcome for patients with recurrent or metastatic disease remains poor. Insight into key biologic processes in ES could provide new therapeutic targets. The particular biologic feature of ES, the fusion of the EWS gene with a member of the ETS family of genes, is present in >95% of cases. The EWS-ETS chimeric protein leads to aberrant transcription that promotes tumor initiation and propagation via prosurvival and antiapoptotic pathways. Recent research has identified cooperating mutations important for ES tumorigenesis. This paper provides a summary of the latest research in ES and discusses potential novel targets for therapy.

No MeSH data available.


Related in: MedlinePlus

Interaction of EWS-FLI1 with transcription factors (green). Examples of induced target genes are red, suppressed genes are blue. Alteration of gene expression by EWS-FLI1 leads to suppression of apoptosis and enhancement of proliferation and migration.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3368441&req=5

fig1: Interaction of EWS-FLI1 with transcription factors (green). Examples of induced target genes are red, suppressed genes are blue. Alteration of gene expression by EWS-FLI1 leads to suppression of apoptosis and enhancement of proliferation and migration.

Mentions: The t(11; 22)(q24; q12) chromosomal translocation that fuses the EWS gene to the FLI1 gene was first identified almost 20 years ago. The precise cellular mechanism by which EWS-FLI1 leads to ES still remains to be determined. The fusion protein product of EWS-FLI1 preferentially binds to consensus ETS motifs and GGAA repeat microsatellite sequences. These binding sites are outside of the promoter regions and located up to more than 5 kb upstream of the regulated genes [9]. EWS-FLI1 lacks a stable structure and contains a high proportion of disordered regions which facilitates interaction with a number of transcription factors as well as ease binding and dissociation from nuclear protein complexes to alter cellular transcriptional activities [10]. Moreover, direct protein interaction has been observed between EWS-FLI1 and RNA polymerase II, CREB-binding protein, BARD1, NROB1 and RNA Helicase A (RHA) [10–12]. The sum effect of binding of EWS-FLI1 to cellular components is threefold: (1) induction of transcription of genes involved in cell cycle regulation and DNA repair, (2) repression of expression of genes involved in cell adhesion, migration and homing such as integrin-, polysaccharide-, and glycosaminoglycan- or heparin-binding proteins, and (3) altered expression of several apoptotic genes (Figure 1) [11–13].


Targeted therapy in Ewing sarcoma.

Lissat A, Chao MM, Kontny U - ISRN Oncol (2012)

Interaction of EWS-FLI1 with transcription factors (green). Examples of induced target genes are red, suppressed genes are blue. Alteration of gene expression by EWS-FLI1 leads to suppression of apoptosis and enhancement of proliferation and migration.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368441&req=5

fig1: Interaction of EWS-FLI1 with transcription factors (green). Examples of induced target genes are red, suppressed genes are blue. Alteration of gene expression by EWS-FLI1 leads to suppression of apoptosis and enhancement of proliferation and migration.
Mentions: The t(11; 22)(q24; q12) chromosomal translocation that fuses the EWS gene to the FLI1 gene was first identified almost 20 years ago. The precise cellular mechanism by which EWS-FLI1 leads to ES still remains to be determined. The fusion protein product of EWS-FLI1 preferentially binds to consensus ETS motifs and GGAA repeat microsatellite sequences. These binding sites are outside of the promoter regions and located up to more than 5 kb upstream of the regulated genes [9]. EWS-FLI1 lacks a stable structure and contains a high proportion of disordered regions which facilitates interaction with a number of transcription factors as well as ease binding and dissociation from nuclear protein complexes to alter cellular transcriptional activities [10]. Moreover, direct protein interaction has been observed between EWS-FLI1 and RNA polymerase II, CREB-binding protein, BARD1, NROB1 and RNA Helicase A (RHA) [10–12]. The sum effect of binding of EWS-FLI1 to cellular components is threefold: (1) induction of transcription of genes involved in cell cycle regulation and DNA repair, (2) repression of expression of genes involved in cell adhesion, migration and homing such as integrin-, polysaccharide-, and glycosaminoglycan- or heparin-binding proteins, and (3) altered expression of several apoptotic genes (Figure 1) [11–13].

Bottom Line: The particular biologic feature of ES, the fusion of the EWS gene with a member of the ETS family of genes, is present in >95% of cases.The EWS-ETS chimeric protein leads to aberrant transcription that promotes tumor initiation and propagation via prosurvival and antiapoptotic pathways.Recent research has identified cooperating mutations important for ES tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, University Medical Center Freiburg, 79106 Freiburg, Germany.

ABSTRACT
Despite marked improvement in the prognosis of patients with nonmetastatic Ewing sarcoma (ES), the outcome for patients with recurrent or metastatic disease remains poor. Insight into key biologic processes in ES could provide new therapeutic targets. The particular biologic feature of ES, the fusion of the EWS gene with a member of the ETS family of genes, is present in >95% of cases. The EWS-ETS chimeric protein leads to aberrant transcription that promotes tumor initiation and propagation via prosurvival and antiapoptotic pathways. Recent research has identified cooperating mutations important for ES tumorigenesis. This paper provides a summary of the latest research in ES and discusses potential novel targets for therapy.

No MeSH data available.


Related in: MedlinePlus