thromboplastin and Carcinoma--Non-Small-Cell-Lung

Surgical treatment of lung cancer is associated with an elevated risk of thrombo-embolic complications. The question is whether the extent of pulmonary resection influences the concentration of serum coagulation system proteins.. This study aims to compare the blood coagulation activation parameters among patients undergoing pneumonectomy and lobectomy due to primary lung cancer.. A prospective study was carried out in 40 patients. Of whom, 30 underwent lobectomy and 10 treated with pneumonectomy. Serum concentrations of tissue factor (TF), tissue factor pathway inhibitor (TFPI), tissue factor pathway inhibitor-activated factor X complex (TFPI/Xa), thrombin-antithrombin complex (TAT), L-selectin, E-selectin and P-selectin were measured on the first and seventh postoperative days.. On the first postoperative day, the results of selected proteins concentrations were similar in both groups. However, on the seventh postoperative day, significantly higher concentrations of TF, TAT complex and E-selectin were found in patients who underwent pneumonectomy (median values: TF: 182.4 pg ml(-1) vs 116.6 pg ml(-1), P=0.031; TAT: 6.2 mg ml(-1) vs 3.9 mg ml(-1), P=0.048; E-selectin 40.24 ng ml(-1) vs 26.54 ng ml(-1), P=0.049).. Pneumonectomy was associated with significantly higher activation of coagulation system on the seventh postoperative day than lobectomy. TAT complex, TF and E-selectin are promising markers of extensive postoperative activation of coagulation and efficacy of antithrombotic prophylaxis.

Topics: Aged; Antithrombin III; Blood Coagulation; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lipoproteins; Lung Neoplasms; Male; Middle Aged; Peptide Hydrolases; Pneumonectomy; Prospective Studies; Pulmonary Embolism; Selectins; Thromboplastin

Human blood monocytes (Mo) and monocyte-derived macrophages (M psi) possess cytotoxic effects against tumor cell lines when appropriately stimulated by various biological response modifiers, e.g., gamma interferon (gamma IFN) and muramyltripeptide (MTP). Activated Mo/M psi represent a new tool for the treatment of human malignancies, termed "adoptive cellular immunotherapy". Activated Mo/M psi express tissue factor procoagulant activity (PCA), which is a physiological trigger of blood coagulation. PCA was evaluated in vitro using a modification of the one-stage recalcification clotting time, and hemostatic changes were studied in vivo in cancer patients. Nine patients with peritoneal carcinomatosis were injected intraperitoneally with activated Mo and 11 patients with non-small cell lung carcinomas were infused intravenously with activated M psi. Hemostatic changes were followed using activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen level, antithrombin III (ATIII) and protein C (PC) activities. Fibrinolytic activity was estimated by euglobulin lysis time and assays for plasminogen and fibrin/fibrinogen degradation products (FDP). These assays were performed before and after each autologous infusion and on days 2 and 3. Activated Mo and M psi expressed potent PCA (85.5 +/- 7.5 U/ml for MTP activated Mo and 50 +/- 5.3 U/ml for gamma IFN activated M psi suspensions). In both groups of patients, APTT, PT, and TT underwent no significant variations. There was no significant consumption of ATIII or PC, and fibrinolysis was not activated during the study period. In the group injected intraperitoneally with MTP-activated Mo, fibrinogen showed a significant and progressive increase in relation to the development of an inflammatory reaction, reaching a maximum average value of 6.1 g/l at the end of the therapy with a concomitant increase in FDP levels. This increase was not observed after intravenous therapy with gamma IFN-activated M psi. No patient suffered from hemorrhagic or thrombotic events. In our experience, repeated injections of activated Mo or M psi expressing potent tissue factor PCA did not induce significant in vivo activation of the coagulation system in cancer patients.

