CR 75th Anniversary Commentary Review Article Commentary on Folkman: "How Is Blood Vessel Growth Regulated in Normal and Neoplastic Tissue?" Hellmut G. Augustin1,2,3 Abstract Angiogenesis is a prerequisite for tumor growth and met- Lecture delivered by Dr. Judah Folkman. Thirty years later, astatic progression. The discovery of the first specificangio- this award lecture is a lively testimony of the visionary mind genic cytokine, VEGF, in 1989 paved the way for the clinical of Dr. Folkman, whose legacy continues to inspire contem- approval of the first antiangiogenic tumor drug 15 years porary angiogenesis research. Cancer Res; 76(10); 2854–6. Ó2016 later. This brief commentary highlights and puts into his- AACR. torical perspective the 1985 G.H.A. Clowes Memorial Award See related article by Folkman J, Cancer Res 1986;46:467-73. Dr. Judah Folkman of Children's Hospital at Harvard Medical these predictions have become a reality, but the field of angio- School (Boston, MA) was the 25th recipient of the American genesis research was still in its infancy when Dr. Folkman deliv- Association for Cancer Research (AACR) G.H.A. Clowes Memorial ered the Clowes lecture 14 years later (less than 100 angiogenesis- Award. This award recognizes outstanding accomplishments related articles were published in 1985 compared with almost in basic cancer research and comes with the honor to deliver an 7,000 per year today). He outlined in his lecture in some detail the award lecture at the annual AACR meeting. Folkman delivered steps of the angiogenic cascade with endothelial cells in post- the award lecture during the 76th Annual Meeting of the AACR in capillary venules degrading their surrounding extracellular matrix Houston, TX, on May 24, 1985. An edited version of his lecture and migrating toward the angiogenic stimulus to only subse- was published in the February 1986 issue of Cancer Research (1). quently proliferate. Outgrowing capillary sprouts eventually anas- The awardee summarized in this lecture 25 years of pioneering tomose to form new capillary loops and networks. research through which his laboratory had essentially single The 1980s were an intense period of hunting for the ominously handedly established the field of angiogenesis research by estab- hypothesized tumor angiogenesis factor (TAF; ref. 5). Shing, lishing techniques for the culture of endothelial cells (2), devel- Folkman, and Klagsbrun had just reported the heparin affinity oping relevant animal models (3), and purifying the first angio- of many growth factors (6). This provided a unique tool to genic growth factor (4). identify growth factors by heparin-affinity chromatography. On the basis of the experiments in isolated perfused organs, Dr. Many new growth factors were identified at the time, including Folkman had published a hypothesis article in the New England the fibroblast growth factor. Some of these were potent endothe- Journal of Medicine in 1971 (i) predicting that tumors would be lial mitogens capable of inducing angiogenesis in cellular settings restricted to microscopic size in the absence of angiogenesis, (ii) and in vivo, yet all factors identified in the mid-1980s turned out to suggesting that tumors secrete diffusible angiogenic molecules, be pleiotropic factors with multiple biologic functions limiting (iii) describing a model of tumor dormancy due to blocked their usefulness as therapeutic targets. angiogenesis, (iv) proposing the term antiangiogenesis for the Dr. Folkman also described in his lecture early attempts to prevention of new capillary sprouts from being recruited into a develop antiangiogenic compounds. Combinations of heparin growing tumor, (v) envisaging the future discovery of angiogen- with different formulations of mineralocorticoids or glucocorti- esis inhibitors, and (vi) proposing the idea that an antibody to a coids were reported to exert potent antiangiogenic activity in tumor angiogenic factor could be an anticancer drug (5). All of cellular assays and tumor angiogenesis experiments. Most of this early angiogenesis inhibitor work did not stand the test of time, but it paved the way for the subsequent identification of specific 1 Division of Vascular Oncology and Metastasis (DKFZ-ZMBH Alliance), angiogenic factors and corresponding inhibitors. German Cancer Research Center, Heidelberg, Germany. 2Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty As early as 1983, Don Senger and Harold Dvorak of Beth Israel Mannheim, Heidelberg University, Heidelberg, Germany. 