thromboplastin and Carcinoma

Factor VIIa (FVIIa)-induced signal transduction is strongly dependent on cellular surface expression of Tissue Factor (TF) and Protease Activated Receptors (PARs). FVIIa signals primarily through PAR2. This contrasts to thrombin which signals primarily via PAR1 and does so without the assistance of a co-receptor, but by binding to an exosite on PAR1. Various TF:FVII-mediated cellular activities are now well documented and have indicated possible links to inflammation, atherosclerosis, angiogenesis, tissue repair, tumor growth and metastasis. Further knowledge about cellular responses induced by coagulation factors has been obtained by gene-expression profiling of MDA-MB-231 cells stimulated with FVIIa or alternatively with PAR1 or PAR2 agonist peptides. These studies and qPCR measurements of the transcription of selected genes in these and other carcinoma cell lines have provided new information about gene expression induced by PAR activation, the gene repertoire induced by TF:FVIIa via PAR2, and how it differs from that induced via PAR1 by thrombin.

Topics: Breast Neoplasms; Carcinoma; Cell Line, Tumor; Factor VIIa; Female; Gene Expression Profiling; Humans; Protein Array Analysis; Receptor, PAR-1; Receptor, PAR-2; Signal Transduction; Thromboplastin

Tissue factor (TF) expression in human cancers has been associated with a procoagulant state and facilitation of metastasis. This study was conducted in order to evaluate if TF was expressed in canine mammary tumours. Forty epithelial mammary tumours from 28 dogs were included. TF expression of the tumours was evaluated by immunohistochemistry using a polyclonal antibody against recombinant canine TF. In addition, thromboelastography, haemostatic and inflammatory parameters were evaluated in the patients. TF was recognized in 44% of benign and 58% of malignant tumours. TF localized to the cytoplasmic membrane of neoplastic luminal epithelial cells and/or diffusely in the cytoplasm. No association was found between TF expression and stage or grade of disease. A significant association between TF expression and antithrombin and plasminogen was found, and extensive TF expression was seen in a lymph node metastasis classified as anaplastic mammary carcinoma from a dog with concomitant disseminated intravascular coagulation (DIC).

Topics: Adenoma; Animals; Antithrombins; Biomarkers, Tumor; Blood Coagulation; Carcinoma; Dog Diseases; Dogs; Female; Gene Expression Regulation, Neoplastic; Inflammation; Mammary Neoplasms, Animal; Neoplasm Grading; Neoplasm Staging; Plasminogen; Thromboplastin

Colorectal cancer (CRC) is a major cause of morbidity and mortality, and the composition of the tumour stroma is a strong predictor of survival in this cancer type. Tissue factor (TF) functions as the trigger of haemostasis together with its ligand coagulation factor VII/VIIa, and TF expression has been found in tumour cells of colorectal tumours. However, TF expression in the CRC tumour stroma or its relationship to patient outcome has not yet been studied. To address this question we developed and validated a specific anti-TF antibody using standardised methods within the Human Protein Atlas project. We used this antibody to investigate TF expression in normal colorectal tissue and CRC using immunofluorescence and immunohistochemistry in two patient cohorts. TF was strongly expressed in a cell population immediately adjacent to the colorectal epithelium. These TF-positive cells were ACTA2-negative but weakly vimentin-positive, defining a specific population of pericryptal sheath cells. In colorectal tumours, TF-positive sheath cells were progressively lost after the adenoma-to-carcinoma transition, demonstrating downregulation of this source of TF in CRC. Furthermore, loss of sheath cell TF was significantly associated with poor overall and disease-specific survival in rectal but not colon cancers. In conclusion, we demonstrate that TF is a marker of a specific cell population in the large intestine, which is lost during CRC progression. Our results highlight the role of the tumour stroma in this cancer type and suggest TF to be a potential prognostic biomarker in rectal cancers through the identification of pericryptal sheath cells.

