Tumour Angiogenesis: A Growth Area—From John Hunter to Judah Folkman and Beyond

Abstract

Angiogenesis is the growth of new blood vessels in the body. Abnormal angiogenesis is recognised as a “common denominator” in many disease processes, and the development of angiogenesis inhibitors holds great hope in the ongoing battle against cancer. The field of angiogenesis has roots in the Hunterian era of the late eighteenth century but did not begin to blossom until the early 1970s when the then controversial findings and conclusions of Judah Folkman, the “father of angiogenesis,” were first published. There were only 65 publications with angiogenesis in the title in the 10 years after Folkman first proposed the idea of tumour angiogenesis, compared to over 9,000 publications from the year 2000 to 2010. In this review we will explore the voyage of discovery from the first observations of John Hunter in the eighteenth century, via the struggle faced by Folkman to prove the importance of angiogenesis, and finally how his determination has led to modern angiogenesis inhibitors being used in everyday clinical practice.

Role of Sirtuins in Tumor Angiogenesis

“…Angiogenesis, the process of formation of new blood vessels from pre-existing ones, is essential for the normal growth, development and wound healing. Apart from this, angiogenesis is also inevitable for tumor growth and metastasis (1)(2)(3)(4)(5). The expression and secretion of various modulators of angiogenesis is regulated by microenvironmental factors like hypoxia and accumulation of different metabolites (6)(7)(8).…”

VEGF-Mediated Signal Transduction in Tumor Angiogenesis

“…Effort persisted in this area and new anti-angiogenic molecules are continuously being developed. They essentially fall into two distinct types: (i) antibody directed toward angiogenic factors such as VEGF, for example, Avastin (Bevacizumab, Genentech) and (ii) small molecules inhibiting cellular signaling by targeting multiple receptor tyrosine kinases among them VEGFR-2, for example, Sutent (Sunitinib, Pfizer) and Nexavar (Sorafenib, Bayer and Onyx Pharmaceuticals) [17].…”

“…Targeting VEGF and VEGFR-2 offers benefit to patients with at least some types of cancer and provides proof of principle that attacking the vasculature is a valid approach to cancer therapy [22]. At present, however, despite important results, the overall clinical benefits of anti-VEGF/VEGFR-2 therapy are still relatively modest: not all cancer patients respond to anti-VEGF treatments, and when they do increased survival may only be measured in weeks or months [17]. This is realistically due to a number of different and not yet fully clarified reasons, which open discussion going beyond the topic of this chapter.…”

“…After the developments of the late 1970s, many other scientists entered the field of angiogenesis and Folkman's skeptics became his competitors [17]. In particular, the 1980s were an intense period of hunting for the hypothesized TAF [8].…”

Clinical experience with ramucirumab: outcomes in breast cancer

“…A multitude of patients, including breast cancer patients, have been treated with this agent since then, and the number of approved and available antiangiogenic therapies has expanded in the past decade. The physiological process these agents disrupt, 'angiogenesis,' is a term considered to be coined by British surgeon Dr. John Hunter in 1787 when he observed and described new vessel growth in the reindeer antler [3]; but as a concept, it is attributed to Dr. Judah Folkman --who hypothesized in his 1971 New England Journal of Medicine paper that tumors needed vessels to grow [4]. This straightforward descriptive term belittles the incredible complexity of the angiogenic switch, which occurs in cells at the epithelial--mesenchymal boundary that ensures tumors have adequate access to the circulation through a chaotic vascular network [5], and has become one of the well-accepted hallmarks of cancer [6].…”