Topics: Aged; Blood Coagulation Tests; Carcinoma, Non-Small-Cell Lung; Drug Evaluation; Female; Hemostasis; Humans; Immunotherapy, Adoptive; Lung Neoplasms; Macrophage Activation; Male; Middle Aged; Monocytes; Thromboplastin

Elevated tissue factor (TF) expression, although restricted in normal tissue, has been reported in multiple solid cancers, and expression has been associated with poor prognosis. This manuscript compares TF expression across various solid tumor types via immunohistochemistry in a single study, which has not been performed previously.. To increase insight in the prevalence and cellular localization of TF expression across solid cancer types, we performed a detailed and systematic analysis of TF expression in tumor tissue obtained from patients with ovarian, esophageal, bladder, cervical, endometrial, pancreatic, prostate, colon, breast, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and glioblastoma. The spatial and temporal variation of TF expression was analyzed over time and upon disease progression in patient-matched biopsies taken at different timepoints. In addition, TF expression in patient-matched primary tumor and metastatic lesions was also analyzed.. TF expression was detected via immunohistochemistry (IHC) using a validated TF-specific antibody. TF was expressed in all cancer types tested, with highest prevalence in pancreatic cancer, cervical cancer, colon cancer, glioblastoma, HNSCC, and NSCLC, and lowest in breast cancer. Staining was predominantly membranous in pancreatic, cervical, and HNSCC, and cytoplasmic in glioblastoma and bladder cancer. In general, expression was consistent between biopsies obtained from the same patient over time, although variability was observed for individual patients. NSCLC biopsies of primary tumor and matched lymph node metastases showed no clear difference in TF expression overall, although individual patient changes were observed.. This study shows that TF is expressed across a broad range of solid cancer types, and expression is present upon tumor dissemination and over the course of treatment.

Topics: Carcinoma, Non-Small-Cell Lung; Female; Glioblastoma; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Squamous Cell Carcinoma of Head and Neck; Thromboplastin

Thrombosis is a common complication of advanced cancer, yet the cellular mechanisms linking malignancy to thrombosis are poorly understood. The unfolded protein response (UPR) is an ER stress response associated with advanced cancers. A proteomic evaluation of plasma from patients with gastric and non-small cell lung cancer who were monitored prospectively for venous thromboembolism demonstrated increased levels of UPR-related markers in plasma of patients who developed clots compared with those who did not. Release of procoagulant activity into supernatants of gastric, lung, and pancreatic cancer cells was enhanced by UPR induction and blocked by antagonists of the UPR receptors inositol-requiring enzyme 1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Release of extracellular vesicles bearing tissue factor (EVTFs) from pancreatic cancer cells was inhibited by siRNA-mediated knockdown of IRE1α/XBP1 or PERK pathways. Induction of UPR did not increase tissue factor (TF) synthesis, but rather stimulated localization of TF to the cell surface. UPR-induced TF delivery to EVTFs was inhibited by ADP-ribosylation factor 1 knockdown or GBF1 antagonism, verifying the role of vesicular trafficking. Our findings show that UPR activation resulted in increased vesicular trafficking leading to release of prothrombotic EVTFs, thus providing a mechanistic link between ER stress and cancer-associated thrombosis.

Topics: Carcinoma, Non-Small-Cell Lung; Endoribonucleases; Guanine Nucleotide Exchange Factors; Humans; Lung Neoplasms; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Proteomics; Thromboplastin; Unfolded Protein Response

To examine the expression of D-dimer, fibrinogen (FIB), leukocyte, C-reactive protein (CRP) and tissue factor (TF) released from monocyte in non-small cell lung cancer (NSCLC) patients with or without venous thromboembolism (VTE) and analyse the correlation, to explore the possible mechanisms.. Seventy-two patients confirmed the diagnosis of lung cancer, among whom 10 with VTE were enrolled into the study from November 2012 to January 2014 in the First Affiliated Hospital of Fujian Medical University and 30 healthy subjects were also enrolled as the control group. Ficoll and Percoll density gradient centrifugation separated of peripheral blood monocyte. Monocyte TF mRNA expression was detected using reverse transcriptase-polymerase chain reaction (RT-PCR).. There were significant differences in different stages of the cancer (P < .05) and no significance among the histopathologic types (P > .05) for the expression of monocyte TF mRNA in NSCLC patients, its expression was significantly higher in cancer with lymph node metastasis than those without lymph node metastasis (P < .01). Meanwhile, in NSCLC patients with VTE, the expression of monocyte TF mRNA was significantly higher than that in patients without VTE (P < .01). Difference of the survival curves between the low monocyte TF mRNA expression and the high monocyte TF mRNA expression was significant (Log-rank x2 = 4.923, P < .05).. Monocyte TF may be a relevant source of TF-mediated thrombogenicity in NSCLC patients and may be associated with prognosis in NSCLC.

