fibrin and Carcinoma--Squamous-Cell

The V2 carcinoma, established from skin carcinomas of cottontail rabbits and transplantable in all strains of domestic rabbits, is a paradigm of invasiveness attainable by squamous cell carcinoma. The main mechanisms contributing to this potential are the pressure of incessant cell proliferation, the capacity of the tumor to grow in compact as well as in dissociated formation, the synthesis of proteinases (chiefly cathepsin B and collagenases) by the tumor cells, and the latter's migratory activity. In addition, the V2 carcinoma elicits a large spectrum of host reactions which favor partly the organism, partly the tumor and thus create the complexity of the invasion phenomenon.

Topics: Animals; Carcinoma, Squamous Cell; Cathepsin B; Cathepsins; Cell Division; Cell Movement; Cottontail rabbit papillomavirus; Disease Models, Animal; Epithelium; Extracellular Matrix; Fibrin; Fibroblasts; Hypercalcemia; Leukocytes; Microbial Collagenase; Neoplasm Invasiveness; Neoplasm Transplantation; Neovascularization, Pathologic; Papilloma; Rabbits; Skin Neoplasms; Tumor Virus Infections

Lung cancer is the leading cause of cancer-related deaths worldwide, and lung squamous carcinomas (LUSC) represent about 30% of cases. Molecular aberrations in lung adenocarcinomas have allowed for effective targeted treatments, but corresponding therapeutic advances in LUSC have not materialized. However, immune checkpoint inhibitors in sub-populations of LUSC patients have led to exciting responses. Using computational analyses of The Cancer Genome Atlas, we identified a subset of LUSC tumors characterized by dense infiltration of inflammatory monocytes (IMs) and poor survival. With novel, immunocompetent metastasis models, we demonstrated that tumor cell derived CCL2-mediated recruitment of IMs is necessary and sufficient for LUSC metastasis. Pharmacologic inhibition of IM recruitment had substantial anti-metastatic effects. Notably, we show that IMs highly express Factor XIIIA, which promotes fibrin cross-linking to create a scaffold for LUSC cell invasion and metastases. Consistently, human LUSC samples containing extensive cross-linked fibrin in the microenvironment correlated with poor survival.

Topics: Animals; Biomarkers, Tumor; Carcinoma, Squamous Cell; Chemokine CCL2; Factor XIIIa; Female; Fibrin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred DBA; Monocytes; Neoplasm Invasiveness

We explored novel functions of tenascin-C by comparing mouse embryonic fibroblasts (MEFs) proficient or deficient in tenascin-C expression. Transcript profiling analysis identified tissue plasminogen activator (tPA) as the most consistently over-expressed gene in all tenascin-C deficient MEFs. This was confirmed by real-time PCR as well as by protein expression analysis. In agreement with these observations, tenascin-C deficient MEFs had an increased capacity to digest fibrin in situ. Consistently, tenascin-C expression in vivo was found to correlate with fibrin deposition in several diseases associated with tenascin-C overexpression such as fibrosis, asthma and cancer. In conclusion, the present study suggests a new role of tenascin-C as a regulator of the fibrinolytic system.

Topics: Animals; Blotting, Western; Carcinoma, Squamous Cell; Down-Regulation; Embryo, Mammalian; Female; Fibrin; Fibrinolysin; Fibroblasts; Gene Expression Profiling; Head and Neck Neoplasms; Humans; Immunohistochemistry; Lung Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Tenascin; Tissue Plasminogen Activator

A number of studies have implicated the fibrin-coagulation-fibrinolysis system in human tumour progression. Interleukin-8 (IL-8) mediates most of the angiogenic activity induced by human oral squamous cell carcinoma (OSCC) cells. We have recently demonstrated that: (1) fibrin is present in association with IL-8 expressing human OSCC cells in vivo and (2) in situ fibrin polymerisation induces a specific, dose and time-dependent upregulation of IL-8 expression from human OSCC cells in vitro. Our present studies extend this observation by demonstrating that in addition to fibrin formed in situ, both fibrin-derived liquid expressates (soluble fibrin) and preformed fibrin clots induced an over eight-fold stimulation of IL-8 expression from human OSCC cells as compared to media controls. IL-8 upregulation by soluble fibrin was dose-dependent. A monoclonal antibody against the N terminal region of the beta chain of human fibrin (Bbeta15-42) inhibited 67% of soluble fibrin-induced IL-8 expression from human OSCC cells. A peptide (GHRP), representing the sequence at the N terminus of this region, induced a dose-dependent stimulation of IL-8 expression, further confirming the role of this region. These studies directly support our hypothesis that fibrin induces protumourigenic factor expression from tumour cells, thus promoting tumour progression. Future studies to further characterise the role of the Bbeta15-42 region in tumour cell activation may lead to the design of peptide antagonists with important therapeutic potential.