Topics: Adenoma; Aged; Aged, 80 and over; Carcinoma; Colorectal Neoplasms; Disease Progression; Female; Humans; Immunohistochemistry; Intestine, Large; Male; Middle Aged; Stromal Cells; Thromboplastin

Procoagulant full-length tissue factor (flTF) and its minimally coagulant alternatively spliced isoform (asTF), promote breast cancer (BrCa) progression via different mechanisms. We previously showed that flTF and asTF are expressed by BrCa cells, resulting in autoregulation in a cancer milieu. BrCa cells often express hormone receptors such as the estrogen receptor (ER), leading to the formation of hormone-regulated cell populations.. To investigate whether TF isoform-specific and ER-dependent pathways interact in BrCa.. Tissue factor isoform-regulated gene sets were assessed using ingenuity pathway analysis. Tissues from a cohort of BrCa patients were divided into ER-positive and ER-negative groups. Associations between TF isoform levels and tumor characteristics were analyzed in these groups. BrCa cells expressing TF isoforms were assessed for proliferation, migration and in vivo growth in the presence or absence of estradiol.. Ingenuity pathway analysis pointed to similarities between ER- and TF-induced gene expression profiles. In BrCa tissue specimens, asTF expression was associated with grade and stage in ER-positive but not in ER-negative tumors. flTF was only associated with grade in ER-positive tumors. In MCF-7 cells, asTF accelerated proliferation in the presence of estradiol in a β1 integrin-dependent manner. No synergy between asTF and the ER pathway was observed in a migration assay. Estradiol accelerated the growth of asTF-expressing tumors but not control tumors in vivo in an orthotopic setting.. Tissue factor isoform and estrogen signaling share downstream targets in BrCa; the concomitant presence of asTF and estrogen signaling is required to promote BrCa cell proliferation.

Topics: Alternative Splicing; Breast Neoplasms; Carcinoma; Cell Division; Cell Line, Tumor; Cell Movement; Disease Progression; Estradiol; Estrogens; Female; Gene Expression Profiling; Humans; Integrin beta1; Neoplasm Grading; Neoplasm Proteins; Neoplasm Staging; Neoplasms, Hormone-Dependent; Protein Isoforms; Receptors, Estrogen; Signal Transduction; Software; Thromboplastin; Tissue Array Analysis

Hypoxia up-regulated expression of tissue factor (TF) may facilitate tumor cell metastasis, but transcriptional mechanisms remain undefined.. To verify the role of Egr-1 in hypoxia-induced TF expression in breast cancer cells, quantitative PCR and Western blot analysis were performed. The secretion of VEGF under hypoxia was detected by enzyme-linked immunosorbent assay (ELISA). Egr-1 and HIF-1α siRNA were transiently transfected into breast cancer cells to evaluate their specific roles.. The increased Egr-1 expression occurring in hypoxic breast cancer cells can up-regulate TF expression and stimulating protein 1(Sp1) was not responsible for the hypoxia-induced expression of TF. HIF-1α mediated the hypoxia-induced up-regulation of TF expression through vascular endothelial growth factor (VEGF). The regulatory effects of Egr-1 on TF under hypoxia were independent of HIF-1α. Either Egr-1 or HIF-1α was responsible for hypoxic induction of tumor cells adhesion. HIF-1α, but not Egr-1, had a pivotal role in human breast cancer cells invasion. Both Egr-1 and HIF-1α were critical to angiogenesis induced by hypoxic conditions in MDA-MB-231 and HUVEC co-cultures. In nude mice, both Egr-1 and HIF-1α small interfering RNA (siRNA) could decrease extravasation of MDA-MB-435 cells in the lung after tail vein injection.. Hypoxia-induced expression of TF in human breast cancer cells depends on Egr-1 and HIF-1α, and both of these proteins may play an important role in breast cancer metastasis, either directly or indirectly through the TF pathway.