Topics: Adult; Aged; Biopsy; Bronchoscopy; Carcinoma, Non-Small-Cell Lung; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Middle Aged; Monocytes; Neoplasm Staging; Prognosis; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Thoracoscopy; Thromboplastin; Tomography, X-Ray Computed

The procoagulant status of patients with non-small cell lung cancer (NSCLC) after chemotherapy is poorly characterized and the role of platelets in hypercoagulative state of NSCLC is unknown. The aim of this study was to evaluate the procoagulant activity (PCA) of platelets in NSCLC before and after chemotherapy. The subjects were 52 patients newly diagnosed with NSCLC. The patients had decreased clotting time compared with healthy subjects, and the thrombin-antithrombin complex increased 2.5-fold after chemotherapy. Platelets in the patients after chemotherapy had enhanced phosphatidylserine (PS) exposure, and shortened coagulation time as well as increased thrombin and fibrin formation of platelets compared with those before chemotherapy. Platelet-derived microparticles increased 2-fold at day 1 and peaked at day 2 post-chemotherapy. Treatment of cisplatin in vitro also resulted in upregulated intrinsic FXa and thrombin formation on platelets with a dose-dependent manner. Platelets treated with aspirin significantly decreased PCA. However, lactadherin blocked PS and inhibited the PCA approximately by 70%. Seven days after chemotherapy, PCA of platelets restored to the baseline as that before chemotherapy, indicating that within a week of chemotherapy patient platelets are highly procoagulant and effective intervention should be taken in case of thrombosis. Our results suggested that platelets after chemotherapy had elevated PCA and may contribute to the hypercoagulative state of NSCLC. Prophylactic anti-coagulant combined with anti-platelet therapy may play an inhibitory role in thrombotic complications in NSCLC.

Topics: Aged; Antigens, Surface; Aspirin; Bleeding Time; Blood Coagulation; Blood Platelets; Carcinoma, Non-Small-Cell Lung; Cell-Derived Microparticles; Female; Humans; Lung Neoplasms; Male; Middle Aged; Milk Proteins; Phosphatidylserines; Platelet Aggregation Inhibitors; Thrombin; Thromboplastin; Thrombosis; Up-Regulation

Chimeric antigen receptor (CAR)-modified T cell (CAR T) is a promising therapeutic option for patients with cancer. Such an approach requires the identification of tumor-specific antigen targets that are expressed in solid tumors. We developed a new third-generation CAR directed against tissue factor (TF), a surface molecule overexpressed in some types of lung cancer, melanoma and other cancers. First, we demonstrated by immunohistochemistry that TF was overexpressed in squamous cell carcinoma and adenocarcinoma of non-small cell lung cancer (NSCLC) and melanoma using a human tissue microarray. In the presence of TF-positive cancer cells, the CAR-modified T cells (TF-CAR T) were highly activated and showed specific cytotoxicity to TF-positive cancer cells in vitro. In established s.c. xenograft and lung metastasis models, TF-CAR T cells could significantly suppress the growth of s.c. xenograft and metastasis of TF-positive cancer cells. Additionally, the safety evaluation of TF-CAR T cells in vivo showed that the treatment did not cause obvious toxicity in mice. Taken together, these findings indicate that TF-CAR T cells might be a novel potential therapeutic agent for the treatment of patients with TF-positive cancers.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Movement; Cell Proliferation; Cytokines; Cytotoxicity, Immunologic; Female; Humans; Immunotherapy, Adoptive; Lung Neoplasms; MCF-7 Cells; Melanoma, Experimental; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Receptors, Antigen, T-Cell; Skin Neoplasms; T-Lymphocytes; Thromboplastin; Time Factors; Transfection; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Alternative Splicing; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Prognosis; Proportional Hazards Models; Risk Assessment; Risk Factors; RNA, Messenger; Thromboplastin; Time Factors; Vascular Endothelial Growth Factor A

