**2.3. Impaired blood flow**

Downregulated to absent TM expression is found in metastatic foci, while forced expression of TM in transgenic mouse models of squamous cell carcinoma lacking TM expression leads to a differentiated epithelial-like phenotype—effect regulated by Snai1 transcription factor [57]. Interference of the TM-PrC system that occurs as a result of lower TM and development of acquired resistance to PrC of cellular type is one of the factors for procoagulant conversion

In response to stimuli from the tumor microenvironment, antagonistic deregulation is observed in endothelial expression of the pairs of vWF/ADAMTS13, TF TFPI, PAI-1/plasmi‐ nogen activators. Cytokine-activated endothelium releases high-molecular complexes of vWF, which are hyper-reactive to platelet aggregation, thrombus formation, and adhesion, whereas expression of ADAMTS13 depolymerase is suppressed [58]. Local procoagulant activity of endothelium is potentiated further by the effects of heparanase, which induces expression of TF and simultaneously dissociates its inhibitor TFPI from the endothelial cell surface [59]. And last but not least, the endothelial cells as a primary source of fibrinolytic activators participate in the induction of hypofibrilinolitic state by defective secretion of plasminogen activators in enhancing the expression of a fibrinolytic inhibitor PAI-1 [60]. Different mechanisms of microvascular dysfunction in combination with activated coagulation are the main pathoge‐

netic factors in the development of thrombotic microangiopathy in malignancies.

Increased angiogenic activity is due to complex processes in which fully differentiated, nonproliferating endothelial cells acquire invasive, migratory, and proliferative properties. The processes of the angiogenic switch are determined by the increased production of positive regulators of angiogenesis (VEGF, FGF2, IL-8, PIGF, FGF-β, PDGF), which originate from tumor cells—they can be mobilized from the extracellular matrix or are released by stromal cells, recruited in the tumor [61]. At the same time, many of these processes are coupled with regulatory coagulation processes. For example, endothelial growth factor VEGF, secreted by the tumor cells, increases endothelial expression of TF, which causes inverse decrease in the expression of the negative angiogenic regulator—thrombospondin [62]. Synthesis and secretion of another potent proangiogenic cytokine—interleukin-8 (IL-8) from endothelial cells —are increased, and the effect is dose dependent on the levels of fibrin deposits [63]. A similar mechanism is responsible for fibrin-induced expression of the gene for TF from umbilical vascular endothelial cells [64]. Additionally, thrombin and coagulation degradation products mediate haptotaxis of endothelial cells by selective exposure of a set of integrins. Thereby, they orientate the formation of capillaries and vasculogenesis in the direction of the angiogenic

Angiopoietin-1,2/Tie2 system is a key regulator of physiologic endothelial angiogenic activity, which controls the proliferation and differentiation of endothelial cells during embryonic development. Tie2 is an endothelial-specific receptor tyrosine kinase whose ligands are angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2). Angiopoietin-1 is secreted by perivascular cells and in complex with Tie2 stabilizes the endothelium in quiescent state and potentiates the maturation of blood vessels. Angiopoietin-2 acts as an antagonist of Ang-1/Tie2. It is

of endothelium.

8 Tumor Metastasis

stimulus [65, 66].

*2.2.3. Switch to proangiogenic phenotype*

In the context of Virchow triad, disturbed blood flow is a predisposing factor for thrombosis. Venous stasis is most often secondary—due to external compression of local or metastatic tumor masses, adenopathy—inflammation caused by the tumor. The main mechanism involves inadequate clearance of coagulation factors and local endothelial hypoxia that induces endothelial expression of TF and platelet activating factor, increased leukocyte adhesion and platelet activation. Additional predisposing factor is the prolonged immobili‐ zation of cancer patients both in hospital and at home. Additive effect of disturbances clearance of activated coagulation factors and hypoxic endothelial damage in conditions of prolonged immobilization contribute to the development of a thrombotic process.
