ABSTRACT
Non-small cell lung cancer (NSCLC) is the most commonly diagnosed cancer and the most frequent cause of cancer-associated mortality worldwide. Tesmin (MTL5) is a 60 kDa protein which has cysteine rich motifs, characteristic of metallothioneins. Tesmin expression was first observed in germ cells during spermatogenesis. Increased tesmin expression in NSCLC has been described previously. Minichromosome maintenance proteins (MCMs) serve a critical role in replication and cell cycle progression, i.e. in NSCLC. The aim of the present study was to evaluate the localization and intensity of tesmin, MCM5 and MCM7 protein expression in NSCLC and their association with the clinicopathological data of patients. Archival paraffin blocks of 243 cases of NSCLC and 104 non-cancerous tissue samples from the surgical margin (control) were obtained from patients treated at the Clinic of Thoracic Surgery of Wroclaw Medical University (Wroclaw, Poland) between 2010 and 2016, and were used for tissue microarrays and immunohistochemical (IHC) experiments. Laser capture microdissection was used for the isolation of cancer cells from 36 frozen samples of NSCLC and 8 control samples, and subsequently, MTL5, MCM5 and MCM7 mRNA expression was detected separately by reverse transcription-quantitative PCR. Positive cytoplasmic and nuclear tesmin, as well as nuclear MCM5 and MCM7 IHC expression were observed in 95.1, 83.67, 95.51 and 100% of the NSCLC cases, respectively. MTL5, MCM5 and MCM7 mRNA expression was observed in 91.66% of the cancer cases for all genes. The statistical analysis revealed increased tesmin IHC expression in cancer cells compared with the control. A positive correlation was observed between the IHC expression of nuclear tesmin and MCM5 proteins (r=0.33; P<0.0001) and nuclear tesmin and MCM7 proteins (r=0.315; P<0.0001). In addition, a positive correlation between the mRNA expression levels of MTL5 and MCM5 (r=0.421; P<0.05), MTL5 and MCM7 (r=0.557; P<0.01) was demonstrated. The survival analysis revealed that the presence of IHC cytoplasmic tesmin expression was a positive prognostic marker in NSCLC (P=0.0524). Furthermore, in vitro experiments performed on the NCI-H1703 cell line revealed that silencing of MTL5 mRNA and tesmin caused the downregulation of the expression levels of MCM5 and MCM7 and decreased the number of cells in the G2 phase. A positive association among tesmin, MCM5 and MCM7 could indicate a possible role of tesmin in the proliferation of NSCLC cancer cells.
ABSTRACT
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.
Subject(s)
Adenocarcinoma/genetics , Lung Neoplasms/genetics , MicroRNAs/genetics , SOXF Transcription Factors/genetics , 3' Untranslated Regions , A549 Cells , Adenocarcinoma/metabolism , Adenocarcinoma of Lung , Aged , Aged, 80 and over , Cell Line, Tumor , Cell Nucleus/metabolism , Down-Regulation , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/metabolism , Male , Middle Aged , SOXF Transcription Factors/metabolismABSTRACT
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.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma/metabolism , Lung Neoplasms/metabolism , Metallothionein/metabolism , Animals , Biomarkers, Tumor/genetics , Carcinoma/pathology , Humans , Lung Neoplasms/pathology , Metallothionein/geneticsABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung/diagnosis , Lung Neoplasms/diagnosis , SOXF Transcription Factors/genetics , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cells, Cultured , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Prognosis , SOXF Transcription Factors/metabolismABSTRACT
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.
