Cytokines and Tumor Angiogenesis.

The term angiogenesis was first coined by John Hunter, a British surgeon, to describe blood vessel formation in reindeer antlers in 1787. The first histologic description of angiogenesis was presented by Arthur Tremain Hertig in 1935, detailing the formation of placental blood vessels. In 1939, based on observations of tumors transplanted to transparent chambers in in vivo animal models, A. G. Ide and colleagues proposed the existence of a tumor-derived factor capable of stimulating blood vessel formation (1). In 1945, G. H. Algire and his co-workers at the National Cancer Institute (NCI) recognized that the blood supply of tumors was derived from the host and was essential for tumor growth (2). The findings of Algire et al. offered the first evidence supporting the association between tumor vasculature and tumor growth. In 1948, I. C. Michaelson postulated that a diffusible angiogenic factor produced by the retina conferred the neovascularization phenotype observed during proliferative diabetic retinopathy and named this soluble factor as "Factor X" (3). Twenty years later, Greenblatt and Shubik (4) and Ehrmann and Knoth (5) demonstrated independently that tumor cells could stimulate vasoproliferation through transfilter diffusion experiments and confirmed the notion of a diffusible angiogenic factor elaborated by tumor cells. In 1971, Judah Folkman further refined the view on the relationship between tumor and its vasculature by hypothesizing that the growth of cancer from a few cell layers thick into a gross tumor requires angiogenic stimuli which are mediated by substances produced by the tumor. He proposed that anti-angiogenic therapy, therefore, might be an effective approach to treating human cancers (6-8). This view on tumor angiogenesis eas provocative and contrary to the prevailing thoughts of the time. Despite not being accepted by the scientific community, Dr. Folkman endeavored along this line of research and initiated the effort that lead to the isolation of the first angiogenic cytokine, basic fibroblast growth factor (bFGF) (9). Findings from his work have come to form the foundation in the molecular understanding of tumor angiogenesis and Dr. Folkman is often regarded as the "father of angiogenesis". [ABSTRACT FROM AUTHOR]