Tissue factor (TF), the main initiator of blood coagulation, is also a signaling protein that regulates cancer progression. TF synthesis was recently shown to be affected by tumor suppressor genes (TSGs) in tumor cell lines. We therefore studied TF gene (F3) expression and the status of genes coding for tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), and serine/threonine kinase 11 (STK11) in non-small cell lung cancer (NSCLC). Heparanase (HPSE) gene expression was also measured because this endo-beta-D-glucuronidase was recently shown to enhance TF gene expression.. TF and heparanase mRNA expression was measured by real-time PCR in 53 NSCLC tumors. Exons 5-8 of TP53 were sequenced from genomic DNA. Mutations of PTEN and STK11 were screened by multiplex ligation-dependent probe amplification.. TF mRNA levels were significantly higher in T(3)-T(4) tumors (P = 0.04) and in stages III-IV of NSCLC (P = 0.03). Mutations of TP53, STK11, and PTEN were identified in 20 (37.7%), 21 (39%), and 20 (37.7%) of tumors, respectively. TF expression was higher in mutated TP53 (TP53(Mut)) (P = 0.02) and PTEN(Mut) (P = 0.03) samples. Moreover, TF mRNA increased from 2700 copies (no mutation) to 11 6415 when 3 TSG were mutated. Heparanase gene expression did not differ according to TF gene (F3) expression or TSG mutation. The median survival time was shorter in patients with tumor TF mRNA levels above median values (relative risk 2.2; P = 0.03, multivariate analysis) and when TP53 was mutated (relative risk 1.8; P = 0.02).. These results provide clear evidence that combined oncogene events affecting TSG dramatically increase TF gene expression in lung tumors. Moreover, this study suggests that TF gene expression could be used as a prognostic marker in NSCLC.

Topics: Adult; Aged; Aged, 80 and over; AMP-Activated Protein Kinase Kinases; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Female; Glucuronidase; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Mutation; Polymerase Chain Reaction; Proportional Hazards Models; Protein Serine-Threonine Kinases; PTEN Phosphohydrolase; Survival Rate; Thromboplastin; Tumor Suppressor Protein p53

Non-small cell lung cancer (NSCLC) comprises of 75% of all lung cancers. Human full length tissue factor (flHTF), the physiological initiator of blood coagulation, is aberrantly expressed in certain solid tumors. FlHTF and its soluble isoform, alternatively spliced human tissue factor (asHTF), have been shown to contribute to thrombogenicity of the blood of healthy individuals. The aim of this study was to quantify flHTF and asHTF on mRNA and protein levels (using immunohistochemistry, immunoblotting, and ELISA) on a panel of human NSCLC tissue and plasma specimens. The tissue factor (TF) expression of 21 pulmonary adenomatous (AC) and 12 normal healthy tissues was assessed by real-time qRT-PCR. The TF protein concentration was quantified by ELISA in a subset of 11 AC and 9 normal tissue specimens as well as in the plasma of 13 lung cancer patients and 15 healthy controls. We found a significant increase in the ratio of flHTF/HGAPDH mRNA in AC (0.24+/-0.06 vs. 0.07+/-0.01; p=0.02 vs. controls) and in asHTF/HGAPDH mRNA (0.027+/-0.01 vs. 0.004+/-0.001; p=0.03 AC vs. controls). AsHTF mRNA expression was significantly lower in patients with stage IA disease compared to patients with higher grade stages, pointing to TF as being a marker of malignancy and metastases. TF protein of lung tumors was significantly increased in AC (p=0.004 vs. controls). TF in plasma was up-regulated in lung cancer patients (334.9+/-95.4 vs. 124.1+/-14.8 pg/ml; p=0.02 vs. controls). Immunohistochemical and immunoblotting data are in line with the increased TF expression, showing elevated blood thrombogenicity of NSCLC patients. The up-regulation of flHTF and, especially, asHTF in AC suggests not only a raised risk of thrombosis, but also of tumor progression, thereby, indicating a poor prognosis in these patients.