Topics: Animals; Breast Neoplasms; Carcinoma; Cell Hypoxia; Cells, Cultured; Coculture Techniques; Early Growth Response Protein 1; Female; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Nude; Neoplasm Metastasis; Thromboplastin

Tissue factor (TF), which has a role in normal tissue haemostasis, was reported to be aberrantly expressed, associated with higher microvascular density and a poor prognosis in intestinal-type gastric adenocarcinoma in the Japanese population. This is the first study to look at the relationship of TF and the metaplasia-adenoma-carcinoma sequence (MACS) of gastric cancer in a European population.. The expression of TF was examined immunohistochemically in 191 gastric tissue samples: (13: normal; 18: intestinal metaplasia; 160: gastric adenocarcinoma) from the European population.. TF was not expressed in normal gastric mucosal cells. A strong intensity of staining was found in intestinal metaplasia cells but in 2 of 18 samples. TF expression increased with advancing stage of gastric cancer (P<0.0001, Jonckheere's test for ordered medians). Stage 3-4 gastric cancers preferentially expressed TF (34%, P=0.04). In comparison with the Japanese study, TF was not expressed at a higher level in intestinal vs diffuse-type gastric cancers and expression had 'no prognostic' significance.. TF may be involved in tumour progression along the MACS of gastric cancer in the European population and is shown to start in precancerous lesions. However, clinical features may differ due to differences in biological features in the two populations, as reflected by differences in TF expression profile.

Topics: Adenocarcinoma; Adenoma; Adult; Aged; Aged, 80 and over; Carcinoma; Disease Progression; Female; Gastric Mucosa; Humans; Immunohistochemistry; Male; Metaplasia; Middle Aged; Prognosis; Stomach; Stomach Neoplasms; Thromboplastin; White People

RNA processing is vital for the high fidelity and diversity of eukaryotic transcriptomes and the encoded proteomes. However, control of RNA processing is not fully established. Σ RNA is a class of conserved large non-coding RNAs (murine Hepcarcin; human MALAT-1) up-regulated in carcinomas. Using antisense technology, we identified that RNA post-transcriptional modification is the most significant global function of Σ RNA. Specifically, processing of the pre-mRNAs of genes including Tissue Factor and Endoglin was altered by hydrolysis of Σ RNA/MALAT-1. These results support the hypothesis that Σ RNA/MALAT-1 is a regulatory molecule exerting roles in RNA post-transcriptional modification.

Topics: Alternative Splicing; Animals; Antigens, CD; Carcinoma; Cells, Cultured; Endoglin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Nuclear Proteins; Oligonucleotide Array Sequence Analysis; Oligonucleotides, Antisense; Rats; Receptors, Cell Surface; RNA Precursors; RNA Processing, Post-Transcriptional; RNA-Binding Proteins; RNA, Long Noncoding; RNA, Neoplasm; RNA, Untranslated; Serine-Arginine Splicing Factors; Thromboplastin

Advanced pancreatic cancer is associated with a high risk of patients developing venous thromboembolism. This increased risk is thought to be tumour-driven and associated with tissue factor (TF) and microparticles. The aim of this study was to investigate the role of TF and phospholipid expression in the procoagulant properties of pancreatic cell lines and microparticles. Pancreatic cancer cell lines (MIA-PaCa-2, ASPC-1 and CFPAC-1) were assessed for expression of TF and microparticle release. Procoagulant potential was determined by a prothrombin time assay. Cell surface expression of TF was highest in CFPAC-1, with low expression on ASPC-1 and little/no expression on MIA-PaCa-2. Clotting time (CT) was cell number and TF-dependent (P < 0.001). Blocking of TF resulted in slower CT for CFPAC-1 and ASPC1 and prevented clotting in MIA-PaCa-2. Microparticles were shown to be procoagulant and the majority of procoagulant potential could be removed by passing cell-free media through a 0.1 μm filter. A dose-dependent CT was observed in both ASPC-1 and CFPAC-1 cell-free media. Furthermore, addition of duramycin prevented microparticle-supported coagulation. The data presented suggest a key role for cell and microparticle surface-expressed TF and phospholipids in coagulation and highlight duramycin-mediated disruption of clotting.

