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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

Insulin receptor, ligands and inhibitory components leading to activation of the MAPK- and PI3K- pathway. Solid lines indicate direct interaction of participating factors, broken lines indicate final effects (i.e. activation of mTOR).
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fig3: Insulin receptor, ligands and inhibitory components leading to activation of the MAPK- and PI3K- pathway. Solid lines indicate direct interaction of participating factors, broken lines indicate final effects (i.e. activation of mTOR).

Mentions: The contribution of the insulin-like growth factor (IGF) pathway to oncogenesis in ES is widely accepted [46, 47]. Binding of IGF-I to the insulin-like growth factor I receptor (IGF-IR) leads to activation of PI3K- and MAPK-pathways promoting proliferation (Figure 3) [48]. Several epidemiological studies suggest a link between IGF-I and ES. The peak incidence of ES in the second decade of life and rising IGF-I levels in puberty appear to be a fundamental part of tumour initiation rather than mere co-incidence [1, 49]. Patients with metastatic disease and low IGF-I levels and high IGFBP3:IGF-I ratios showed a trend towards improved survival [50]. Moreover, there is data linking elevated IGF-I blood levels to increased risk of breast, colon or prostate cancer [48, 51]. Molecular studies have shown that (1) the aberrant transcription driven by EWS-FLI1 leads to repression of insulin-like growth factor binding protein 3 (IGFBP3) [52], (2) IGF-I is induced by the ES fusion protein [53] and (3) in NIH3T3 cells and embryonic stem cells, in addition to direct IGFBP3 repression, IGFBP3 expression is further diminished by EWS-ETS repression of transforming growth factor beta receptor type II (TGFβRII) expression. TGFβ was shown to induce IGFBP3 and to mediate growth inhibition in breast cancer cells [54–56].


Targeted therapy in Ewing sarcoma.

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

Insulin receptor, ligands and inhibitory components leading to activation of the MAPK- and PI3K- pathway. Solid lines indicate direct interaction of participating factors, broken lines indicate final effects (i.e. activation of mTOR).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Insulin receptor, ligands and inhibitory components leading to activation of the MAPK- and PI3K- pathway. Solid lines indicate direct interaction of participating factors, broken lines indicate final effects (i.e. activation of mTOR).
Mentions: The contribution of the insulin-like growth factor (IGF) pathway to oncogenesis in ES is widely accepted [46, 47]. Binding of IGF-I to the insulin-like growth factor I receptor (IGF-IR) leads to activation of PI3K- and MAPK-pathways promoting proliferation (Figure 3) [48]. Several epidemiological studies suggest a link between IGF-I and ES. The peak incidence of ES in the second decade of life and rising IGF-I levels in puberty appear to be a fundamental part of tumour initiation rather than mere co-incidence [1, 49]. Patients with metastatic disease and low IGF-I levels and high IGFBP3:IGF-I ratios showed a trend towards improved survival [50]. Moreover, there is data linking elevated IGF-I blood levels to increased risk of breast, colon or prostate cancer [48, 51]. Molecular studies have shown that (1) the aberrant transcription driven by EWS-FLI1 leads to repression of insulin-like growth factor binding protein 3 (IGFBP3) [52], (2) IGF-I is induced by the ES fusion protein [53] and (3) in NIH3T3 cells and embryonic stem cells, in addition to direct IGFBP3 repression, IGFBP3 expression is further diminished by EWS-ETS repression of transforming growth factor beta receptor type II (TGFβRII) expression. TGFβ was shown to induce IGFBP3 and to mediate growth inhibition in breast cancer cells [54–56].

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