Topics: Adenocarcinoma; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Humans; Immunohistochemistry; Lung Neoplasms; Neoplasm Metastasis; RNA, Messenger; Thromboplastin; Thrombosis

Tissue factor (TF) is the physiological trigger of blood coagulation, but it could also have an important role in cancer by regulating VEGF expression and angiogenesis.. TF expression was studied by real-time PCR in lung tumors of 64 patients with non-small-cell lung cancer (NSCLC) and by immunohistochemical analysis. The gene expression of two VEGF isoforms, VEGF165 and VEGF189, was also evaluated. Microvascular density (MVD) was studied by measuring Von Willebrand Factor (VWF) mRNA levels and by immunohistochemistry using an anti-CD34 antibody.. TF mRNA levels were significantly lower than in corresponding non-affected lung tissues. However, TF expression was higher in T3-T4 tumors and this result was confirmed by immunohistochemistry. VEGF189 mRNA levels were ten times higher than those of VEGF165 and well correlated with TF mRNA levels. MVD was lower in the inner part of tumors than in the adjacent non-affected lung without being related to TF expression. Finally, codon 12 K-ras mutation was found in 8 lung carcinomas, and higher TF and VEGF189 mRNA levels were measured in mutated tissues (p < 0.001).. These results suggest that high TF expression in lung tumors may result from K-ras mutation and contribute to NSCLC progression, probably via mechanisms other than angiogenesis.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Gene Expression; Genes, ras; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Mutation; Neovascularization, Pathologic; Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Thromboplastin; Vascular Endothelial Growth Factor A; von Willebrand Factor

To evaluate the expression of tissue factor (TF), urokinase-type plasminogen activator (uPA), and urokinase-type plasminogen activator receptor (uPAR) in non-small cell lung cancer (NSCLC) tissues and to find their roles in lymph node metastasis, vascular involvement and prognosis.. Immunohistochemistry was used to examine the expression of TF, uPA, and uPAR in the tumor tissues of 97 NSCLC patients obtained during operation and 40 samples of normal lung tissues at least 5 cm away from the tumor tissues. The correlations of expression of TF, uPA, and uPAR with the clinicopathologic parameters were analyzed by chi2 test. The survival rates were calculated by Kaplan-Meier method.. TF, uPA, and uPAR were diffusely expressed in the carcinoma cell cytoplasm with the positive rates of 61.9%, 58.8%, and 61.9% respectively; however, they were only weakly expressed in the scattered macrophage and fibroblast cells in the normal lung tissues. TF expression was correlated with tumor angiogenesis as measured by microvessel density (P < 0.01); TF(34/47), uPA(33/47), and uPAR (39/47) expressions were all positively correlated with lymph node metastasis (P < 0.05, P < 0.05, and P < 0.01), and the uPAR expression was positively correlated with vascular involvement (P < 0.01). The agreement between TF and uPAR expression was significant (r = 0.432, P < 0.01). Co-expression of TF and uPAR was significantly correlated with lymph node metastasis and vascular involvement. Kaplan-Meier survival analysis showed that median the survival time of the patients with TF, uPAR and TF-uPAR positive tumor was shorter than that of the patients with TF, uPAR and TF-uPAR negative tumors (P < 0.01).. TF promotes angiogenesis, and uPAR contributes to lymph node metastasis and vascular involvement. Co-expression of TF and uPAR may play an important role in the metastasis and prognosis of NSCLC.

Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Female; Follow-Up Studies; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lung; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Prognosis; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Thromboplastin; Urokinase-Type Plasminogen Activator

Tissue factor (TF) is a type I transmembrane protein and the initiator of the extrinsic blood coagulation pathway. TF plays a critical role in tumor development and its overexpression is observed in many tumors. To understand the prevalence and relative level of TF expression in non-small-cell lung cancer (NSCLC), we analyzed 50 NSCLC tumors by immunohistochemical staining and found that 88% of human NSCLC tumors overexpressed TF. We then generated a high affinity anti-TF antibody, TF278, which specifically binds TF on the surface of cells and is internalized upon binding. An 111In-labeled TF278 demonstrated favorable tumor accumulation in an SW-900 xenograft tumor model with a maximum mean percent of injected dose per gram of tissue (%ID/g) of 73.1% at 96 hours postinjection. In addition, we labeled the antibody with 90Y and tested its ability to inhibit the growth of tumors in an SW-900 xenograft tumor model in immunocompromised mice. The 90Y-TF278 slowed the growth of SW-900 tumors at a 50 microCi dose and completely regressed SW-900 tumors at a 150 microCi dose with little toxicity.

