Cell Signaling Pathways and Nuclear PTEN and FOXO3a Dysregulation in Pleural Mesotheliomas
M Angeles Montero, M Alejandra Gabaldon, M Teresa Salcedo, Natalia Tallada, Teresa Moline, Javier Hernandez-Losa, Enriqueta Felip, Susana Cedres, Santiago Ramon y Cajal. University Hospital Vall d'Hebron, Barcelona, Spain
Background: Pleural mesothelioma (PM) is a malignant, highly aggressive neoplasia with little understanding of its pathogenesis. Several studies have indicated that activation of Protein Kinase pathways (PKP) contributes to PM proliferation and survival, and others have identified over-expression of several factors (EGFR, MET, IGFR and VEGFR). But there are very few reports about downstream mTOR factors and PTEN. The aim of our work was to identify the possible PKP activation in PM and pleuritis and to determine significant differences between them which explain the lack of response to their targeted therapies.
Design: Thirty-two (32) cases of mesothelioma (22 epithelioid, 4 biphasic and 6 sarcomatoid) and nineteen (19) cases of pleuritis were selected from our files from 2003 to 2010. Formaline-fixed, paraffin-embedded block was used for all the immunostainings and a whole complete section, instead of TMA were studied. The following primary antibodies were used: pmTor, 4E-BP1, p4EB-P1, pS6rb, pMapk, eiF4E, peiF4E, PTEN, pAKT and FOXO3A. Staining intensity, percentage of positive cells and localization of the staining were compared for each marker. To reduce the subjectivity we applied the formula Hscore. The comparative study was performed using the statistical test of Mann Whitney.
Results: PM showed nuclear over-expression of 4EBP1 (p=0.017) and FOXO3a (p=0.0007) and decrease nuclear PTEN (p=0.0004). In the cytoplasm there was a decrease of pS6 (p=0,0001), pmTOR (p=0,0344) and pMAPK (p=0.0921) and increase of eIF4E (p=0,0012). Pleuritis cells showed granular cytoplasmic FOXO3a expression (0.0009) with higher expression of pmTOR, pMAPK, pS6 in the cytoplasm and higher levels of nuclear PTEN than PM.
Conclusions: a) mTOR and MAPK pathways are activated in pleuritis. b) In pleural mesotheliomas, interestingly, cytoplasmic eIF4E overexpression may be predictive of poor prognosis. c) In pleural mesotheliomas vs pleuritis there is a significant down-regulation of nuclear suppressor PTEN activity and nuclear up-regulation of FOXO3a. The study of these factors may open new approaches in the treatment of PM.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 293, Wednesday Morning