Topics: Aged; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Interleukin-8; Macromolecular Substances; Male; Mouth Neoplasms; Oligopeptides; Peptide Fragments; Structure-Activity Relationship; Tumor Cells, Cultured; Up-Regulation

We have recently demonstrated that fibrin induces a specific, dose- and time-dependent upregulation of the angiogenic factor interleukin 8 (IL-8) from human oral squamous cell carcinoma (OSCC) cells in vitro. In this study we begin to test the hypothesis that fibrin induces IL-8 expression from tumor cells in vivo by studying their in vivo association in OSCC.. The presence of fibrin(ogen) was initially evaluated in 20 archival human OSCCs by means of immunohistochemistry with a polyclonal antibody. The presence of fibrin and IL-8 was then studied in 19 sections from 8 different patients' head and neck tumors (including 6 OSCCs) by means of immunohistochemistry with a monoclonal antibody against fibrin. These 8 tumors had been treated with inhibitors of new fibrin formation and degradation immediately after surgical removal.. Fibrin staining was found in 100% of the tumor sections tested. IL-8 staining was found in the cytoplasm of tumor cells in 100% of the studied tumors, including areas adjacent to fibrin.. These data demonstrate an in vivo association between fibrin and IL-8 in OSCC. These studies support our hypothesis that fibrin induces expression of protumorigenic factors such as IL-8 from tumor cells in vivo.

Topics: Antibodies; Antibodies, Monoclonal; Carcinoma, Squamous Cell; Coloring Agents; Cytoplasm; Fibrin; Fibrinogen; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Interleukin-8; Mouth Neoplasms; Tumor Cells, Cultured; Up-Regulation

In recent studies, we have demonstrated that fibrin is present in association with tumor cells in oral squamous cell carcinoma (OSCC) in vivo. We hypothesized that this fibrin can directly induce the expression of known angiogenic factors from oral tumor cells. Since IL-8 is known to be the major inducer of angiogenesis caused by these cells, we examined the ability of fibrin to stimulate IL-8 expression from OSCC cells in vitro. A physiologically relevant concentration of fibrin was found to cause a dose and time-dependent stimulation of IL-8 expression from oral and pharyngeal tumor cells but not from a non-tumorigenic oral cell line. Fibrinogen, thrombin and collagen were all unable to induce significant IL-8 expression, establishing the specificity of fibrin in causing this response. Gel filtration chromatography confirmed the molecular identity of the IL-8 antigen detected in the ELISA system used. These results suggest that fibrin may promote angiogenesis in oral tumors in vivo by directly upregulating the expression of IL-8 from tumor cells.

Topics: Analysis of Variance; Carcinoma, Squamous Cell; Cell Line; Dose-Response Relationship, Drug; Epithelium; Fibrin; Humans; Interleukin-8; Mouth Mucosa; Mouth Neoplasms; Neoplasm Proteins; Neovascularization, Pathologic; Pharyngeal Neoplasms; Stimulation, Chemical; Time Factors; Tumor Cells, Cultured

Immunohistochemistry was applied to AMeX-fixed tissue sections of 12 adenocarcinomas of the stomach (seven intestinal adenocarcinomas and five diffuse carcinomas), 12 adenocarcinomas of the pancreas (nine ductal adenocarcinomas and three signet ring carcinomas), and 12 squamous cell carcinomas of the larynx obtained at surgical resection to examine the possibility of extravascular activation of blood coagulation in cancer tissues by exploring the in loco patterns of distribution of fibrinogen, a final product of blood coagulation, fibrin, and a by-product of coagulation reactions (prothrombin fragment 1+2). Gastric, pancreatic, and laryngeal cancers exhibited fibrinogen antigen in abundance throughout the tumor stroma. Fibrin was detected along the edges of nests of carcinoma cells and at the host-tumor interface. Prothrombin fragment 1+2 was present in the blood vessels in areas of neoangiogenesis at the host-tumor interface (gastric and pancreatic cancer tissues) and on the tumor cell bodies (pancreatic and laryngeal cancer tissues). The presence of prothrombin fragment 1+2 in cancer tissues appears to be a good indicator of coagulation activation and thrombin generation at the tumor burden.

