Immunologic Identification of Tissue Factor (Thromboplastin) Synthesized by Cultured Fibroblasts

The proliferative capacity of bone marrowcells from thymus-deprived nude mice wasinvestigated in lethally irradiated recipients. Although the colony-forming capacityof these cells was found to be similar tothat of normal littermates, a reduction inthe number of nucleated cells was observed in the bone marrow of nude mice.Moreover when the radioprotective effectof such cells was studied, it was foundthat 5 x 10⁵ or 2 x 10⁶ bone marrowcells from nude mice were less effectivein restoring hemopoiesis and establishingpermanent chimerism than similaramounts of bone marrow cells of normalcontrols. In addition, irradiated animalssurviving after injection of bone marrowcells from nude mice were found to havelower immune responses to SRBC thannormal chimeras. The possibility that mortality of irradiated recipients injected withbone marrow of nude mice is due to thepresence of a latent infective agent or ofsome inhibitory factor of hematopoiesis inthe bone marrow of such nude mice isshown to be improbable. Alternatively it issuggested that nude mice suffer from anintrinsic defect in the proliferative capacityof their bone marrow colony-forming cells(CFUs).

Submitted on February 12, 1973 Revised on March 29, 1973 Accepted on April 20, 1973     

Factor analysis of the WISC and WISC-R: A Polish comparison

The factor structures of the WISC and WISC-R were secured for a group of Polish fourth-grade students (N = 30). Consistent with American findings, the WISC Verbal, Performance, and Full Scale IQs were higher than those on the WISC-R. On both measures, factor results favor the two-factor solution, which approximates Wechsler's Verbal and Performance scales. A third factor, which failed to simulate Freedom from Distractibility, accounted for approximately 10% of the explained variance. On this factor, Coding was heavily weighted, but Arithmetic and Digit Span loadings ranged from modest to negative. Results provide support for the application of the Wechsler instruments in cross-cultural settings and for interpreting the third factor according to the dynamics of specific cultures.     

In vitro stimulation of monocyte tissue factor activity by autologous platelets

Washed human platelets were found to enhance phytohemagglutinin (PHA)-stimulated tissue factor (TF) synthesis when incubated with autologous mononuclear cell cultures. Furthermore, platelets increased TF synthesis even when no other stimulator was present during the incubation. Experiments utilizing similar cultures derived from blood of patients with Glanzmann's disease, von Willebrand's disease, and platelet storage pool disease indicated that platelets with each of these genetic defects possessed the capacity to enhance the synthesis of this initiator of coagulation by unstimulated cells as did normal platelets. The degree of platelet enhancement varied between individuals, but for any given donor, the extent of the effect depended on the concentration of platelets used. The effect was demonstrable at platelet/monocyte ratios ranging from a low of approximately 15 to the highest ratio used, about 300. For comparison the ratio of these two cellular elements in normal human blood is estimated to be approximately 1,000. These findings may reflect a relationship between these two cell types that can occur in vivo.     

Rationale for clinical trials of coagulation: reactive drugs in hepatocellular carcinoma

Evidence for the regulation of cancer growth by components of the blood coagulation mechanism provides abundant opportunity for the development of novel hypotheses for the experimental treatment of malignancy. Information available on the heterogeneity in mechanisms of interaction between various cancer cell types, and procoagulant and fibrinolytic pathways, platelets, glycosaminoglycan-regulated growth factors and cell-adhesion molecules indicates that insightful clinical trial design may allow targeting of individual cancer cell types with agents capable of intercepting mechanisms of growth control that are relevant to specific tumor types. This paper reviews the evidence that the common anticoagulant, heparin, inhibits hepatocellular carcinoma cell proliferation and hepatocellular carcinoma tumor dissemination in experimental animals. Clinical trials of heparin performed to date have shown increased tumor response rates and survival in other tumor types. Expression of urokinase-type plasminogen activator by hepatocellular carcinoma cells enhances tumor cell proliferation, motility, invasiveness and metastatic dissemination. Inhibition of the urokinase-type plasminogen activator/plasmin system by protease inhibitors such as aprotinin (Trasylol, Bayer) have shown improvement in the clinical course of certain tumor types. These data suggest that drugs that are well-known in the field of vascular medicine may find a role in the treatment of hepatocellular carcinoma, a common tumor type that has resisted containment by other means.     

Occurrence of components of fibrinolysis pathways in situ in neoplastic and nonneoplastic human breast tissue

The occurrence and distribution of components of fibrinolysis pathways were determined using immunohistochemical techniques applied to 10 cases of primary carcinoma of the breast, normal breast tissue obtained from two patients undergoing reductive mammoplasty, and three cases of benign breast tumors. Tumor cells stained for urokinase- and tissue-type plasminogen activators, plasminogen activation inhibitor-1, plasminogen, and plasmin-antiplasmin complex neoantigen. The tumor connective tissue stained for fibrinogen and its D fragment plasmin digestion product. By contrast, only occasional nonneoplastic duct epithelial cells stained for urokinase- and tissue-type plasminogen activators and there was little or no staining for the other antigens tested. These results are consistent with the existence of local amplification of expression of enzymatically active plasminogen activators, and particularly of urokinase-type plasminogen activator, in situ in primary breast cancer tissue. These features distinguish malignant from benign breast tissue and may modulate neoplastic progression through an effect on tumor cell proliferation, invasion, and metastatic dissemination.     

Clotting factors in tumour tissue: implications for cancer therapy

Considerable progress has been made recently in understanding the mechanisms and significance of coagulation activation in human malignancy. Neoplastic cells may activate coagulation reactions directly, that is through contact with coagulation factors; or indirectly by formation of cytokines capable of activating certain host cells such as macrophages or endothelial cells. Data suggest that at least two autoregulatory pathways involving components of coagulation and fibrinolysis pathways exist. In one of these, tumour cell procoagulants lead to generation of thrombin in the tumour periphery. Thrombin is a mitogen that may also contribute to tumour stoma formation. Alternatively, tumour cells may express urokinase responsible for generation of cell surface-related proteolysis that may facilitate tumour cell proliferation, invasion and metastasis. An appreciation of these diverse mechanisms may permit rational design of clinical trials of agents capable of interrupting relevant pathways.