Pasello Giulia, Urso Loredana, Mencoboni Manlio, Grosso Federica, Ceresoli Giovanni Luca, Lunardi Francesca, Vuljan Stefania Edith, Bertorelle Roberta, Sacchetto Valeria, Ciminale Vincenzo, Rea Federico, Favaretto Adolfo, Conte PierFranco, Calabrese Fiorella
Department of Clinical and Experimental Oncology, Medical Oncology 2, Istituto Oncologico Veneto IRCCS Padova, Italy.
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
Oncotarget. 2015 Dec 8;6(39):42053-66. doi: 10.18632/oncotarget.5974.
Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treatment options. Sarcomatoid/biphasic mesotheliomas are characterized by more aggressive behaviour and a poorer prognosis compared with the epithelioid subtype. To date prognostic and tailored therapeutic biomarkers are lacking. The present study analyzed the expression levels of MDM2 and HIF1alpha in different histologic subtypes from chemonaive MPM patients. Diagnostic biopsies of MPM patients from four Italian cancer centers were centrally collected and analyzed. MDM2 and HIF1alpha expression levels were investigated through immunohistochemistry and RT-qPCR. Pathological assessment of necrosis, inflammation and proliferation index was also performed. Molecular markers, pathological features and clinical characteristics were correlated to overall survival (OS) and progression free survival (PFS). Sixty MPM patients were included in the study (32 epithelioid and 28 non-epithelioid). Higher levels of MDM2 (p < 0.001), HIF1alpha (p = 0.013), necrosis (p = 0.013) and proliferation index (p < 0.001) were seen mainly in sarcomatoid/biphasic subtypes. Higher levels of inflammation were significantly associated with epithelioid subtype (p = 0.044). MDM2 expression levels were correlated with HIF1alpha levels (p = 0.0001), necrosis (p = 0.008) and proliferation index (p = 0.009). Univariate analysis showed a significant correlation of non-epithelioid histology (p = 0.04), high levels of necrosis (p = 0.037) and proliferation index (p = 0.0002) with shorter PFS. Sarcomatoid/biphasic and epithelioid mesotheliomas showed different MDM2 and HIF1alpha expression levels and were characterized by different levels of necrosis, proliferation and inflammation. Further studies are warranted to confirm a prognostic and predictive role of such markers and features.
恶性胸膜间皮瘤（MPM）是一种侵袭性肿瘤，预后较差且治疗选择有限。与上皮样亚型相比，肉瘤样/双向性间皮瘤具有更具侵袭性的行为和更差的预后。迄今为止，缺乏预后和个性化治疗生物标志物。本研究分析了初治MPM患者不同组织学亚型中MDM2和HIF1α的表达水平。从四个意大利癌症中心收集并集中分析了MPM患者的诊断活检样本。通过免疫组织化学和RT-qPCR研究MDM2和HIF1α的表达水平。还进行了坏死、炎症和增殖指数的病理评估。将分子标志物、病理特征和临床特征与总生存期（OS）和无进展生存期（PFS）进行关联分析。该研究纳入了60例MPM患者（32例上皮样和28例非上皮样）。MDM2（p < 0.001）、HIF1α（p = 0.013）、坏死（p = 0.013）和增殖指数（p < 0.001）水平较高主要见于肉瘤样/双向性亚型。较高的炎症水平与上皮样亚型显著相关（p = 0.044）。MDM2表达水平与HIF1α水平（p = 0.0001）、坏死（p = 0.008）和增殖指数（p = 0.009）相关。单因素分析显示，非上皮样组织学（p = 0.04）、高水平的坏死（p = 0.037）和增殖指数（p = 0.0002）与较短的PFS显著相关。肉瘤样/双向性和上皮样间皮瘤显示出不同的MDM2和HIF1α表达水平，并具有不同程度的坏死、增殖和炎症特征。有必要进行进一步研究以证实这些标志物和特征的预后及预测作用。
