No abstract

Recent studies have demonstrated the involvement of SOX18 transcription factor in blood and lymphatic vessel development, as well as in wound healing processes. SOX18 expression has been noted in cancer cells of various tumours, including lung cancer. However, the exact role of SOX18 expression in non-small cell lung cancer (NSCLC) remains to be determined. The present study, therefore, assessed its expression in 198 cases of NSCLC, consisting of 94 adenocarcinomas (AC), 89 squamous cell carcinomas (SQC) and 15 large cell carcinomas (LCC). The analysis utilized immunohistochemistry (IHC) and, in 42 cases, molecular methods. SOX18 expression was also determined in NSCLC cell lines (NCI-H1703, NCI-H522 and A549) and in normal lung fibroblasts (IMR-90). SOX18 was found to be expressed in nuclei, as well as in the cytoplasm of cancer cells, in the majority of studied cases. SOX18 mRNA expression was significantly lower in NSCLC than in non-malignant lung tissue (p<0.0001). However, SOX18 protein expression levels were higher in NSCLC tissues (p<0.005) and in the examined lung cancer cell lines. No SOX18 expression was noted in the IMR-90 cell line. In paraffin sections, a positive correlation between the Ki-67 antigen and nuclear SOX18 expression (r=0.17, p<0.05) was noted. In univariate survival analysis, cytoplasmic SOX18 expression correlated with poor patient outcome in the whole study and in AC cohorts (both p<0.05). Based on these results, SOX18 may be involved in the progression of NSCLC.

Abstract. Recent studies show that low expression of ċ hain in T and NK cell leads to impaired anti-tumour immunity in patients with cancer, poor prognosis, and shorter overall survival. Therefore, monitoring ˙chain expression may be useful in assessing immune competence in lung cancer patients and in following changes during anticancer therapies. Such studies concerning small-cell and non-small cell lung cancer (SCLC and NSCLC, respectively) have not been published so far. The expression of ˙chain and IFN-Á in peripheral blood (PB) T and NK cells from SCLC and NSCLC patients at advanced (III, IV) stages were analysed before and after chemotherapy with etoposide and cisplatin using flow cytometry. Serum concentrations of TGF-ß1 and IL-10 were also estimated at each time point tested. Before therapy, impaired ˙chain expression was observed in all the patients corresponding with increased levels of immuno-suppressive cytokines in sera compared with controls. Decreased IFN-Á production in T cells from all patients was also demonstrated. In NK cells, IFN-Á was secreted at lower levels in NSCLC patients, while in the SCLC group it was normal. After chemotherapy, restoration of ˙expression in NK cells and its insignificant increase in T cells in SCLC patents corresponding with normalization of TGF-ß secretion were noted. In contrast, NSCLC patients retained impaired ˙expression in T and NK cells. SCLC and NSCLC patients showed a profound defect in IFN-Á secretion in T and NK cells upon treatment. There were no differences in studied parameters between NSCLC and SCLC groups before and after chemotherapy. This is the first report of impaired ˙expression in PB T and NK cells in patients with SCLC and NSCLC in advanced stages, which may result from higher levels of immunosuppressive cytokines in sera. After cytostatic treatment, all the studied patients, including those with initial good response to chemotherapy, remained with profound abnormalities in T and NK cells, which could have dramatic consequences regarding severely impaired anti-tumour immunity.

The molecular pathogenesis of the development of non-small cell lung carcinomas (NSCLCs) is extremely complex. Understanding the molecular basis of the development of this malignant tumor may enable the use of targeted therapy, which may result in a better treatment outome for these patients. Adenocarcinoma (AC) is the most common NSCLC subtype, equally common among smokers and non-smokers, and its pathogenesis remains unknown. The SOX18 protein is an important protein that plays a role in the development of blood and lymphatic vessels during the process of embryogenesis. Recent studies have also shown that the SOX18 protein may play a significant role in tumors, including lung cancers. In the present study, we analyzed the expression of the SOX18 protein and the mRNA level in postoperative samples of AC and non-malignant lung tissues (NMLTs), and a disparity in both levels was observed. Based on our previous observations that miR-7a and miR-24-3p are able to modulate SOX18 expression in NSCLC, the main aim of this study was to verify the miRNA modulation of the SOX18 transcript with the use of the MirTrap System in established lung cancer cell lines NCI-H1703, NCI-H522 and A549. The SOX18 mRNA expression level was significantly lower in AC than that noted in the NMLTs (P<0.0001). However, the protein levels were higher in AC cases compared to levels noted in the NMLTs (P<0.0001). Additionally, correlations between the RQ values of SOX18 in NMLT and AC cases (r=0.8195, P=0.0001), and between miR-7a and miR24-3p in AC cases (r=0.4344, P=0.0016), were noted. In conclusion, we confirmed that miR-7a and miR-24-3p are more highly expressed in NMLTs than in the AC samples, and that they modulate the SOX18 transcript in NSCLC cells.