Topics: Adenocarcinoma; Adult; Aged; Bacteriocins; Blood Coagulation; Blood Coagulation Tests; Carcinoma; Cell Line, Tumor; Cell-Derived Microparticles; Culture Media, Conditioned; Female; Humans; Male; Middle Aged; Organ Specificity; Pancreas; Pancreatic Neoplasms; Peptides; Phosphatidylethanolamines; Phosphatidylserines; Prothrombin Time; Thrombin; Thromboplastin; Venous Thromboembolism

Tissue factor (TF) is the major physiological initiator of the coagulation cascade and has an important function in the morbidity and mortality associated with many disease states, including cancer-associated thrombosis and atherosclerosis. TF normally exists in a partially encrypted state and its de-encryption on circulating monocytes, platelets or endothelial cells by inflammatory mediators can lead to thrombosis. Furthermore, many cancer cells express large amounts of TF and these cells communicate readily with the circulation through the fenestrated tumor endothelium. To assess agents or conditions that modulate the encryption state of TF, we developed a continuous assay for the determination of TF procoagulant activity (PCA) in a cell-based system. We have shown the use of this assay at detecting agents that de-encrypt TF thereby leading to an increase in TF PCA in three cancer cell lines, namely, T24/83 bladder carcinoma cells and PC-3 and DU145 prostate cancer cells. Further, through use of this assay, we have shown that the endoplasmic reticulum calcium pump inhibitor, thapsigargin, stimulates the de-encryption of TF. The continuous assay for the determination of TF PCA proved to have inherently less intra- and inter-assay variability than the widely used discontinuous assay and is considerably less labor intensive. Further, the continuous assay produced progress curves that were compatible with curve fitting to allow for the determination of the nature of reaction as well as rate constants for the underlying enzymes, TF/FVIIa and FXa. The continuous assay for the assessment of TF PCA on intact cells is applicable for high-throughput screening to allow for the determination of compounds that modulate TF PCA.

Topics: Biomarkers, Tumor; Carcinoma; Cell Line, Tumor; Cell Physiological Phenomena; Cell Survival; Endoplasmic Reticulum; Enzyme Inhibitors; Humans; Immunoblotting; Neoplasm Proteins; Thapsigargin; Thromboplastin; Urinary Bladder Neoplasms

Expression of the principal initiator of coagulation, tissue factor (TF), by colorectal cancer (CRC) cells is involved in tumoral angiogenesis and metastasis progression, after binding of factor VIIa (FVIIa) to TF and generation of TF-FVIIa activity. We thus hypothesized that inhibition of the TF pathway by active site-blocked FVIIa (FFR-FVIIa) may prevent the development of hepatic metastasis in CRC.. Rat tumoral cells (DHDK12 proB cells) expressing high levels of TF were injected in the portal vein in syngenic BDIX rats. Rats received intraperitoneal injection of either FFR-FVIIa, from d 3 to d 7 (adjuvant treatment) (n = 19), or solvent buffer (n = 18) (control group). Additionally, cancer cells were infused subcutaneously in 20 other rats, which were assigned to FFR-FVIIa adjuvant treatment (n = 10), or buffer treatment (n = 10). Macroscopic and histological analysis was performed at d 14.. In the control group, infusion of cancer cells resulted in development of macroscopic hepatic tumors in 17/18 rats. In the adjuvant FFR-FVIIa group, macroscopic hepatic tumors were visible on the liver surface in 3/19 rats (P = 0.002 versus control). All rats with subcutaneous injection of proB cells exhibited macroscopic tumors, with no significant difference between the control and the treated ones.. Inhibition of the proteolytic activity of TF-FVIIa complex blunted hematogenous hepatic metastasis, suggesting that TF-FVIIa is a relevant target for the prevention of hepatic metastasis in CRC. TF-blocking agents should be investigated as adjuvant treatment in this setting.

