摘要：
Background: Lung cancer remains the major cause of cancer mortality in the world. In addition to primary prevention, earlier detection and more targeted treatments, tailored on the biological characteristics of the tumor and its microenvironment, could significantly reduce morbidity and mortality for this disease. The real efficacy of lung cancer screening by spiral-computed tomography (CT) in heavy smokers is still to be defined since, in spite of a proved capacity to detect small asymptomatic nodules, the frequency of false positive CTs as well as unnecessary treatments is very high if compared to the limited mortality reductions. The development of biomarkers able to identify tumors in a pre-clinical phase and to track the different aggressiveness of lung tumors is of paramount importance. microRNAs (miRNAs) represent a recently identified class of regulatory molecules and several studies showed that miRNA are involved in lung tumor development and progression and also circulate in plasma and serum of lung cancer patients.Materials and Methods: We analyzed miRNA profiles of lung tumors, normal lung tissues and plasma samples from cases with variable prognosis identified in two independent spiral-CT screening trials where multiple plasma samples, collected from one to four years before radiological detection of the disease were available.Results: We found miRNA expression profiles associated with aggressiveness of the disease and poor survival in tumors and also in normal lung tissues of the patients, thus proving the critical influence of a smoking-related lung microenvironment on tumor progression. Specific microRNA signatures were identified in plasma samples collected up to two years before spiral-CT detection of the disease, thus able to catch the earlier biological phases of disease development. We also defined a plasma signature that discriminates subjects according to aggressiveness of their future tumors, and in particular the occurrence of early metastatic but spiral-CT invisible lung tumors or small spiral-CT detected lesions with aggressive potential. Of interest plasma miRNas involved in the signatures of lung cancer risk and of aggressive disease more closely reflected miRNAs expressed in the normal lung rather than those characterizing the tumor samples of patients, supporting the concept that normal lung microenvironment has a critical influence on tumor development and aggressiveness.Conclusion: These results open up the prospective of using plasma miRNAs as non invasive lung cancer biomarkers.
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