Subject(s)
Nerve Tissue Proteins/metabolism , Skin Diseases/metabolism , Skin Neoplasms/metabolism , Skin/metabolism , Adult , Aged , Aged, 80 and over , Carcinoma, Basal Cell/metabolism , Carcinoma, Squamous Cell/metabolism , Female , Humans , Keratosis, Actinic/metabolism , Male , Metallothionein 3 , Middle AgedABSTRACT
BACKGROUND: Nogo-B was recently shown to be involved in proliferation, apoptosis and invasiveness of cancer cells, whereas its specific receptor (NgBR) was found to be up-regulated in estrogen receptor-α positive breast cancer. No data are currently available concerning their expression in non-small cell lung carcinomas (NSCLC). MATERIALS AND METHODS: Expression of Nogo isoforms and NgBR was studied in 191 NSCLC. RESULTS: Higher Nogo-A/B immunoreactivity was noted in cancer cells of squamous cell carcinomas (SQC) compared to adenocarcinomas (p<0.001). Stage II-IV tumors had the lowest Nogo-A/B expression (p<0.0001) compared to stage I cases. Nogo-A/B expression decreased with increasing SQC malignancy grade (p=0.026). Significant NgBR mRNA down-regulation was associated with larger primary tumor size (p=0.039), lymph node involvement (p=0.039) and advancement stage (p=0.0054). Low NgBR mRNA expression predicted poor patients outcome (p=0.029). CONCLUSION: The current data may point to the involvement of Nogo isoforms and NgBR in the pathogenesis of NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung/chemistry , Lung Neoplasms/chemistry , Myelin Proteins/physiology , Receptors, Cell Surface/physiology , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/etiology , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Immunohistochemistry , Lung Neoplasms/etiology , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Myelin Proteins/analysis , Myelin Proteins/genetics , Neoplasm Staging , Nogo Proteins , Protein Isoforms/analysis , Protein Isoforms/genetics , Protein Isoforms/physiology , RNA, Messenger/analysis , Receptors, Cell Surface/analysis , Receptors, Cell Surface/geneticsABSTRACT
BACKGROUND: Over the last years, evidence has accumulated that an increased expression of pyruvate kinase M2 isozyme (PKM2) is related to neoplastic transformation as well that its plasma concentrations might be a marker of lung cancer progression. MATERIALS AND METHODS: In the present manuscript an immunohistochemical technique was used to detect the expression of two pyruvate kinase isoforms: PKM1 (muscle isozyme of PK) and PKM2 as well Ki-67 antigen on paraffin sections of 218 cases of non-small cell lung cancer (NSCLC) of different histological types and grades of malignancy. RESULTS: A significant correlation between expressions of both pyruvate kinase isoforms in all NSCLC types was found (r=0.42, p<0.0001). Expression levels of PKM1 and PKM2 were independent of the histological classification of the tumor and patients' clinicopathological data. CONCLUSIONS: PKM2 and PKM1 have no value as predictive markers of NSCLC regardless of the histological type and grade of malignancy.
Subject(s)
Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/pathology , Carrier Proteins/biosynthesis , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Membrane Proteins/biosynthesis , Thyroid Hormones/biosynthesis , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/biosynthesis , Cytoplasm/enzymology , Female , Humans , Immunohistochemistry , Ki-67 Antigen/biosynthesis , Male , Middle Aged , Neoplasm Grading , Paraffin Embedding , Prognosis , Thyroid Hormone-Binding ProteinsABSTRACT
Sarcoidosis is a granulomatous disease of unknown cause. It could affect many organs, including nervous system. A forty two years old female patient with neurosarcoidosis is described. The disease began with the lung and thoracic lymph nods involvement. After mediastinoscopy sarcoidosis was histopathologicaly confirmed. A few months after the diagnosis of neurological symptoms appeared in the form of seizure, the vibration of the eyelids and numbness around the mouth. MRI revealed changes in the brain typical for neurosarcoidosis. After corticosteroids treatment excellent recovery was achieved, confirmed in next MRI.