3German Hospital at Harvard Medical School had reported the isolation of Cancer Consortium, Heidelberg, Germany. a tumor-derived factor that potently stimulates vascular perme- Corresponding Author: Hellmut G. Augustin, Medical Faculty Mannheim ability, called the vascular permeability factor (VPF; ref. 7), yet this (CBTM), Heidelberg University, and German Cancer Research Center Heidelberg discovery was left largely unnoticed and the article was in the first (DKFZ-ZMBH Alliance), Im Neuenheimer Feld 280, Heidelberg D-69221, 5 years after its publication cited only 45 times (citations until Germany. Phone: 4962-2142-1500; Fax: 4962-2142-1515; E-mail: April 2016: 2,600 times). This changed only when Napoleone [email protected] Ferrara of Genentech published the discovery of the first endo- doi: 10.1158/0008-5472.CAN-16-1123 thelial cell–specific growth factor in 1989 that he called VEGF (so Ó2016 American Association for Cancer Research. far, 3,700 citations; ref. 8), which turned out to be identical to 2854 Cancer Res; 76(10) May 15, 2016 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 2016 American Association for Cancer Research. Regulation of Blood Vessel Growth VPF. This landmark discovery was made around the same time of clinical implementation, the objectives and the mechanism- by Folkman's laboratory and published jointly with Ferrara of-action of antiangiogenic intervention in human tumor only 7 months later (9). The discovery of VEGF as the first specific patients are less clear than ever. Both vascular regression (as angiogenesis factor set in motion the revolution in the field postulated by Folkman) as well as vascular normalization (i.e., of angiogenesis research, with the most dramatic growth in pruning of the most immature intratumoral vessels to leave the 1990s, that has resulted, 15 years after the discovery of behind a more normal appearing and thereby chemotherapy- VEGF, in the clinical approval of the first angiogenesis inhibitor, facilitating vasculature) contribute to antiangiogenic therapy, the VEGF-neutralizing antibody bevacizumab, for the treat- yet the contribution of these two processes, regression and ment of metastatic colorectal cancers (more than 6,000 citations normalization, in different types of human tumors is not at so far; ref. 10). all understood. Moreover, little is known about the temporal Folkman knew at the time of the award lecture that the "real" effects of antiangiogenic intervention. All these limitations angiogenic factors had not yet been discovered. He stated in the severely contribute to the difficulties in the rational and mech- concluding remarks: "In my more grandiose moments, I think anism-based advancement of antiangiogenesis. of a day to come when it may be possible to use angiogenesis Ad ii: VEGF comes close to the magic TAF postulated by inhibitors as an adjunct to conventional therapy." He also Folkman. VEGF stands up high in the hierarchy of events that wrote: "Hopefully, we may eventually learn enough about the leads to the growth of new blood vessels, yet VEGF is not the angiogenic process so that other diseases dominated by abnor- only specific angiogenesis factor. Combinations with factors mal angiogenesis, e.g., many types of ocular neovasculariza- controlling later steps of the angiogenic cascade are in advanced tion, might be brought under control." Both of these statements clinical development. For oncology, combinations of anti- are a most remarkable reflection of Folkman's visionary mind. VEGF/VEGFR with anti-angiopoietin-2 are most advanced in Folkman had envisioned antiangiogenesis as an adjunct to clinical development. For ophthalmology, the combination of conventional therapy, not as replacing it. When antiangiogenic anti-VEGF with anti-PDGFRb is in phase III clinical trials. tumor monotherapy turned out to be ineffective at the begin- Future developments in the fieldalsoholdgreatpromisethat ning of the millennium, the field of antiangiogenesis research antiangiogenic drugs contribute to remodeling the tumor almost collapsed. It was not until 2003 when the combination microenvironment in a way that they do not just facilitate of antiangiogenesis and chemotherapy proved to be more chemotherapy, but that they may also be key to improving effective than chemotherapy alone. The addition of an anti- the efficacy of tumor-curing immunotherapies. angiogenic drug extended median overall survival by 25% The legacy of Judah Folkman is still very much alive. His (from 15.6 to 20.3 months) in a phase III colorectal cancer brilliant mind has left the community with a plethora of still study involving more than 800 patients (10). The second unanswered questions: What are the biologic consequences of statementofFolkmanturnedouttobesimilarlyvisionary: angiogenesis stimulators being short-lived and locally acting, antiangiogenesis has become part of standard first-line tumor whereas the angiogenesis inhibitors supposedly are long-lived therapy, yet its efficacy is to this day rather limited,