Significance of tumor microenvironment on the genesis of: Interstitial fluid, angiogenesis, haemostatic/haemorheologic abnormalities. Pathogenesis and therapeutic aspects

In order for tumors to grow more than a few millimetres in size, new vasculature must be established. However, the new vascular support is generally inefficient, poorly organized and cannot keep up with the pace of the tumor proliferation. This creates undernourished and hypoxic regions in a new environment, with neo-vasculature having a perturbed structure and function. Two abnormalities are peculiarly important. The first is an excessive leakiness of the endothelium due to a malfunction of Starling's law that regulates liquid distribution across the endothelium, resulting in increased accumulation of liquid in the tumor interstitium. The second is the enhanced procoagulant activity of the endothelium, as shown by numerous clinical and experimental findings on the interaction between the tumor and the coagulation and fibrinolytic systems. Through these interactions, tumor growth and dissemination are enhanced while the tumor can generate a matrix supporting neoangiogenesis. In the unique tumor microenvironment, both endothelial cells and tumor cells express a wide variety of factors, including procoagulants, cell adhesion molecules, vasomotor substances and cell survival signals. The up-regulation by tumor microenvironment of MET oncogenes and other hemostatic oncogenes further contribute to alterations of the hemostatic balance. Platelets (PLTs), leukocytes (LKs), and red blood cells (RBCs) behave differently in the tumor capillary lumen, than in normally capillary lumen, such as being more hemoconcentrated. These alterations create the conditions for an anomalous hemorheology and leukocyte endothelium interaction. PLTs, LKs, and RBCs may bind to the fibrin that envelopes tumor cells in the capillary lumen, and form a cocoon-like structure that protect them from colliding with the endothelium, and from immune surveillance, and thus not eliminated by the body's defensive system. This feature contributes partially to tumor progression and metastasization. We believe that these findings may have important therapeutic implications. In this overview, an attempt will be made to describe how tumor cells abrogate normal physiologic mechanisms to suit the environment for their own purposes and review the common pathways between coagulation, angiogenesis and the unique tumor patho-physiology.