Lung cancer is the most common cancer worldwide, accounting for over 1.37 million deaths annually. The clinical outcome and management of lung cancer patients could be substantially improved by the implementation of non-invasive biomarker assays for the early detection, prognosis as well as prediction and monitoring of treatment response. MicroRNAs (miRNAs) have been implicated in the regulation of virtually all signaling circuits within a cell and their dysregulation has been shown to play an essential role in the development and progression of cancer. Recently, miRNAs were found to be released into the circulation and to exist there in a remarkably stable form. Furthermore, various cancers were shown to leave specific miRNA fingerprints in the blood of patients suggesting that cell-free miRNAs could serve as non-invasive biomarkers for the detection or monitoring of cancer and putative therapeutic targets. Since that, a considerable effort has been devoted to decode the information carried by circulating miRNAs. In the current review, we give an insight into the mechanisms of miRNA release into the bloodstream, their putative functional significance and systematically review the studies focused on the identification of cell-free miRNAs with the diagnostic, prognostic, and predictive significance in lung cancer and discuss their potential clinical utility.

The identification of novel cancer-related and immunogenic proteins is still a challenge to be faced to improve antigen-specific tumor immunotherapy. The category of so-called cancer-testis (CT) antigens is one of the most perspective groups of proteins for anticancer immune response activation as normally they are expressed in immunoprivileged tissues and are immunogenic if aberrantly generated in tumors. The heterogeneous group of proteins called sperm-associated antigens (SPAG) might encompass novel CT antigens owing to their common expression in male germ cells, their ability to elicit immune response underlying infertility, and lately proposed oncogenic properties. We carried out a comprehensive analysis of the expression pattern in various normal and cancerous tissues and assessed the frequency of spontaneous humoral immune response against members of the SPAG group in cancer patients using phage-displayed antigen microarrays. Our results show that out of 15 analyzed SPAG genes only SPAG1, SPAG6, SPAG8, SPAG15, and SPAG17 are predominantly expressed in testis, whereas the others are ubiquitously expressed with only a testis-associated alternative splice variant of SPAG16. mRNA expression of SPAG1, SPAG6, and alternative splice variants of SPAG8, SPAG16, and SPAG17 was elevated in various tumors with frequencies ranging from approximately 10% to 70%. The upregulation of SPAG6 in lung and breast cancer was confirmed by immunohistochemical analysis of tumor and normal tissue microarrays. Cancer-associated spontaneous humoral immune response was detected against SPAG1, SPAG6, SPAG8, and a novel testis-specific splice variant of SPAG17 and ascribe these as novel CT antigens that potentially are applicable as immunotherapeutic targets and serologic biomarkers.

Summary. Aim: Aberrant Sonic hedgehog (Shh) pathway signaling has been described in small cell lung cancer (SCLC), as well discrepancies, when analyzing expression of pathway components in SCLC cell lines vs tumor biopsies. Shh key component GLI1 was evaluated in advanced SCLC and data correlated with patient survival. Materials and Methods: GLI1 expression was analyzed by quantitative real-time polymerase chain reaction in pre-treatment fresh frozen tumor biopsies of 12 advanced SCLC patients and mRNA level of GLI1 was compared in short-term vs long-term survivor’s samples (stratified by median survival, independent samples t-test). Results: Expression of GLI1 mRNA was significantly higher in long-term (> 9.6 months, n = 6) survivor’s biopsies than in short-term (≤ 9.6 months, n = 6) survivors (p = 0.0196, 95% CI: 0.000016 to 0.000147, two-tailed independent samples t-test). Conclusion: High GLI1 mRNA expression in SCLC was found to be positive prognostic marker associated with longer survival. Further research is needed for validation of these results due to the small number of patients in the study.

Despite the fact, that lung cancer is more common among older smoking men, however it may also develop among young women without a smoking anamnesis. We report here a history of a non-smoking woman, 40 years old, with a diagnosis of lung adenocarcinoma at IV stage. Despite the fact, the woman received three lines of palliative chemotherapy, the disease progressed. After the sample of the tumor was tested by genetic approach, ROS1 mutation was detected, and the patient was treated with a ROS1 inhibitor, Crizotinib. Sharp improvement was observed already after the first week of treatment. After one-month adenocarcinoma shrink, and specific supraclavicular lymph nodes disappeared. Unfortunately, due to problems with financing the treatment was stopped, after what the disease began to progress rapidly, and the patient died after a month due to brain metastasis. This case is noteworthy also because the patient was first diagnosed a thrombophilia with thrombi present in deep calf veins, left heart ventricle and lungs Adenocarcinoma was discovered occasionally when during video-assisted thoracoscopic surgery biopsy specimen was taken from suspicious mass in the lower lobe of the right lung. This story reminds us that lung carcinoma may start with a paraneoplastic syndrome, like thrombophilia as in this case and finding of adenocarcinoma of the lung in young, non-smoking persons is indicative for possible ROS1 gene mutation. In such cases early treatment with ROS1 protein-tyrosine kinase inhibitors should be started as soon as possible.

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Cancer stem cells may be responsible for tumour regrowth and acquisition of resistance in small cell lung cancer (SCLC). The Hedgehog pathway regulates survival and proliferation of tissue progenitor and stem cell populations, promoting the expression of stem cell related and proliferative genes. We evaluated the Sonic Hedgehog (Shh) embryonic signalling pathway in relapsed SCLC. Expression levels of Shh related genes GLI1, SMO, SUFU, PTCH1, HHIP, BCL2, BMI, ZEB1, ZEB2, N-MYC, Twist1 were analysed by qRT-PCR in matched pre-treatment and relapsed tumour fresh frozen biopsies of three SCLC patients. Expression of each gene was compared using the paired samples t-test, as well as comparison of mean expression levels was done. Data were statistically interpreted using the MedCalc version 10.2.0.0 software. 2.9-fold lower mean mRNA expression of the major Hedgehog activation indicator GLI1 was observed in relapsed samples (p = 0.0529). Mean expression of six Shh inducible genes, PTCH1, HHIP, N-MYC, ZEB2, Twist1, ZEB1, was also downregulated by 2.6-, 2.2-, 1.9-, 1.8-, 1.2-, 1.1-fold, respectively (p = 0.4252, p = 0.1268, p = 0.2480, p = 0.1169, p = 0.1480, p = 0.7595, respectively). 1.8-fold mean expression decrease was found for Gli activator Smo (p = 0.4111). Only the Shh pathway inhibitor SUFU and two other examined Hedgehog signalling inducible genes BCL2 and BMI in relapsed SCLC showed 0.8-, 0.9-,and 0.8-fold increase of expression, respectively (p = 0.3074, p = 0.7921, and p = 0.3822, respectively). To our knowledge, this is the first report of comparison of Shh signalling in matched pre-treatment and relapsed SCLC biopsies. Our data show decreased activity for majority of Shh pathway components in relapsed SCLC, although difference did not reach statistical significance.