Inhibition of malignant angiogenesis

Abstract

Angiogenesis is the formation of new blood vessels. It is a dominant feature in various angiogenic diseases such as diabetic retinopathy, arthritis, haemangiomas and psoriasis (I-4). Tumour growth is highly dependent on angiogenesis: every increase in the tumour-cell population must be preceded by an increase in new capillaries that converge upon the tumour, and thus angiogenesis has been directly correlated with tumour growth and metastasis (5). Neovascularization assists the shedding of cells from the primary tumour (61, and decreased angiogenesis is associated with a decreased number of metastases (7). An angiogenic process maintaining tumour growth can be inhibited and retarded by specific agents targeted to the signal transduction pathway. For example, when a tumour lacking high-affinity receptors for basic fibroblastic growth factor (bFGF) was grown in nude mice, the stimulatory effect of systemic bFGF could be blocked by the administration of neutralizing monoclonal antisera to bFGF (8). Angiogenesis starts and develops in response to two sets of extracellular signals: soluble angiogenic factors and insoluble extracellular matrix factors. It is a cascade of processes involving microvascular endothelial cells at several levels (Figure I). Endothelial cells are stimulated to degrade the basement membrane and to migrate into the perivascular stroma. Migrating endothelial cells produce type IV collagenase and other members of the matrix metalloproteinase family and serine proteinases. They also initiate a capillary sprout (9). Many of the endothelial cells that comprise tumour-associated vasculature are in an immature, cycling and activated state, in contrast to the endothelial cells associated with normal tissue and organ blood vessels. Under normal physiological conditions, the formation of new blood vessels is tightly repressed. The switch to the angiogenic phenotype involves a change in the local equilibrium between positive and negative regulators of angiogenesis. This may provide an anticancer strategy to eliminate endothelial cells associated with malignancy. The turnover time of vascular endothelium in normal tissues is several years, whereas the turnover of tumour endothelial cells resembles that of bone marrow cells being approximately 5 days. Angiogenic molecules may stimulate endothelial cells to proliferate as rapidly as bone marrow cells (IO). Tumour neovascularization is mediated by angiogenic molecules, which