Subject(s)
Central Nervous System Diseases/diagnosis , Sarcoidosis/diagnosis , Adrenal Cortex Hormones/therapeutic use , Adult , Brain/pathology , Central Nervous System Diseases/drug therapy , Central Nervous System Diseases/pathology , Female , Humans , Magnetic Resonance Imaging , Remission Induction , Sarcoidosis/drug therapy , Sarcoidosis/pathologyABSTRACT
BACKGROUND: Podoplanin, a small mucin-type transmembrane protein has been shown in several studies to be expressed in cancer-associated fibroblasts (CAFs) and affect patient outcome. MATERIALS AND METHODS: We evaluated podoplanin expression in CAFs in a cohort of 257 patients with invasive ductal breast carcinomas (IDCs) using three different assessment scales based on the number of positive cells alone or in combination with the reaction intensity. RESULTS: Two of the utilized scales yielded prognostic information concerning patients' overall survival (OS), but scores were not independent prognostic factors in the multivariate analysis. On the contrary, two scales based on the combination of cell positivity and reaction intensity had no significant impact on patients' OS, but they were significantly correlated with a greater number of analysed clinicopathological parameters. CONCLUSION: In summary, podoplanin expression in CAFs may be considered a possible marker of poor prognosis in IDC, however, caution should be taken as the results varied regarding the utilized scales.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/mortality , Carcinoma, Ductal, Breast/mortality , Fibroblasts/pathology , Membrane Glycoproteins/metabolism , Stromal Cells/pathology , Adult , Aged , Aged, 80 and over , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , Female , Fibroblasts/metabolism , Follow-Up Studies , Humans , Immunoenzyme Techniques , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prognosis , Stromal Cells/metabolism , Survival RateABSTRACT
BACKGROUND: Currently, there is little knowledge concerning expression of metallothionein-III (MT-III), also known as growth-inhibitory factor, in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In this study, we evaluated MT-III expression in 184 patients using immunohistochemistry and in 61 cases using real-time polymerase chain reaction. RESULTS: MT-III mRNA expression was significantly higher in NSCLC as compared to non-malignant lung tissues (NMLT; p<0.0086). MT-III expression was noted in the cytoplasm and nucleus of cancer cells. Significantly lower nuclear MT-III (p<0.0001) expression and significantly higher cytoplasmic MT-III (p=0.0068) expression was noted in the pneumocytes of NMLT, as compared to NSCLC. Nuclear MT-III expression was significantly higher in G1 cases as compared to G2 (p=0.0308) and G3 (p=0.0194) cases. Low cytoplasmic MT-III expression was associated with larger primary tumour size (p=0.0378). Lower MT-III mRNA and cytoplasmic MT-III expression was associated with poor patient outcome (p=0.0410 and p=0.0347, respectively). CONCLUSION: MT-III expression may have an impact on the pathogenesis of NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung/etiology , Gene Expression Regulation, Neoplastic , Lung Neoplasms/etiology , Nerve Tissue Proteins/physiology , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Nucleus/chemistry , Female , Humans , Immunohistochemistry , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Metallothionein 3 , Middle Aged , Nerve Tissue Proteins/analysis , Nerve Tissue Proteins/genetics , RNA, Messenger/analysisABSTRACT
Metallothioneins (MT) are intracellular, low molecular weight proteins (6-7 kDa) involved in binding of metal ions, scavenging of free radicals, cell proliferation and apoptosis and resistance to certain chemotherapeutics. Four basic families of MT proteins are distinguished: MT-I, MT-II, MT-III, MT-IV, within each of them different isoforms occur. The study aimed at examining the expression level of nine MT isoforms: MT-1A, -1B, -1E, -1F, -1G, -1H, -1X, MT-2A and MT-IV by using real-time PCR and MT-I/II expression by immunohistochemical (IHC) technique in 69 cases of non-small cell lung cancer (NSCLC) and 12 non-malignant lung tissues (NMLT) and to correlate them with patients clinicopathological data and Ki-67 antigen expression. Out of all the analyzed cases, 62 (89.9%) demonstrated an increased MT-I/II expression. MT-1B, 1F, -1G, -1H and MT-1X were significantly up-regulated, whereas MT-1E was significantly down-regulated in NSCLC as compared to NMLT. Only in two cases MT-IV mRNA expression was noted. Significant positive correlations were observed between each particular MT isoform expressions. Higher MT-1F and MT-1A mRNA expression was associated with larger primary tumor size (P=0.0362 and P<0.0001, respectively). Moreover, up-regulated MT-1F mRNA expression was associated with higher grade of malignancy of NSCLC (P=0.0085). Higher MT-1B mRNA expression was associated with squamocellular and adenocarcinoma subtype of NSCLC (P=0.0358). Univariate analysis showed, that up-regulated MT-1F and MT-2A mRNA predicted poor patients' survival (P=0.0206 and P=0.0097, respectively). The levels of MT-1F and MT-2A mRNA could be considered as new markers of poor prognosis of NSCLC patients.
Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/metabolism , Metallothionein/biosynthesis , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Down-Regulation , Female , Humans , Ki-67 Antigen/biosynthesis , Lung Neoplasms/pathology , Male , Metallothionein/genetics , Middle Aged , Neoplasm Grading , Prognosis , Protein Isoforms/biosynthesis , RNA, Messenger/biosynthesis , Up-RegulationABSTRACT
BACKGROUND: Metallothioneins (MTs) are low molecular weight proteins present both in normal and neoplastic cells. They protect cells from the effects of heavy metals and from damage induced by free radicals. MT bind heavy metals, exert an anti-apoptotic effect and stimulate proliferation of neoplastic cells. The role of MTs in carcinogenesis has not been fully clarified yet. This study aimed at the evaluation of the intensity of metallothionein (MT-I/II) expression in various histological types of non-small cell lung cancer (NSCLC) and correlation of the expression intensity with clinical/pathological parameters and Ki-67 and minichromosome maintaince protein 2 (MCM-2) proliferation markers. PATIENTS AND METHODS: The studies were performed on archival material, originating from 145 patients, 105 men and 40 women (65 adenocarcinomas, 67 squamous cell carcinomas, 13 large cell carcinomas). RESULTS: A positive correlation was noted between expression of MT-I/II and expressions of Ki-67 (r=0.1863, p=0.0248) and MCM-2 (r=0.1766, p=0.0336) in NSCLC overall. The most pronounced expression of MT-I/II was noted in the large cell carcinomas. The expression of MT-I/II was significantly lower in the adenocarcinomas than in the squamous cell carcinomas (p=0.0028) and large cell carcinomas (p=0.0485). The expression of MT-I/II showed no differences related to individual degrees of NSCLC malignancy. Univariate analysis demonstrated no significant differences in overall survival related to the expression intensity of MT-I/II, Ki-67 or MCM-2, but the survival of the patients with high expression of MT-I/II and Ki-67 in the neoplastic cells, as compared to low expression of MT-I/II and Ki-67, was shorter (the difference approached statistical significance, p=0.067). CONCLUSION: MT-I/II expression is evident in proliferating NSCLC neoplastic cells, pointing to the prognostic importance of parallel expression of MT-I/II and Ki-67.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Cycle Proteins/metabolism , Cell Proliferation , Ki-67 Antigen/metabolism , Lung Neoplasms/metabolism , Metallothionein/metabolism , Nuclear Proteins/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Neoplasms/pathology , Male , Minichromosome Maintenance Complex Component 2ABSTRACT
INTRODUCTION: Leptin, protein taking part in body mass regulation, might play a role in cancer cachexia development. The aim of the study was to measure leptin serum levels in cachectic, non-cachectic lung cancer patients, healthy controls and to correlate leptin concentration with nutritional status markers. MATERIAL AND METHODS: 40 lung cancer patients were enrolled into the study: 20 with cachexia, 20 without cachexia, and 10 healthy controls. Leptin serum concentration, body mass, BMI, arm circumference and skin triceps fold thickness were measured in each subject. RESULTS: Serum leptin level in cachectic cancer patients was significantly lower than in non-cachectic and healthy controls. Leptin concentration correlated with body mass, arm circumference and skin triceps fold thickness. CONCLUSIONS: Cachectic lung cancer patients have significantly lower serum leptin concentrations than non-cachectic patients and healthy controls which may suggest, that leptin does not play an important role in cancer cachexia development. Leptin levels positively correlate with good nutritional status markers. Non-cachectic lung cancer patients have similar leptin serum levels as healthy controls.
