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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

Initiation of apoptosis and death signalling through TRAIL receptors.
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Related In: Results  -  Collection


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fig2: Initiation of apoptosis and death signalling through TRAIL receptors.

Mentions: Apoptosis via death receptors serves as the principal pathway in immune-mediated antitumour response and represents an attractive target for therapy. In susceptible cells, interaction of a death ligand with its corresponding death receptor leads to formation of DISC (death-induced signalling complex) and direct high level of activation of caspase-8 and downstream effector caspases (type I cells). In cells with only low levels of activated caspase-8 generated (type II cells), activation of downstream caspases is mediated via the mitochondrial loop after cleavage of BID, a BH3 domain containing BCL-2 family protein, by caspase-8 [28]. FAS-FASL-, and DR4-/DR5-TRAIL- (TNF-related apoptosis-inducing ligand)-induced apoptosis represent prototypical apoptotic signalling pathways (Figure 2) [29]. Although FAS and FASL are expressed in a wide range of ES cell lines, most ES cell lines are not sensitive to FAS-induced apoptosis. Additional inhibition of antiapoptotic factors by cycloheximide or upregulation of proapoptotic factors such as by IFN-γ are often required for FAS-mediated apoptosis in ES cells [30]. Deregulation of BCL2 family members may be responsible for this resistance as FAS-sensitive cell lines had a higher expression of the proapoptotic protein BAD and lower levels of the antiapoptotic protein BAR [31]. In contrast to the inconsistent sensitivity to FAS-mediated apoptosis in ES cells, TRAIL induces apoptosis in about 80% of ES cell lines expressing the corresponding DR4 and DR5 death receptors in vitro [32, 33]. Nevertheless, a fraction of ES cells is resistant to TRAIL-induced apoptosis by virtue of low or absent expression of caspase-8 and subsequent inhibition of the downstream apoptotic cascade [34]. Interestingly, caspase-8 may be upregulated by interferon-γ (IFN-γ) via the STAT1 pathway, to render previously resistant cells susceptible to TRAIL [3, 35]. Concentrations of IFN-γ required for TRAIL induced apoptosis in these ES cells were as low as 20 U/mL; an amount fourfold lower than concentrations found in sera of patients treated with IFN-γ for other diseases [34].


Targeted therapy in Ewing sarcoma.

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

Initiation of apoptosis and death signalling through TRAIL receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Initiation of apoptosis and death signalling through TRAIL receptors.
Mentions: Apoptosis via death receptors serves as the principal pathway in immune-mediated antitumour response and represents an attractive target for therapy. In susceptible cells, interaction of a death ligand with its corresponding death receptor leads to formation of DISC (death-induced signalling complex) and direct high level of activation of caspase-8 and downstream effector caspases (type I cells). In cells with only low levels of activated caspase-8 generated (type II cells), activation of downstream caspases is mediated via the mitochondrial loop after cleavage of BID, a BH3 domain containing BCL-2 family protein, by caspase-8 [28]. FAS-FASL-, and DR4-/DR5-TRAIL- (TNF-related apoptosis-inducing ligand)-induced apoptosis represent prototypical apoptotic signalling pathways (Figure 2) [29]. Although FAS and FASL are expressed in a wide range of ES cell lines, most ES cell lines are not sensitive to FAS-induced apoptosis. Additional inhibition of antiapoptotic factors by cycloheximide or upregulation of proapoptotic factors such as by IFN-γ are often required for FAS-mediated apoptosis in ES cells [30]. Deregulation of BCL2 family members may be responsible for this resistance as FAS-sensitive cell lines had a higher expression of the proapoptotic protein BAD and lower levels of the antiapoptotic protein BAR [31]. In contrast to the inconsistent sensitivity to FAS-mediated apoptosis in ES cells, TRAIL induces apoptosis in about 80% of ES cell lines expressing the corresponding DR4 and DR5 death receptors in vitro [32, 33]. Nevertheless, a fraction of ES cells is resistant to TRAIL-induced apoptosis by virtue of low or absent expression of caspase-8 and subsequent inhibition of the downstream apoptotic cascade [34]. Interestingly, caspase-8 may be upregulated by interferon-γ (IFN-γ) via the STAT1 pathway, to render previously resistant cells susceptible to TRAIL [3, 35]. Concentrations of IFN-γ required for TRAIL induced apoptosis in these ES cells were as low as 20 U/mL; an amount fourfold lower than concentrations found in sera of patients treated with IFN-γ for other diseases [34].

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