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Blood, 15 October 2007, Vol. 110, No. 8, pp. 2786-2787.
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HEMOSTASIS
Comment on Shi et al, page 2899
Endostatin finds a new partner: nucleolin
Judah Folkman
CHILDREN'S HOSPITAL AT HARVARD MEDICAL SCHOOL
In this issue of Blood, Shi and colleagues examine the endostatin binding of nucleolin on angiogenic endothelial cells, as well as the transport of nucleolin to the nucleus, where it prevents proliferation—thus revealing a novel mechanism for endostatin's antiangiogenic activity.
During the past 3 years, 8 new drugs with antiangiogenic activity have received approval from the Food and Drug Administration of the United States for the treatment of cancer and age-related macular degeneration, and have also been approved in more than 30 other countries. These are mainly antibodies, aptamers, or synthetic molecules. They block at least 1 to 3 proangiogenic proteins or their receptors.1 This new class of drugs has been prescribed for more than 1.2 million patients. More than 50 drugs with antiangiogenic activity are in phase 2 or 3 clinical trials.2 Since 1980, 28 endogenous angiogenesis inhibitors, including platelet factor 4, angiostatin, endostatin, thrombospondin-1, tumstatin, and canstatin, have been discovered in blood or tissues.3,4 At this writing, more than 1000 reports on endostatin have been published since its discovery in 1997, and reveal that endostatin has the broadest antitumor spectrum of the endogenous angiogenesis inhibitors. It is also the first endogenous inhibitor to receive approval for anticancer therapy, under the trade name "Endostar" in China.
The integrin  5ß1 has been proposed as a receptor for endostatin, and endostatin has been shown to regulate an entire program of antiangiogenic gene expression in human microvascular endothelial cells stimulated by VEGF or bFGF.5 Nevertheless, certain antiangiogenic actions of endostatin have no molecular explanation and remain as open questions. In this issue of Blood, Shi and colleagues address 3 of these questions. Why does endostatin specifically target angio-genic blood vessels, but not quiescent blood vessels? Why does endostatin inhibit tumor angiogenesis with virtually no toxicity in animal studies and clinical trials? Why has the antiangiogenic activity of endostatin appeared to be heparin-dependent in previous studies? These questions are answered by a novel and important finding: that nucleolin is expressed on the surface of proliferating angiogenic human microvascular endothelial cells, but not on the surface of quiescent endothelium. In angiogenic endothelial cells, the cell-surface nucleolin binds endostatin and transports it to the nucleus, where endostatin inhibits phosphorylation of nucleolin. Phosphorylation of nucleolin induced by VEGF or bFGF has been reported to be essential for cell proliferation. Furthermore, endostatin does not inhibit proliferation of many types of tumor cells per se, possibly because while they express nucleolin on their surfaces, they do not internalize it in the presence of endostatin. The heparin binding sites on nucleolin were found to be critical for endostatin. Increasing concentrations of exogenous heparin dissociated the binding of endostatin to nucleolin.
The article by Shi and colleagues is also thought-provoking because the endostatin-nucleolin connection is now fertile soil for future studies. For example, it will be interesting to learn how specific the binding of endostatin is to nucleolin compared with other proteins that also bind to endostatin, as reported by the authors. Furthermore, it will be helpful if the relationship of nucleolin to other cell-surface endostatin-binding proteins can be uncovered, particularly 5ß1. Will this endostatin-nucleolin connection lead to the uncovering of a mechanism for the biphasic,  -shaped anticancer dose-response curve recently reported for endostatin,6 and originally shown for the antiendothelial activity of interferon ?7 This biphasic dose response is common to other angiogenesis inhibitors. Endostatin increases nucleolin expression in human microvascular endothelial cells in vitro by approximately 20%.5 Is p53-mediated inhibition of angiogenesis, in part through increased expression of endostatin,8,9 also regulated by nucleolin? Because the endothelial-cell expression of another endogenous angiogenesis inhibitor, thrombospondin-1, is up-regulated by endostatin, is thrombospondin-1 indirectly nucleolin-dependent? Are any other endogenous angiogenesis inhibitors regulated by binding to nucleolin? Angiogenesis in wound healing and pregnancy is not delayed by high endostatin levels, as for example in individuals with Down syndrome, or in animals receiving endostatin therapy.10 Is this because proliferating endothelial cells in reproduction and repair do not express nucleolin on their cell surface, or do not internalize it?
The novel role for nucleolin, as a regulator of the antiangiogenic activities of endostatin, has fundamental implications for understanding the biology of endostatin and for its clinical application.
Acknowledgments
Acknowledgment: I thank Sandra Ryeom and Kashi Javaherian for helpful discussions.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. 
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- In Davis DW, Herbst RS, Abbruzzese JL (Eds.). Antiangiogenic Cancer Therapy2008;Boca Raton, FL CRC.
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Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin
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