Subject(s)
Cachexia/blood , Leptin/blood , Lung Neoplasms/blood , Adolescent , Adult , Aged , Biomarkers/blood , Cachexia/etiology , Female , Humans , Lung Neoplasms/complications , Male , Middle Aged , Nutritional Status , Young AdultABSTRACT
We describe the case of a 61-year-old male patient, in which the search for the cause of chronic respiratory failure, severe pulmonary hypertension and secondary erythrocytosis resulted in a diagnosis of combined pulmonary fibrosis and emphysema (CPFE). This is a unique, recently characterised syndrome with upper-lobe emphysema and pulmonary fibrosis of the lower lungs. The cause is unknown, but one of the main risk factor remains smoking. The patient was a heavy smoker (over 40 pack-years). He complained of dyspnoea on exertion and cough. Physical examination revealed basal crackles and cyanosis. The patient had severe reduction in diffusing capacity, out of proportion to his lung volumes (DLCO 27% of predicted value, FEV1 2.95 l (100%), FVC 4.41 l (118%), FEV1/FVC (66%). The blood gas showed hypoxemia (pO2 37 mm Hg), hypocapnia and respiratory alkalosis. Diagnosis was based on chest computer tomography, which revealed upper lobe emphysema and lower lobe ground glass changes and honeycombing. Severe pulmonary hypertension (SPAP 80 mm Hg) was confirmed by echocardiography and right cardiac catherisation. The patient received long-term oxygen therapy, inhaled corticosteroid and Ca-blocker.
Subject(s)
Hypertension, Pulmonary/etiology , Nicotiana/adverse effects , Pulmonary Emphysema/diagnostic imaging , Pulmonary Emphysema/etiology , Pulmonary Fibrosis/diagnostic imaging , Pulmonary Fibrosis/etiology , Electrocardiography , Humans , Hypertension, Pulmonary/diagnosis , Male , Middle Aged , Pulmonary Emphysema/therapy , Pulmonary Fibrosis/therapy , Radiography , Respiratory Function Tests , SyndromeABSTRACT
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 lung 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.
Subject(s)
Lung Neoplasms/metabolism , Lymphangiogenesis , Animals , Humans , Vascular Endothelial Growth Factor Receptor-3/metabolism , Vascular Endothelial Growth Factors/metabolismABSTRACT
Recent studies show that low expression of zeta chain in T and NK cell leads to impaired anti-tumour immunity in patients with cancer, poor prognosis, and shorter overall survival. Therefore, monitoring zeta 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 zeta chain and IFN-gamma 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-beta1 and IL-10 were also estimated at each time point tested. Before therapy, impaired zeta chain expression was observed in all the patients corresponding with increased levels of immuno-suppressive cytokines in sera compared with controls. Decreased IFN-gamma production in T cells from all patients was also demonstrated. In NK cells, IFN-gamma was secreted at lower levels in NSCLC patients, while in the SCLC group it was normal. After chemotherapy, restoration of zeta expression in NK cells and its insignificant increase in T cells in SCLC patents corresponding with normalization of TGF-beta secretion were noted. In contrast, NSCLC patients retained impaired zeta expression in T and NK cells. SCLC and NSCLC patients showed a profound defect in IFN-gamma 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 zeta 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.
Subject(s)
Interferon-gamma/immunology , Killer Cells, Natural/immunology , Lung Neoplasms/immunology , T-Lymphocytes/immunology , ZAP-70 Protein-Tyrosine Kinase/immunology , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cisplatin/therapeutic use , Etoposide/therapeutic use , Female , Flow Cytometry , Humans , Interferon-gamma/drug effects , Interleukin-10/blood , Killer Cells, Natural/drug effects , Lung Neoplasms/blood , Lung Neoplasms/drug therapy , Male , Middle Aged , T-Lymphocytes/drug effects , Transforming Growth Factor beta1/blood , Transforming Growth Factor beta1/drug effects , ZAP-70 Protein-Tyrosine Kinase/drug effectsABSTRACT
The cachexia-anorexia syndrome (CACS) is common and important implication of cancer. It occurs in 30% to 80% cancer patients. At the time of diagnosis of lung cancer CACS is not yet very important problem, but the weight loss increases with progression of the cancer. CACS is characterized by anorexia, weight loss, weakness, impaired immune system and metabolic dysfunction. Weight loss is a potent stimulus to food intake in normal humans. The persistence of anorexia in cancer patients, therefore, implies a failure of this adaptive feeding response. The weight loss in patients with CACS differs from that in simple starvation or anorexia nervosa. Most research effort has focused on the role of cytokines as mediators of CACS. The role of TNF-alpha, IL-1 and IL-6 in CACS development has been evaluated and confirmed in many research, but some investigators suggest that the changes in cytokines' levels could be the result rather than the cause of CACS. A few of the latest studies concentrate on the role of nuclear factor kappa B and prevention of CACS by its inhibitors. CACS is an independent predictor of shorter survival and increases the risk of treatment failure and toxicity.