Topics: Animals; Antibodies; Antigens; Carcinoma, Non-Small-Cell Lung; Endocytosis; Humans; Mice; Mice, Nude; Radiation Dosage; Thromboplastin; Tissue Distribution; Treatment Outcome; Xenograft Model Antitumor Assays; Yttrium Radioisotopes

Tissue factor (TF), an initiator of the extrinsic coagulation cascade, is also expressed in a wide range of cancer cells and plays an important role in cancer progression and metastasis, as well as in processes independent of the blood coagulation pathway. For example, by acting as an adhesion molecule enabling tissue invasion, TF may play a key role in the metastatic process and angiogenesis in non-small cell lung cancer (NSCLC).. To further investigate the role of TF on tumor cell invasion in NSCLC, we measured the TF mRNA expression in the tumors of 42 NSCLC patients using real-time quantitative reverse transcription - polymerase chain reaction carried out in a LightCycler. We then compared the TF mRNA expression with histological evidence of invasion of blood and lymphatic vessels by tumor cells.. Although there was no significant relationship between the TF mRNA expression and the invasion of lymphatic vessels, the TF mRNA expression was significantly higher in tumors that invaded blood vessels (Log(10) TF mRNA/GAPDH mRNA = 2.16 +/- 0.18) than in those that did not (1.59 +/- 0.16; P = 0.03).. These results suggest that TF plays a major role in blood vessel invasion by tumor cells in NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neovascularization, Pathologic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Thromboplastin

Tissue factor (TF) is an initiator of the extrinsic cascade of blood coagulation. Although recent studies have revealed a relationship between metastatic properties and TF expression in some neoplastic cells, the significance of TF in lung cancer, especially in non-small-cell lung cancer (NSCLC), is still unclear. In this study, TF was detected in NSCLC cell lines by functional study, Western blot analysis and immunocytochemical staining. TF levels in eight NSCLC cell lines were also quantitated by enzyme-linked immunosorbent assay (ELISA), and TF expression was evaluated in 55 specimens of surgically resected NSCLCs. NSCLC cell lines derived from metastatic lesions produced high levels of TF (48.3+/-23.5 ng 10(-6) cells, mean +/- s.e.m.), whereas those derived from primary lesions produced low levels of TF (0.2+/-0.1 ng 10(-6) cells). Immunohistochemical studies disclosed significantly stronger staining for TF in cells from NSCLC patients with metastasis than in those without metastasis. Among the 28 patients with metastasis, ten were strongly positive, 16 were moderately positive and two were negative for TF. In contrast, among the 27 patients without metastasis, only two were strongly positive, 18 were moderately positive and seven were negative for TF. Therefore, malignant cells from patients with lung cancer produce various levels of TF, and TF may play an important role in the metastatic process.

Topics: Biomarkers, Tumor; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Enzyme-Linked Immunosorbent Assay; Humans; Immunohistochemistry; Lung Neoplasms; Neoplasm Metastasis; Thromboplastin; Tumor Cells, Cultured

Tissue factor (TF) is the physiological initiator of blood coagulation. It has been suggested that TF also regulates tumor growth and angiogenesis. We therefore used immunohistochemistry to analyze the expression of TF and angiogenesis in non-small-cell lung carcinomas of 191 patients. A significant association was found between TF expression and microvessel density (MVD): TF-negative carcinomas more frequently exhibited low MVD. Additionally, a significant relationship between TF expression and the expression of vascular endothelial growth factor (VEGF) was discovered. TF was also compared with the resistance of the carcinomas to doxorubicin, as measured in vitro: TF-negative tumors were more frequently resistant to doxorubicin than were TF-positive tumors. Kaplan-Meier survival analysis revealed that survival times were longer in patients with TF-negative tumors than in patients with TF-positive tumors. These data suggest that TF functions as an additional angiogenic factor that could be used as a new prognostic and predictive factor for non-small-cell lung carcinomas.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Immunohistochemistry; Lung Neoplasms; Middle Aged; Neovascularization, Pathologic; Prognosis; Survival Analysis; Thromboplastin