The Discovery of Angiogenesis Factors

  • Domenico Ribatti


Until the early 1970s it was widely assumed that tumors did not produce specific angiogenic proteins. The conventional widsom was that tumor vasculature was an inflammatory reaction to dying or necrotic tumor cells. Previous studies had shown that tumor-stimulated vessel growth did not require direct contact between tumor and host tissue (Greenblatt and Shubik 1968; Ehrman and Knoth 1968). This made sense to Folkman, who reasoned that a soluble factor would be more likely to reach nearly than distant blood vessels. He and his colleagues isolated an angiogenic factor in 1971 (Folkman et al. 1971). The homogenate of a Walker 256 carcinoma – a breast tumour of Sprague-Dawley rats – was fractionated by gel-filtration on Sephadex G-100. The fraction that exhibited the strongest angiogenic activity had a molecular weight of about 10,000 daltons and consisted of 25% RNA, 10% proteins, and 58% carbohydrates, plus a possible lipid residue that appeared to be protective. It was inactivated by digestion with pancreatic ribonuclease, or by heating at 56 °C for 1 h, and was not modified when kept at 4 °C for 3 months, nor when treated with trypsin for more than 3 days. This active fraction was subsequently called “tumour angiogenesis factor” (TAF) (Folkman et al. 1971). Histone and non-histone fractions were separated by CM sephadex chromatography. The histone fraction showed no activity but the non-histone proteins contained strong angiogenic activity (Tuan et al. 1973). Both the cytoplasmic and the nuclear fractions of tumor cells stimulated angiogenesis. In the nuclear fraction, this was found to be associated with non-histonic proteins (Tuan et al. 1973). TAF has since been non-destructively extracted from several tumor cell lines, and several low molecular weight angiogenic factors have been isolated, again from the Walker 256 carcinoma. These factors induced a vasoproliferative response in vivo when tested on rabbit cornea or chick CAM, and in vitro on cultured endothelial cells (Mc Auslan and Hoffman 1979; Weiss et al. 1979; Fenselau et al. 1981).


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Authors and Affiliations

  • Domenico Ribatti
    • 1
  1. 1.Department of Basic Medical Sciences, Neurosciences and Sensory OrgansUniversity of Bari Medical SchoolBariItaly

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