In 1939, Gordon Ide and colleagues adapted a technique to study the growth of blood vessels around tumour tissue transplanted into the rabbit ear. Observing robust tumour growth and induction of a complex vascular network, they made the seminal suggestion that tumours might produce a 'vessel growth- stimulating substance'. In 1945, Glenn Algire and colleagues furthered these studies by a detailed kinetic analysis of the vascular response to tumour transplants. They postulated that the growth advantage of a tumour cell over its normal counterpart might not be owing to "some hypothetical capacity for autonomous growth inherent within the [tumour] cell," but rather to its ability to continuously induce angiogenesis — that is, the formation of new blood vessels. This insightful conclusion presaged the realization that a tumour would not efficaciously grow in the absence of a blood supply and, therefore, that inhibiting development of the tumour vasculature could be exploited as a therapeutic strategy.
In 1968, Melvin Greenblatt and Philippe Shubik showed that tumour transplants stimulated the proliferation of blood vessels even when a physical barrier — a Millipore filter — was placed between the tumour and the host stroma. They concluded that the vessel growth-stimulating substance of Ide and co-workers was a true diffusible substance that could, in theory, be identified. In 1971, Judah Folkman and colleagues isolated just such a 'tumour angiogenic factor (TAF)' from tumour extracts, and proposed that the growth of malignancies might be prevented if TAF activity were blocked.
Folkman expanded on this concept in his visionary synthesis of the contemporary tumour-angiogenesis literature, and proposed that tumour cells secrete a soluble factor that stimulates the proliferation of endothelial cells, that these in turn control tumour expansion and, in the absence of new vessel growth, that tumours do not increase beyond 2–3 mm in size, entering instead a state of 'dormancy'. He further speculated that anti-angiogenesis — that is, inhibiting the recruitment of new blood vessels into a tumour and thereby inducing dormancy, such as by an antibody directed against TAF — might be a powerful approach to tumour therapy.
The proposal by Folkman of targeting the vasculature rather than the tumour cell itself was a complete departure from conventional therapeutic strategies, and was not initially well received by the oncology community. Moreover, angiogenesis was no hotbed of research at the time — the number of angiogenesis papers published in 1971 could be counted on just one hand. Yet, the Folkman article rekindled interest in angiogenesis and inspired new investigators to join the field.
Nonetheless, it was another 18 years before Napoleone Ferrara and colleagues purified and subsequently identified the gene encoding vascular endothelial growth factor (VEGF), which is a secreted protein that can stimulate both vascular endothelial cell proliferation in vitro and angiogenesis in vivo. An isoform of VEGF proved to be identical to vascular permeability factor, which was cloned simultaneously by Pamela Keck and co-workers, and was originally identified by Harold Dvorak and colleagues in 1983. Soon thereafter, two groups independently showed that the cells nearest to areas of low oxygen (hypoxia) in a tumour, and therefore in most need of blood vessels, had the highest expression of VEGF, and that hypoxia could directly induce expression of VEGF in cells in culture. Gregg Semenza and colleagues would later identify hypoxia-inducing factor 1 (HIF1) as the transcription factor responsible for VEGF expression under hypoxia.
In the meantime, Ferrara and colleagues provided definitive evidence that VEGF stimulates tumour angiogenesis and growth in mice by inhibiting its function using a blocking antibody. This finding paved the way for the development and clinical application of a humanized version of the antibody, bevacizumab (Avastin). Based on early and encouraging success in cancer patients when used in conjunction with chemotherapy, bevacizumab was approved by the United States Food and Drug Administration in 2004 for the treatment of metastatic colorectal cancer, bringing validation to the Folkman hypothesis of more than 30 years earlier that targeting the tumour vasculature is a viable strategy to treat cancer.
