by Arjan Griffioen, Tumor Angiogenesis Laboratory, University Hospital, Maastricht, The Netherlands, a.griffioen at intmed.unimaas.nl
- Formation of new blood vessels
Definition of Angiogenesis
Angiogenesis is the formation of new capillary vasculature out of pre-existing blood vessels under the regulation of growth factors and inhibitors. It occurs in physiological (e.g. wound healing, ovulation, placental growth) and pathological (e.g. cancer, arthritis, inflammation) conditions .
The formation of new blood vessels out of preexisting capillaries, or angiogenesis, is a sequence of events that is of key importance in a broad array of physiologic and pathologic processes. Normal tissue growth such as in embryonic development, wound healing and the menstrual cycle is characterized by dependence on new vessel formation for the supply of oxygen and nutrients as well as removal of waste products. Also, in a large number of different and non-related diseases, formation of new vasculature is involved in abnormal physiology. Among these pathologies are diseases such as tissue damage after reperfusion of ischemic tissue or cardiac failure, where angiogenesis is low and should be enhanced to improve disease conditions. In a larger number of diseases excessive angiogenesis is part of the pathology. These diseases include cancer (both solid and hematologic tumors), cardiovascular diseases (atherosclerosis, restenosis), chronic inflammation (rheumatoid arthritis, Crohn's disease), diabetes (diabetic retinopathy), psoriasis, endometriosis and adiposity. These diseases may benefit from therapeutic inhibition of angiogenesis. The initial recognition of angiogenesis being a therapeutically interesting process, began in the oncological arena in the early 1970s, when the hypothesis was put forward that tumors are highly vascularized and thereby vulnerable at the level of their blood supply. It was hypothesized that the process of angiogenesis might be a target for therapy. Since then, it was only after the discovery of the first compounds with specific angiostatic effects in the early 1990s, that the research field of angiogenesis rapidly expanded and provided an increasing body of evidence that inhibition of angiogenesis could attenuate tumor growth (1, 2). The endothelial cells that line the blood vessels play a pivotal regulatory role in the execution of angiogenesis. The sequence of events in endothelial cells that follow the initiation of angiogenesis by exposure to (e.g. tumor derived) angiogenic stimulation consists of:
- synthesis of proteases that degrade the extracellular matrix,
- migration towards the stimulus,
- proliferation to increase the number of endothelial cells,
- differentiation in order to form a functional vessel (Fig.).
Negative interference in the different steps of the angiogenesis cascade enables different approaches for treatment of cancer:
1. Neutralization of angiogenic factors - antivascular endothelial cell growth factor (VEGF) antibodies, dominant negative VEGF-receptors.
2. Inhibition of VEGF-receptors - anti-VEGFreceptor antibodies.
3. Desensitization of VEGF mediated intracellular signalling pathways - VEGF receptor tyrosine kinase inhibitor (e.g. SU5416, PTK787).
4. Inhibition of matrix metalloproteinases (marimastat, prinomastat).
5. Inhibition of endothelial cell adhesion (antiavb3- integrin antibody Vitaxin).
6. Inhibition of endothelial cell migration (interferon- alpha).
7. Inhibition of endothelial cell proliferation (TNP-470, angiostatin, endostatin, anginex).
Angiogenesis: Clinical Aspects
While many anti-angiogenic therapies for treating cancer were highly active in animal models, clinical results so far tend to be rather disappointing. This may either be a result of the fact that the most promising anti-angiogenic compounds have not been tested in the clinic yet, or that the read-out systems available for measuring clinical efficacy of anti-tumor drugs are not suitable for measuring anti-angiogenic effects. One of the advantages of anti-angiogenic therapy is believed to be the lack of induction of resistance to the therapy (3). This is explained by the fact that endothelial cells are genetically stable cells that are considered not to mutate into drug resistant variants. Although this is a beneficial feature of the anti-angiogenic approach, it is expected that inhibitors of angiogenesis will be used in future in combination with other anti-cancer modalities such as chemotherapy, irradiation and/or immunotherapy.
1. Griffioen A, Molema G (2000) Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases and chronic inflammation. Pharmacol Rev 52: 237-268
2. Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27- 31
3. Boehm T, Folkman J, Browder T, OReilly M S (1997) Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390: 404-407
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