Topics: Animals; Carcinoma; Cell Line, Tumor; Colorectal Neoplasms; Factor VIIa; Liver Neoplasms; Male; Neoplasm Metastasis; Neoplasms, Experimental; Rats; Thromboplastin

Tissue factor (TF) is the principal physiologic initiator of coagulation. It also plays an important role in tumor growth and metastasis possibly by contributing to angiogenesis. We evaluated the expression of TF in benign and malignant prostate tissue and correlated it with the expression of the pro-angiogenic protein, vascular endothelial growth factor (VEGF). We used a tissue microarray (TMA) constructed from 80 archival prostatectomy specimens. Core samples were collected from benign prostate tissue (BP) (n= 77), high-grade prostatic intraepithelial neoplasia (PIN) (n= 26), and carcinoma (PCa) (n= 93). TMA sections were stained with an immunopurified polyclonal TF antibody and a rabbit polyclonal VEGF. Two pathologists manually scored staining in epithelial cells using the German Immunoreactive Score. Positive staining for TF was seen predominantly in PCa with rare positive glands in BP and PIN. TF expression was significantly lower in BP versus PCa specimens (p< .001) and in PIN versus PCa specimens (p< .001). Positive staining for VEGF was seen in PCa, BP, and PIN. Rates of VEGF expression were also significantly lower in BP versus PCa specimens (p= .003) but not in PCa versus PIN (p= .430). The majority of PCa samples positive for TF were also positive for VEGF (p< .001). Our findings reinforce the link between angiogenesis and TF expression in PCa. We suggest further exploration of TF-mediated pathways leading to increased tumor aggressiveness in PCa, and the possible use of anti-TF agents in PCa.

Topics: Carcinoma; Humans; Immunohistochemistry; Male; Neovascularization, Pathologic; Prostatectomy; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Thromboplastin; Tissue Array Analysis; Vascular Endothelial Growth Factor A

Thromboembolic complications are frequently associated with advanced cancer. Interestingly, one of the major initiators of blood coagulation, tissue factor (TF), is reported to be overexpressed in several tumor types and can be found on both tumor cells and tumor vasculature. Although the exact mechanisms have yet to be elucidated, TF expressed on tumor cells can trigger intracellular signaling events through various pathways that can lead to tumor angiogenesis, proliferation, and metastasis. There exists preclinical evidence that disruption of TF dependent signaling can effectively inhibit tumor cell migration, metastasis, and angiogenesis. Here, we report for the first time that an antibody to tissue factor can also prevent tumor growth in vivo. Prophylactic administration of CNTO 859, a humanized anti-human TF antibody, was shown to inhibit experimental lung metastasis of MDA-MB-231 human breast carcinoma cells by over 99% compared to a control antibody. Furthermore, therapeutic doses of CNTO 859 were shown to reduce tumor incidence and growth of orthotopically implanted MDA-MB-231 cells.

Topics: Animals; Antibodies, Monoclonal; Breast Neoplasms; Carcinoma; Cell Proliferation; Female; Humans; Immunoglobulin G; Lung Neoplasms; Mice; Mice, Inbred Strains; Thromboplastin; Xenograft Model Antitumor Assays

Interaction between platelet and carcinoma cell contributes to pathogenesis of cancer-related thrombosis and metastasis. This study investigated whether physical exercise affects platelet-nasopharyngeal carcinoma cell (NPC) interaction and platelet-promoted tissue factor (TF) and matrix metalloproteinase (MMP) activities of NPC. Thirty sedentary men performed on three occasions moderate-intensity exercise [MIE, 60% maximal oxygen consumption (V(.)o(2max)) for 40 min] and high-intensity exercise (HIE, up to V(.)o(2max)), with and without warm-up exercise (WUE, 60% V(.)o(2max) for 20 min) on a bicycle ergometer. Before and immediately after exercise, platelet-NPC aggregation, the TF, MMP-2 and MMP-9 expressions and activities, and TF pathway inhibitor (TFPI) and tissue inhibitor of MMP-1 levels of NPC and platelet were measured. The results of this study demonstrated that HIE enhanced platelet-NPC aggregation in the presence of fibrinogen and was accompanied by increased platelet-promoted TF activity, expression of NPC, decreased platelet-promoted MMP-2 and MMP-9 activities, and TFPI release of NPC, whereas these alterations to HIE on platelet-NPC interactions were ameliorated by WUE pretreatment. Conversely, MIE reduced the formation of platelet-NPC aggregates, but did not change the TF, TFPI, MMP-2, MMP-9, tissue inhibitor of MMP activities, and/or levels of NPC mediated by platelet. It is concluded that HIE may enhance aggregation and coagulation and reduce MMP bioactivity related to platelet-NPC interactions, by raising the binding affinity to fibrinogen and TF activity and expression and lowering TFPI release and MMP-2 and -9 activities. These effects on HIE diminish after WUE. However, MIE minimizes the risk of thrombosis induced by platelet-NPC interactions.