Subject(s)
Anorexia/etiology , Cachexia/epidemiology , Cachexia/etiology , Lung Neoplasms/complications , Lung Neoplasms/epidemiology , Anorexia/blood , Biomarkers, Tumor/blood , Cachexia/blood , Humans , Interleukin-1/blood , Interleukin-6/blood , Lung Neoplasms/blood , Poland/epidemiology , Syndrome , Tumor Necrosis Factor-alpha/blood , Vascular Endothelial Growth Factor A/bloodABSTRACT
UNLABELLED: The pathogenesis of cancer anorexia-cachexia syndrome (CACS) is very complicated. In development of this syndrome play a role: metabolism of glucose, tumor necrosis factor (TNF), interleukin 1, interleukin 6, interferon a, interferon y, the oncological treatment and many other factors. Vascular endothelial growth factor (VEGF) is the most important proangiogenic factor. It promotes new vessels development, enhances vascular permeability and recruits monocytes. Many factors play a role in regulation of VEGF level. One of the most important is transforming growth factor beta (TGF-beta). Vascular endothelial growth factor and TGF-beta play a role in inflammation reaction too. The aim of this study was the evaluation of correlation between VEGF and TGF-beta in CACS in lung cancer. MATERIAL AND METHOD: We measured the serum level of VEGF and TGF-beta in 40 patients with lung cancer (20 with and 20 without CACS) and in control group. The serum level was measured by ELISA method. RESULTS: The correlation between VEGF and TGF-beta was not statistically significant in patients with CACS (p = 0.67), but the statistical significance was in patients without CACS (p = 0.006) and in control group (p = 0.035). CONCLUSION: Results suggest, that VEGF regulation in CACS may be more complicated.
Subject(s)
Anorexia/blood , Cachexia/blood , Lung Neoplasms/blood , Transforming Growth Factor beta/blood , Vascular Endothelial Growth Factor A/blood , Anorexia/complications , Cachexia/complications , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Lung Neoplasms/complications , Male , Middle AgedABSTRACT
Cancer anorexia-cachexia syndrome( CACS) occurs in 30-80% of patients with cancer. CACS is connected with poor prognosis and higher risk of treatment complications. CACS belongs to the common cause of death in cancer patients. Main role in the development of this syndrome play cytokines like TNF, interleukin 1 and 6 and interferon alpha and gamma. The importance of a lot of other substances is still unknown. VEGF promotes new vessels development,enhance vascular permeability and plays a role in inflammatory reaction. The aim of this study was comparison of VEGF levels in patients with lung cancer with and without CACS and in control group. The serum levels of VEGF were measured by ELISA method. The VEGF was significatly higher in patients with lung cancer then in control group (p = 0.004). There were no correlations between VEGF and weight lost, histological type and stage of disease. This suggest that VEGF doesnt play a role in development of CACS.
Subject(s)
Anorexia/etiology , Biomarkers, Tumor , Cachexia/etiology , Lung Neoplasms/blood , Lung Neoplasms/complications , Vascular Endothelial Growth Factor A/blood , Aged , Anorexia/blood , Anorexia/pathology , Cachexia/blood , Cachexia/pathology , Female , Humans , Karnofsky Performance Status , Lung Neoplasms/pathology , Male , Middle Aged , Reference Values , SyndromeABSTRACT
Tobacco dependence is a chronic, relapsing disease causing an enormous burden of deaths. The aim of the study was a one year evaluation of the efficacy of bupropion SR supported by an educational program in the treatment of nicotine dependence and analysis of the reasons of relapses. 54 smokers were enrolled. The 12-month continuous abstinence rate was 28.3%. The most common cause of relapses in the treatment period was craving for cigarettes, in the post-treatment period stress.