Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease – a combined tissue microarray, in vitro and in vivo study

BMC Cancer

Ágnes Márk³  Melinda Hajdu³  Zsófia Váradi¹  Tamás Béla Sticz³  Noémi Nagy³  Judit Csomor³  Lajos Berczi³  Viktória Varga³  Monika Csóka¹  László Kopper³  Anna Sebestyén² 

[1] 2nd Department of Pediatrics, Semmelweis University, Tűzoltó u. 7-9, Budapest 1094, Hungary

[2] Tumor Progression Research Group of Joint Research Organization of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary

[3] 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest 1085, Hungary

关键词: Hodgkin-lymphoma xenograft;    TMA;    Rapalogs;    Hodgkin-lymphoma;    mTOR activity;   

Others  :  1079741
DOI  :  10.1186/1471-2407-13-250

 received in 2012-10-11, accepted in 2013-04-25,  发布年份 2013

【 摘 要 】

Background

Targeting signaling pathways is an attractive approach in many malignancies. The PI3K/Akt/mTOR pathway is activated in a number of human neoplasms, accompanied by lower overall and/or disease free survival. mTOR kinase inhibitors have been introduced in the therapy of renal cell carcinoma and mantle cell lymphoma, and several trials are currently underway. However, the pathological characterization of mTOR activity in lymphomas is still incomplete.

Methods

mTOR activity and the elements of mTOR complexes were investigated by immunohistochemistry on tissue microarrays representing different human non-Hodgkin-lymphomas (81 cases) and Hodgkin-lymphomas (87 cases). The expression of phospho-mTOR, phospho-4EBP1, phospho-p70S6K, phospho-S6, Rictor, Raptor and Bcl-2, Bcl-xL, Survivin and NF-kappaB-p50 were evaluated, and mTOR activity was statistically analyzed along with 5-year survival data. The in vitro and in vivo effect of the mTOR inhibitor rapamycin was also examined in human Hodgkin-lymphoma cell lines.

Results

The majority (>50%) of mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, anaplastic large-cell lymphoma and Hodgkin-lymphoma cases showed higher mTOR activity compared to normal lymphoid tissues. Hodgkin-lymphoma was characterized by high mTOR activity in 93% of the cases, and Bcl-xL and NF-kappaB expression correlated with this mTOR activity. High mTOR activity was observed in the case of both favorable and unfavorable clinical response. Low mTOR activity was accompanied by complete remission and at least 5-year disease free survival in Hodgkin-lymphoma patients. However, statistical analysis did not identify correlation beetween mTOR activity and different clinical data of HL patients, such as survival. We also found that Rictor (mTORC2) was not overexpressed in Hodgkin-lymphoma biopsies and cell lines. Rapamycin inhibited proliferation and induced apoptosis in Hodgkin-lymphoma cells both in vitro and in vivo, moreover, it increased the apoptotic effect of chemotherapeutic agents.

Conclusions

Targeting mTOR activity may be a potential therapeutic tool in lymphomas. The presence of mTOR activity probably indicates that the inclusion of mTOR inhibition in the therapy of Hodgkin-lymphomas may be feasible and beneficial, especially when standard protocols are ineffective, and it may also allow dose reduction in order to decrease late treatment toxicity. Most likely, the combination of mTOR inhibitors with other agents will offer the highest efficiency for achieving the best clinical response.

【 授权许可】

   
2013 Márk et al.; licensee BioMed Central Ltd.

【 图 表 】

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