Molecular regulation of tumor angiogenesis: mechanisms and therapeutic implications.

Angiogenesis, the process of new capillary formation from a pre-existing vessel plays an essential role in both embryonic and postnatal development, in the remodeling of various organ systems, and in several pathologies, particularly cancer. In the last 20 years of angiogenesis research, a variety of angiogenic regulators, both positive and negative, have been identified. The discovery of several anti-angiogenic factors has led to the development of novel cancer therapies based on targeting a tumor's vascular supply. A number of these new therapies are currently being tested in clinical trials in the U.S.A. and elsewhere. A major advance in the field of anti-angiogenic therapy occurred recently when the FDA approved Avastin (bevacizumab), the first solely anti-angiogenesis therapy approved for treatment of human cancer. While it has long been appreciated that tumor growth and progression are dependent on angiogenesis, it is only recently that progress has been made in elucidating the molecular mechanisms that regulate the earliest stage in the angiogenic program, the angiogenic switch. This checkpoint is characterized by the transition of a dormant, avascular tumor into an active, vascular one. Anti-angiogenic therapies to date have essentially been designed to suppress the neovasculature in established tumors. However, identifying the mechanisms that cause a tumor to acquire an angiogenic phenotype may lead to the discovery of new therapeutic modalities and complementary diagnostics that could be used to block the angiogenic switch, thereby preventing subsequent tumor progression. In this chapter on the role of angiogenesis in cancer, we (1) provide an overview of the process of angiogenesis with special regard to the molecules and physiological conditions that regulate this process, (2) review recent studies describing the use of anti-angiogenic approaches in the treatment of a variety of human cancers, and (3) discuss the recent literature focused on the study of the molecules and molecular mechanisms that may be regulating the initiation of the angiogenic phenotype in tumors, and the clinical impact that this knowledge may have in the future.