Topics: Adult; Blood Platelets; Carcinoma; Cell Aggregation; Exercise; Humans; Lipoproteins; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Thromboplastin; Thrombosis; Tissue Inhibitor of Metalloproteinase-1

Tissue factor (TF) is a procoagulant that plays an important part in tumor angiogenesis. We sought to determine the role of preoperative serum TF levels in predicting clinical outcome in patients with ovarian cancer.. TF expression was determined by reverse transcriptase polymerase chain reaction in ovarian cell lines. Using enzyme-linked immunosorbent assay, we assessed preoperative serum TF levels in 98 women with invasive epithelial ovarian carcinoma, 30 with low malignant potential (LMP) tumors, 16 with benign tumors, and a separate validation group of 39 women with adnexal masses. Clinical information was gathered from chart review.. TF was expressed in four of the five ovarian cancer cell lines, but absent in the nontransformed cells. Ovarian cancer patients had a median preoperative serum TF level of 85.2 pg/mL, which was significantly higher than in those with LMP tumors (12.8 pg/mL; P < .01) and benign adnexal disease (30.7 pg/mL; P < .01). TF >or= 190 pg/mL was significantly associated with decreased patient survival (P < .01). After adjusting for other clinical variables in a multivariate Cox regression model, TF >or= 190 pg/mL was an independent prognostic factor (P < .01). Analysis of serum TF levels from the validation set confirmed that high TF (>or=190 pg/mL) was associated with a 3.4-fold increase in risk of death from disease (P = .02) and shorter survival (P = .01).. Preoperative serum TF levels are significantly elevated in patients with ovarian carcinoma. Elevated preoperative TF level is an independent prognostic factor for death from disease.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma; Cell Line, Tumor; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Profiling; Humans; Middle Aged; Neovascularization, Pathologic; Ovarian Neoplasms; Predictive Value of Tests; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Survival Analysis; Thromboplastin

Colorectal cancer is the third most often cause of morbidity and mortality due to cancer in Poland. Thromboembolic complications are common events during the course of the disease. It is well known that hemostatic proteins play an important role in cancer progression. The purpose of the study was to evaluate the in loco interactions among colorecatal cancer and coagulation factors. 21 cases of G2 colorectal adenocarcinoma obtained during surgical resection were examined. Immunohistochemical procedures according to ABC method were employed. Tissue factor (TF) and coagulation factors II, VII, X, IX were observed in cancer cells and except factors II and IX--in tumor associated macrophages. TF was also demonstrated in endothelial cells of small blood vessels. Strong expression of fibrinogen was observed among connective tissue at some distance around malignant tumor while weaker expression was found in tumor stroma. Expression of F(1+2), the by-product of thrombin generation, was revealed in cancer cells, macrophages and in the tumor stroma. The results indicate extravascular activation of blood coagulation in loco in colorectal cancer that is TF-dependent.

Topics: Blood Coagulation; Blood Coagulation Factors; Carcinoma; Colorectal Neoplasms; Factor IXa; Factor VII; Factor X; Fibrin; Fibrinogen; Humans; Immunohistochemistry; Neovascularization, Pathologic; Prothrombin; Thromboplastin

