Document Detail


Evaluation of the mTOR pathway in ocular (uvea and conjunctiva) melanoma.
MedLine Citation:
PMID:  20173664     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Ocular melanoma is the most common eye malignancy in adults. It usually arises in the uvea, mostly in the choroid and less frequently in the conjunctiva. There is no curative therapy available when it becomes metastatic. The etiopathogenesis of uvea and conjunctiva melanomas is still poorly understood. The mammalian target of rapamycin (mTOR) pathway is involved in many biological processes and has been implicated in the development of cutaneous melanoma tumours. The mTOR pathway is an important target for anticancer drug development, and an inhibitor of this pathway has already been approved for use in humans to treat advanced renal cell carcinoma. The aim of this study was to evaluate the contribution of the mTOR pathway in uvea and conjunctiva melanomas. We analysed specific mTOR pathway effectors using immunohistochemical analysis of 30 uvea and eight conjunctiva melanoma samples. We assessed the association with prognostic clinical-pathological features, and performed mutational analysis on the BRAF and NRAS genes. None of the cases had mutations in either BRAF or NRAS. Expression of phospho-AKT Thr308 was associated with metastatic uvea melanomas. In conjunctiva melanomas, overactivation of the mTOR pathway, as confirmed by high phospho-AKT Ser473 and Thr308, S6 and p4EBP1 Thr37/46 levels, was associated with adverse prognostic parameters (mitotic index and tumour thickness). Conjunctiva melanomas displayed high expression of phospho-mTOR effectors in contrast with uvea melanomas, in which PTEN seemed to downregulate the mTOR pathway. Characterizing the expression of PTEN, AKT and pS6 Ser235/236 might be a useful predictive tool for deciding whether to use mTOR inhibitors to treat conjunctiva melanomas.
Authors:
Helena Pópulo; Paula Soares; Ana Sofia Rocha; Paula Silva; José Manuel Lopes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Melanoma research     Volume:  20     ISSN:  1473-5636     ISO Abbreviation:  Melanoma Res.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-03-12     Completed Date:  2010-06-14     Revised Date:  2012-06-21    
Medline Journal Info:
Nlm Unique ID:  9109623     Medline TA:  Melanoma Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  107-17     Citation Subset:  IM    
Affiliation:
Institute of Pathology and Molecular Immunology, University of Porto (IPATIMUP), São João, Porto, Portugal.
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MeSH Terms
Descriptor/Qualifier:
DNA Mutational Analysis
Eye Neoplasms / genetics,  metabolism*,  pathology
Genes, ras
Humans
Immunohistochemistry
Intracellular Signaling Peptides and Proteins / genetics,  metabolism*
Melanoma / genetics,  metabolism*,  pathology
Middle Aged
PTEN Phosphohydrolase / genetics,  metabolism
Protein-Serine-Threonine Kinases / genetics,  metabolism*
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins c-akt / genetics,  metabolism
Ribosomal Protein S6 Kinases / genetics,  metabolism
Signal Transduction / physiology
TOR Serine-Threonine Kinases
Tissue Array Analysis
Chemical
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/BRAF protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins B-raf; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/Ribosomal Protein S6 Kinases; EC 3.1.3.67/PTEN Phosphohydrolase

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