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.

Mechanisms Regulating Angiogenesis & Haemostasis

Angiogenesis in pre invasive and invasive breast cancer

The onset of angiogenesis in premalignant breast disease has important implications in tumour biology, as well as in the development of preventative strategies. Ongoing studies are examining the mechanisms controlling angiogenesis and lymphangiogenesis in normal breast, benign, premalignant, pre-invasive and invasive breast cancer. These innovative studies indicate that angiogenesis occurs earlier in the spectrum of breast disease then previously predicted which may be controlled by both hypoxia and non-hypoxia dependent pathways. In addition studies are investigating the expression and localisation of the proteolytic enzymes and their natural inhibitors and the growth factors which regulate angiogenesis in cancer. The role of the various elements of the haemostasis pathway are far from complete. Further insights into the relationships between angiogenesis and haemostasis in breast cancer may lead to an improved prediction of tumour grade in breast cancer and the development of more effective therapeutic strategies.

Angiogenesis and haemostasis in wound healing

In humans the mechanisms controlling, maturation, maintenance and regression during physiological angiogenesis remain unclear. In wound healing the pathways controlling haemostasis and angiogenesis are strictly regulated, therefore once elucidated should help identify the abnormal pathways in non-healing wounds and cancer. An improved understanding of the processes involved may be exploited to induce vascular regression in tumours and non healing wounds Normal skin and scar tissue is being collected from mastectomy patients and patients undergoing caesarean section. Studies are documenting the pattern and morphology of vessels, the process of cell death, protease and angiogenic factor profiles and vascular regression in the maturing scar, in addition to investigating the factors responsible for controlling capillary network formation in vitro.