Tissue factor (TF), the cell-surface receptor for coagulation factor VIIa, supports metastasis. Equally important for this process are (a) interactions of the TF cytoplasmic domain, which binds the mobility-enhancing actin-binding protein 280, and (b) the formation of a proteolytically active TF-VIIa complex on the tumor cell surface. In primary bladder carcinoma cells, we find that this complex localizes to the invasive edge, in proximity to tumor-infiltrating vessels that stain intensely for TF pathway inhibitor (TFPI-1), the major inhibitor of the protease activity of the complex. In culture, binding of VIIa to TF-expressing tumor cells is sufficient to allow cell adhesion, migration, and intracellular signaling on immobilized TFPI-1. Immobilized heparin, a mimic for extracellular matrix-associated proteoglycans, binds physiological concentrations of TFPI-1 in a conformation that supports TF-VIIa-dependent cell adhesion. Consistent with a functional role of TFPI-1 in complex extracellular matrices, we show that TF cooperates with integrin-mediated adhesion and migration on composite matrices that contain ligands for both integrins and the TF-VIIa complex. This study thus provides evidence for a novel mechanism of protease-supported migration that is independent of proteolytic matrix degradation but rather involves protease-dependent bridging of TF's extracellular domain to an ECM-associated inhibitor.

Topics: Carcinoma; Cell Adhesion; Cell Movement; Cysteine Endopeptidases; Dose-Response Relationship, Drug; Endopeptidases; Epithelium; Factor VIIa; Fibronectins; Glycoproteins; Heparin; Humans; Immunohistochemistry; Lipoproteins; Neoplasm Proteins; Pregnancy Proteins; Signal Transduction; Thromboplastin; Tumor Cells, Cultured; Urinary Bladder Neoplasms

The blood coagulation mechanism may support tumor progression by several mechanisms including promotion of cell proliferation and angiogenesis. Immunohistochemical procedures were applied to AMeX-fixed sections of twelve cases of squamous cell carcinoma of the larynx obtained at surgical resection to determine the presence and distribution of tissue factor (TF), tissue factor pathway inhibitor (TFPI), other coagulation factors, fibrinogen, and fibrin in situ. TF antigen was present in normal squamous epithelial cells and tumor cells, predominantly in immature tumor cells in the vicinity of the host-tumor interface. Tumor cells stained also for factors VII and X. Staining for TFPI antigen was demonstrated in the connective tissue stroma adjacent to the tumor, in microvascular endothelial cells, and in normal squamous epithelial cells. Fibrinogen and factor XIIIa were distributed throughout the tumor connective tissue stroma. Fibrin (thrombin-cleaved fibrinogen) was detected at the host-tumor interface and along the margins of tumor nodules. Tumor cells in carcinoma of the larynx express a functional, TF-initiated pathway of blood coagulation. Interpretation of these findings together with the results of clinical trials of inhibitors of TF-induced coagulation activation versus effects of inhibitors of TF expression suggest novel approaches to the experimental therapy of laryngeal carcinoma.

Topics: Blood Coagulation; Carcinoma; Humans; Laryngeal Neoplasms; Lipoproteins; Neovascularization, Pathologic; Thromboplastin

Topics: Breast; Breast Neoplasms; Carcinoma; Female; Humans; Immunohistochemistry; Pregnancy; Thromboplastin

Tissue factor (TF) is an integral membrane glycoprotein which, as the receptor and essential cofactor for coagulation factors VII and VIIa (FVII and FVIIa, respectively), is the primary cellular activator of the coagulation protease cascade. Previous studies on the procoagulant activity of a variety of cell types (either lysed or in the intact state) have variously been interpreted as showing that TF is either stored intracellularly or is present in a cryptic form in the surface membrane. Using mAbs to TF, we have directly investigated the subcellular localization and functional activity of TF in lipopolysaccharide-stimulated blood monocytes and J82 bladder carcinoma cells. Blocking of surface TF of viable cells with inhibitory anti-TF mAbs abolished greater than 90% of TF activity of the intact cells as well as of lysed cells. Furthermore, quantitative analysis of the binding of FVII and anti-TF mAb to J82 cells demonstrated that all surface-expressed TF molecules were capable of binding the ligand, FVII. By immunoelectron microscopy, TF was present only in the surface membrane of monocytes and J82 cells, although the latter also contained apparently inactive TF antigen in multivesicular bodies. On the intact cell surface the catalytic activity of the TF-FVIIa complex was investigated and found to be markedly less relative to cell lysates. Membrane alterations that affect the cofactor activity of TF may be a means of regulating the extent of initiation of the coagulation protease cascade in various cellular settings.

