Hemostasis and cerebral metastases in a model system.
TL;DR: Feinauer et al. as mentioned in this paper focus on central nervous system (CNS) metastases generated by embolization of tumor cells into the cortical capillary network in a mouse model and early thrombotic events that might facilitate metastasis.
About: This article is published in Blood.The article was published on 2021-03-04 and is currently open access. It has received None citations till now.
References
More filters
••
TL;DR: The panorama of acute microvessel responses to focal cerebral ischemia provide opportunities to understand interrelationships between neurons and their microvascular supply and changes that underlie a number of central nervous system neurodegenerative disorders.
Abstract: Cerebral microvessels have a unique ultrastructure form, which allows for the close relationship of the endothelium and blood elements to the neurons they serve, via intervening astrocytes To focal ischemia, the cerebral microvasculature rapidly displays multiple dynamic responses Immediate events include breakdown of the primary endothelial cell permeability barrier, with transudation of plasma, expression of endothelial cell-leukocyte adhesion receptors, loss of endothelial cell and astrocyte integrin receptors, loss of their matrix ligands, expression of members of several matrix-degrading protease families, and the appearance of receptors associated with angiogenesis and neovascularization These events occur pari passu with neuron injury Alterations in the microvessel matrix after the onset of ischemia also suggest links to changes in nonvascular cell viability Microvascular obstruction within the ischemic territory occurs after occlusion and reperfusion of the feeding arteries ("focal no-reflow" phenomenon) This can result from extrinsic compression and intravascular events, including leukocyte(-platelet) adhesion, platelet-fibrin interactions, and activation of coagulation All of these events occur in microvessels heterogeneously distributed within the ischemic core The panorama of acute microvessel responses to focal cerebral ischemia provide opportunities to understand interrelationships between neurons and their microvascular supply and changes that underlie a number of central nervous system neurodegenerative disorders
590 citations
••
TL;DR: The extrinsic pathway of blood coagulation is initiated when blood is exposed to non-vascular-cell–bound tissue factor in the subendothelial space and activates factors IX and X of the intrinsic and common coagulated pathways, respectively.
Abstract: Hemostasis is a physiologic mechanism that maintains blood in a fluid state within the circulation. The coagulation of blood is mediated by cellular components and soluble plasma proteins. In response to vascular injury, circulating platelets adhere, aggregate, and provide cell-surface phospholipid for the assembly of blood-clotting enzyme complexes. The extrinsic pathway of blood coagulation is initiated when blood is exposed to non-vascular-cell–bound tissue factor in the subendothelial space (Figure 1). Tissue factor binds to activated factor VII, and the resulting enzyme complex activates factors IX and X of the intrinsic and common coagulation pathways, respectively. Factor IX activated by the . . .
582 citations
••
TL;DR: Cellular events during the initiation of brain metastasis by breast cancer cells are revealed and the earliest host responses to incoming cancer cells after carotid artery injection are documents in immunodeficient and immunocompetent mouse models.
Abstract: Brain metastases are difficult to treat and mostly develop late during progressive metastatic disease. Patients at risk would benefit from the development of prevention and improved treatments. This requires knowledge of the initial events that lead to brain metastasis. The present study reveals cellular events during the initiation of brain metastasis by breast cancer cells and documents the earliest host responses to incoming cancer cells after carotid artery injection in immunodeficient and immunocompetent mouse models. Our findings capture and characterize heterogeneous astrocytic and microglial reactions to the arrest and extravasation of cancer cells in the brain, showing immediate and drastic changes in the brain microenvironment on arrival of individual cancer cells. We identified reactive astrocytes as the most active host cell population that immediately localizes to individual invading tumor cells and continuously associates with growing metastatic lesions. Up-regulation of matrix metalloproteinase-9 associated with astrocyte activation in the immediate vicinity of extravasating cancer cells might support their progression. Early involvement of different host cell types indicates environmental clues that might codetermine whether a single cancer cell progresses to macrometastasis or remains dormant. Thus, information on the initial interplay between brain homing tumor cells and reactive host cells may help develop strategies for prevention and treatment of symptomatic breast cancer brain metastases.
266 citations
••
TL;DR: It is suggested that microvascular fibrin deposition accumulates in a time-dependent manner during focal cerebral ischemia/reperfusion and that exposure of plasma to perivascular tissue factor is partially responsible for occlusion formation.
Abstract: Ischemic cerebral injury is associated with activation of the blood coagulation cascade. To elucidate the contribution of fibrin formation to microvascular injury during focal cerebral ischemia and reperfusion, we have studied the time course and the localization of fibrin deposition in cerebral microvessels and the surrounding tissues during ischemia/reperfusion in a well-described nonhuman primate model.
Cerebral tissues from adolescent male baboons were examined after 2-hour middle cerebral artery occlusion (n = 3) and after 3 hours of middle cerebral artery occlusion and 1-hour (n = 6), 4-hour (n = 3), and 24-hour (n = 4) reperfusion; tissues from control primates (n = 3) also were examined. Fibrin deposition was detected by immunohistochemical techniques using the fibrin-specific monoclonal antibody MH-1. The number and size distribution of microvessels associated with fibrin were quantified by video-imaging microscopy.
Fibrin was associated with microvessels only in the ischemic zone where severe neuronal injury was documented, its frequency increasing with the reperfusion period (F4,26 = 3.80, P < .05). Extravascular fibrin deposition was significantly increased by 24-hour reperfusion compared with the other subjects (P < .05). Preischemia infusion of the anti-tissue factor monoclonal antibody TF9-6B4 resulted in significant reduction of intramicrovascular fibrin (P < .038 versus no intervention) at 1-hour reperfusion but had no effect on extravascular fibrin deposition.
These results suggest that microvascular fibrin deposition accumulates in a time-dependent manner during focal cerebral ischemia/reperfusion and that exposure of focal cerebral ischemia/reperfusion and that exposure of plasma to perivascular tissue factor is partially responsible for occlusion formation. During ischemia the large plasma protein fibrinogen extravasates and interacts with parenchymal tissue factor, forming significant extravascular fibrin by 24 hours of reperfusion.
199 citations
••
TL;DR: It is proposed that astrocytes forming the glia limitans around the neural vasculature and deep to the meninges are intimately involved in controlling hemorrhage in the brain.
Abstract: Hemostasis in the brain is of paramount importance because bleeding into the neural parenchyma can result in paralysis, coma, and death. Consistent with this sensitivity to hemorrhage, the brain contains large amounts of tissue factor (TF), the major cellular initiator of the coagulation protease cascades. However, to date, the cellular source for TF in the central nervous system has not been identified. In this study, analysis of murine brain sections by in situ hybridization demonstrated high levels of TF mRNA in cells that expressed glial fibrillary acidic protein, a specific marker for astrocytes. Furthermore, primary mouse astrocyte cultures and astrocyte cell lines from mouse, rat, and human constitutively expressed TF mRNA and functional protein. These data indicated that astrocytes are the primary source of TF in the central nervous system. We propose that astrocytes forming the glia limitans around the neural vasculature and deep to the meninges are intimately involved in controlling hemorrhage in the brain. Finally, we observed an increase in TF mRNA expression in the brains of scrapie-infected mice. This modulation of TF expression in the absence of hemorrhage suggested that TF may function in processes other than hemostasis by altering protease generation in normal and diseased brain.
154 citations