Microcirculation Research Group

Angiogenesis

The growth maturation and remodelling of new blood vessels from an existing host vascular network is a prerequisite for the growth and development of primary and secondary tumours. Whilst this is a critical step in the development of tumours, the process occurs in a limited range of healthy tissues such as the ovary and endometrium during the menstrual cycle, in healing wounds and tissue remodelling. Angiogenesis is a complex, highly regulated process comprising a multifactorial cascade of events which involves degradation of components of the extracellular matrix, followed by the migration, proliferation and differentiation of endothelial cells to form tubules and eventually new vessels. The process is regulated by a balance of endogenous angiogenesis stimulators (such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and the angiopoeitin family), and inhibitors (such as angiostatin, endostatin and thrombospondin) in addition to proteolytic enzymes (such as matrix metalloproteinases), their natural inhibitors, (tissue inhibitors of metalloproteases (TIMPs)) and the local production of cytokines.

The Coagulation Cascade

Usually controlling blood loss during vascular damage, this is normally inactive due to the balance between pro- and anti-coagulant proteins in the bloodstream. However, when damage to the vascular endothelium occurs, exposure of the subendothelial matrix mobilizes both haemostatic and angiogenic systems to prevent excessive bleeding into the surrounding tissues, and subsequently repairs the defects in the vessel wall. Given this interplay, it is hardly surprising that angiogenesis and coagulation cascade interact in a manner that has implications for the design of treatments for cancer. Blood coagulation and fibrinolysis influence tumour angiogenesis directly, thereby contributing to tumour growth. Moreover, platelets, which play a central role in the coagulation cascade, release numerous factors that stimulate or inhibit angiogenesis. In addition elements of the coagulation cascade act as regulators of angiogenesis, including tissue factor, thrombin and fibrin.