Topics: Antibodies, Monoclonal; Carcinoma; Cell Compartmentation; Cell Membrane; Factor VII; Factor Xa; Humans; Immunoenzyme Techniques; In Vitro Techniques; Lipopolysaccharides; Microscopy, Electron; Monocytes; Serine Endopeptidases; Thromboplastin; Tumor Cells, Cultured; Urinary Bladder Neoplasms

A new epithelial cell line derived from undifferentiated carcinoma of human renal pelvis, designated KP 1, was established in vitro. The cell line has been passaged 190 times in vitro for 5 years and 9 months. The predominant cell in KP 1 was a tear-drop-shaped cell. Doubling time of the cell line was 35 h. The malignant epithelial character of this line was verified by carcinogenicity in the subcuticular layer of nude mice and by karyotypic analysis which revealed the cells to be completely aneuploid with a model chromosome number in the hypertriploid range. KP 1 cells were shown to produce both tissue thromboplastin and plasminogen activator which was immunologically identical to urokinase, the plasminogen activator in urine.

Topics: Animals; Carcinoma; Cell Line; Female; Humans; In Vitro Techniques; Karyotyping; Kidney Neoplasms; Kidney Pelvis; Mice; Middle Aged; Plasminogen Activators; Thromboplastin

Experiments were made to evaluate the potential role played by thrombogenic factors on the hematogenous arrest of circulating tumor cells in mice with demonstrable coagulopathies associated with the presence of a primary tumor, by administration of "therapeutic" doses of anticoagulants. The effects of warfarin, aspirin and heparin administration on the early arrest patterns of 125IdUrd-labelled TA3 carcinoma and Gardner lymphosarcoma cells injected intravenously into tumor-bearing mice were examined. Several hematologic parameters of carcinoma- and lymphosarcoma-bearing animals were measured prior to anticoagulation experiments and the results indicated that mice had coagulopathies similar to those found in cancer patients with disseminated intravascular coagulation syndrome, i.e., thrombocytopenia and elevated fibrinogen levels. Despite the presence of coagulation abnormalities and effective anticoagulation in recipient animals, all three agents were without effect on localization patterns of both tumor types. It was concluded that the proposed involvement of thrombogenesis in metastasis was probably not due to any role played by those clotting factors inhibited by aspirin, warfarin and heparin in early intravascular tumor cell arrest.

Topics: Animals; Anticoagulants; Aspirin; Blood Coagulation; Carcinoma; Heparin; Lymphoma, Non-Hodgkin; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Neoplastic Cells, Circulating; Thromboplastin; Warfarin

Topics: Adenocarcinoma; Adult; Aged; Animals; Blood Coagulation; Carcinoma; Disseminated Intravascular Coagulation; Female; Fibrinolysis; Humans; Male; Middle Aged; Prothrombin; Rabbits; Stomach Neoplasms; Thrombin; Thromboplastin

Topics: Adult; Aged; Arthritis; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Carcinoma; Factor VIII; Female; Fibrinolysin; Hepatitis; Humans; Liver Diseases; Male; Middle Aged; Necrosis; Rectal Neoplasms; Thrombin; Thromboplastin; Vaginal Neoplasms

Topics: Adult; Blood Circulation Time; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Breast Neoplasms; Carcinoma; Factor XI; Factor XI Deficiency; Female; Hemorrhage; Hemorrhagic Disorders; Humans; Mastectomy; Methods; Microscopy, Phase-Contrast; Plasma Substitutes; Prothrombin Time; Thromboplastin

Topics: Animals; Carcinoma; Cautery; Electrocoagulation; Mice; Neoplasms, Experimental; Thromboplastin

Topics: Carcinoma; Humans; Neoplasm Recurrence, Local; Stomach Neoplasms; Thrombophlebitis; Thromboplastin