Metallothioneins (MTs) are low weight proteins involved in several key cellular processes such as metal ions homeostasis, detoxification and scavenging of free radicals. Four groups of MTs are distinguished: MT-1, MT-2, MT-3 and MT-4. Regardless of the type, MTs are characterized by high content of cysteine, responsible for their biological properties such as binding of relevant zinc and copper ions, as well as toxic ions such as lead and cadmium. MTs were additionally shown to protect cells against oxidative stress damage and participate in differentiation, proliferation and/or apoptosis of normal and cancer cells. Many studies of different neoplasms showed association of elevated MTs levels with occurrence of chemo- and radiotherapy resistance and poor patients' outcome. In this review, we summarize and discuss the potential mechanism of action of metallotioneins in lung physiology and pathology.

Metallothionein-3 (MT-3) has been shown to be expressed in several malignancies and to have an impact on patients’ survival in breast and urinary bladder cancer cases. However, its expression has not been determined in normal skin or in its malignant lesions. MT-3 expression was studied using immunohistochemistry in 17 cases of normal skin, 18 of actinic keratosis (AK), 39 of squamous cell carcinoma (SCC), and 23 of basal cell carcinoma (BCC). Low MT-3 expression was observed in normal skin epidermis with faint or no expression in the epidermis basal layer. Significantly higher MT-3 expression was noted in AK (P = 0.007) and SCC (P < 0.0001), as compared with normal skin epidermis. BCC cases were characterized by the lowest MT-3 expression of all the examined groups, which was significantly lower in comparison to normal skin epidermis, AK, and SCC (P = 0.009; P < 0.0001 and P < 0.0001, respectively). In conclusion, MT-3 may be involved in the development of SCC.

Abstract:Lung cancer represents one of the most frequent causes of death due to neoplastic disease in Poland and around the world. The high mortality which accompany neoplastic diseases used to be ascribed mainly to dissemination of cancerous cells. Studies on animal models suggest that tumour lymphangiogenesis represents the principal factor in the process of metastases formation. Lymphangiogenesis involves a process of formation of new lymphatic vessels from already existing lymphatic capillaries. Lymphangiogenesis is stimulated by vascular endothelial growth factors (VEGF) and other, recently reported factors, such as, e.g., cyclooxygenase 2, fibroblast growth factor 2, angiopoetin-1 and the insulin-resembling growth factor. In lymphangiogenesis a key role is played by neutropilin 2 or podoplanin and this promoted development of studies on lymphangiogenesis. Activation of VEGF-C/VEGF-D/VEGFR-3 axis increases motility and invasiveness of neoplastic cells, promotes development of metastases in several types of tumours such as, e.g., lung cancer, mammary carcinoma, cancers of the neck, prostate and large intestine. In recent years lymphangiogenesis provided topic of many studies. A positive correlation was detected between expressions of VEGF-C/D and VEGFR-3 in non-small cell lun cancer. In patients with lung cancer with high expression of VEGF-C a markedly abbreviated survival was noted. Positive correlation was detected between expression of VEGF-C and VEGF-D on one hand and expression of LYVE-1 on the other in sentinel lymph nodes with metastases of neoplastic cells in patients with non-small cell lung cancer. Also, high density of lymphatic vessels and high density of intraneoplastic microvessels proved to be independent poor prognostic indices in patients with non-small cell lung cancer. Extensive hope is linked to studies on inhibitors of lymphangiogenesis, which may improve results of treatment also in tumour patients.

Zespół jadłowstrętu i wyniszczenia nowotworowego (CACS) stanowi częste i poważne powikłanie choroby nowotworowej. Występuje u 30–80% chorych. W chwili rozpoznania raka płuca nie stanowi jeszcze poważnego problemu, ale spadek masy ciała postępuje wraz z rozwojem choroby nowotworowej. Zespół ten charakteryzuje się jadłowstrętem, utratą masy ciała, osłabieniem, upośledzeniem funkcji układu immunologicznego oraz zaburzeniami metabolicznymi. Utrata masy ciała w warunkach prawidłowych pobudza apetyt i przyjmowanie pokarmu—zaburzenie tego mechanizmu jest jedną z cech CACS. Utrata masy ciała w CACS różni się od obserwowanej w przypadku głodzenia. Wiele badań koncentruje się na ocenie roli cytokin w rozwoju CACS. Przedmiotem badań są głównie TNF-α, IL-1 i IL-6. W wielu doniesieniach potwierdzono ich rolę w rozwoju CACS, nie brakuje też jednak wątpliwości, czy zmiany obserwowane w ich stężeniach są przyczyną, czy raczej tylko skutkiem. Część najnowszych badań koncentruje się na roli czynnika jądrowego kappa B i zapobieganiu rozwojowi CACS przez zastosowanie jego inhibitorów. Zespół jadłowstrętu i wyniszczenia nowotworowego jest niekorzystnym czynnikiem prognostycznym oraz zwiększa ryzyko powikłań leczenia onkologicznego.