Topics: Adenocarcinoma; Biomarkers; Blood Coagulation; Carcinoma, Squamous Cell; Fibrin; Gastrointestinal Neoplasms; Immunohistochemistry; Laryngeal Neoplasms; Neovascularization, Pathologic; Pancreatic Neoplasms; Peptide Fragments; Prothrombin; Stomach Neoplasms; Stromal Cells

We present a patient with a large tumor embolus attached to a pacemaker electrode leading to multiple pulmonary emboli. At postmortem examination, this thrombus was composed of clusters of well-differentiated squamous cell carcinoma intermingled with fibrin. Tumor involvement was not evident in the myocardium, endocardium, or epicardium. The primary tumor was discovered in the lower intrathoracic esophagus. Tumor microemboli from the esophageal primary lesions may have accumulated around the pacemaker electrode due to turbulent flow in this region, producing a large and friable tumor embolus.

Topics: Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Electrodes, Implanted; Esophageal Neoplasms; Fatal Outcome; Fibrin; Hemorheology; Humans; Male; Neoplastic Cells, Circulating; Pacemaker, Artificial; Pulmonary Embolism

Extravascular fibrin deposition is frequently observed within and around neoplastic tissue and has been implicated in various aspects of tumor growth. The distribution of fibrin deposits was investigated in squamous cell carcinomas representing different stages of tumor progression of the larynx (n = 25) and hypopharynx (n = 9) by immunofluorescent techniques. Double and treble labelings were used to detect fibrinogen and fibrin in combination with marker antigens for tumor cells (cytokeratin), endothelial cells (von Willebrand factor), macrophages (recognized by KiM7), as well as factor XIII subunit A (FXIIIA) and tenascin (an embryonic extracellular matrix protein newly expressed during tumorigenesis). All tissue samples showed specific staining for fibrinogen/fibrin. Fibrin deposition was localized almost exclusively in the connective tissue compartment of tumors with characteristic accumulation at the interface of connective tissue and the tumorous parenchyma. In certain tumor samples showing highly invasive characteristics, fibrin deposits were observed in close association with tumor blood vessels in the tumor cell nodules. The overlapping reactions with polyclonal antibody to fibrinogen/fibrin and monoclonal antibody to fibrin indicate the activation of the coagulation cascade resulting in in situ thrombin activation and fibrin formation. Fibrin was crosslinked and stabilized by FXIIIA as revealed by urea insolubility test. Accumulation of phagocytozing macrophages detected by Ki M7 monoclonal antibody could be seen in areas of fibrin deposition. The blood coagulation factor XIIIA was detected in and around the cells labeled with Ki M7 antibody. Tenascin and fibrin deposits were found in the same localization in the tumor stroma and in association with tumor blood vessels within the tumor cell nodules. Neither fibrin nor tenascin were detected in the histologically normal tissue adjacent to tumors. The close association between fibrin deposits and macrophage accumulation strongly suggests the active participation of tumor-associated macrophages in the formation of stabilized intratumoral fibrin that facilitates tumor matrix generation and tumor angiogenesis.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Disease Progression; Female; Fibrin; Fibrinogen; Fluorescent Antibody Technique, Indirect; Humans; Hypopharyngeal Neoplasms; Keratins; Laryngeal Neoplasms; Macrophages; Male; Middle Aged; Neoplasm Proteins; Tenascin; Thrombophilia; Transglutaminases

Involvements of interleukin-6 (IL-6) and fibrinogen in cancer development have been independently studied. However, the association of these molecules in cancer patients remains uncertain. This study was conducted to clarify the association according to the clinicopathological characteristics of lung cancer patients.. Serum IL-6 levels assayed in 339 patients without pleural effusion were assessed according to clinical stage, histological type of the cancer and levels of fibrin (ogen) degradation products (FDP), and C-reactive protein (CRP).. Elevations of serum IL-6 levels more than 4 pg/ml were found in 37.8% of all patients. According to the clinical stage and histological type, the elevations were significantly more frequent in the advanced stage (44.7%), in squamous cell (49.1%) and large cell carcinomas (63.6%). Similarly, the frequency of the elevated cases (> 400 mg/dl) and the mean value of the fibrinogen level were also higher in the advanced stage (54.2%, 455.0 mg/dl) and large cell carcinoma (54.6%, 459.3 mg/dl), respectively. The elevations of fibrinogen, FDP and CRP levels were found to be related to those of the IL-6 level.. In lung cancer, serum IL-6 elevations are particularly frequent in the advanced stages of patients with squamous cell and large cell carcinoma, which are associated with the elevated levels of fibrinogen, suggesting a possibility that IL-6 was involved not only directly, but also indirectly, through regulating plasma fibrinogen with promotion of cancer development in vivo.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; C-Reactive Protein; Carcinoma, Large Cell; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Interleukin-6; Lung Neoplasms; Male; Middle Aged

Mechanisms of coagulation activation in situ were studied by means of immunohistochemical techniques applied to surgically resected primary adenocarcinomas and squamous cell carcinomas of the lung. Findings in these two histologic types were similar. Double-labeling techniques using macrophage-specific antibody together with antibody to either tissue factor, factor VII, factor X, or factor V revealed coincident staining for each of these coagulation factors on tumor-associated macrophages. Staining of tumor cells for these factors was rare and inconsistent. Both macrophages and fibroblasts in the tumor connective tissue stained for the a subunit of factor XIII. Fibrinogen was abundant throughout the tumor connective tissue, but staining for fibrin and D-dimer cross-linked sites of fibrin was restricted to areas adjacent to macrophages, indicating that thrombin was generated in association with tumor macrophages but not with tumor cells. By contrast, tumor cells stained diffusely for urokinase-type plasminogen activator and focally for thrombomodulin. These findings contrast with those reported previously for small cell carcinoma of the lung and suggest that coagulation activation in adenocarcinoma and squamous cell carcinoma of the lung may occur indirectly through activation of certain host cells such as macrophages. By contrast, tumor cell plasminogen activator may mediate certain aspects of the malignant phenotype in these tumor types.

Topics: Adenocarcinoma; Antibody Specificity; Antigens, Neoplasm; Blood Coagulation; Carcinoma, Squamous Cell; Fibrin; Fibrinolysis; Humans; Immunohistochemistry; Lung Neoplasms; Macrophages; Thrombin; Urokinase-Type Plasminogen Activator

A 40-year-old woman was hoarse for five months due to a pleomorphic adenoma in the false vocal cord. The peripheral, ulcerated portion of the tumor had undergone squamous metaplasia, and this was initially misdiagnosed as squamous cell carcinoma. For that reason, the patient received radiation treatment, but the tumor remained unchanged. It was then locally excised, and the patient was still free of disease 14 years later. This case illustrates the hazard of misinterpreting squamous metaplasia in pleomorphic adenoma, the resistance of this tumor to irradiation, and the satisfactory long-range response to local excision.

Topics: Adolescent; Adult; Aged; Biopsy; Carcinoma, Squamous Cell; Diagnosis, Differential; Female; Fibrin; Humans; Laryngeal Neoplasms; Male; Middle Aged; Neoplasms, Germ Cell and Embryonal

Thromboplastic and fibrinolytic activities of V2 and V7 carcinomas, the two transplantable rabbit tumors of the same viral origin, were studied in relation to fibrin deposition and thrombus formation in the tumors. Thromboplastic activity of V7 carcinoma was comparatively high, while that of V2 carcinoma was as low as that of muscle tissue. More fibrin deposits in the stroma and more thrombi in the small vessels were found at the advancing border of V7 carcinoma than that of V2 carcinoma. These differences might be associated with higher thromboplastic activity of V7 carcinoma than that of V2 carcinoma. Fibrinolytic activity of both tumors was high and it was confirmed to be localized in the tumor cells by Todd's method. Fibrin deposits in the stroma were found more abundantly somewhat apart from the advancing border of the tumor nests of both tumors. It was suggested that plasmin activated by plasminogen activator released locally from the tumor cells might digest fibrin deposited in the stroma just close to the tumor nests.

Topics: Animals; Carcinoma, Squamous Cell; Fibrin; Fibrinolysis; Male; Neoplasms, Experimental; Plasminogen Activators; Rabbits; Thromboplastin; Thrombosis

Topics: Adenocarcinoma; Adult; Aged; Alpha-Globulins; Blood Coagulation Disorders; Blood Protein Electrophoresis; Bronchial Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Heparin; Humans; Infusions, Parenteral; Lung Neoplasms; Macroglobulins; Male; Middle Aged; Time Factors

Topics: Blood Vessels; Carcinoma, Squamous Cell; Chemical Precipitation; Female; Fibrin; Humans; Uterine Cervical Neoplasms