Abstract
Dr Judah Folkman was frequently described as a highly compassionate physician who served his patients not only by performing surgery and offering them comfort and reassurance, but also by working tirelessly in the laboratory to find new approaches to the treatment of disease. His dedication to understanding the role of angiogenesis, the formation of new blood vessels, in human disease has given rise to new treatments for several diseases, including inflammatory diseases, vision-threatening diseases of the eye and, as will be emphasized in this Perspective, cancer.
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References
Folkman, M. J., Long, D. M. Jr & Becker, F. F. Tumor growth in organ culture. Surg. Forum 13, 81–83 (1962).
Folkman, J., Long, D. M. Jr & Becker, F. F. Growth and metastasis of tumor in organ culture. Cancer 16, 453–467 (1963).
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
Folkman, J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann. Surg. 175, 409–416 (1972).
Cavallo, T., Sade, R., Folkman, J. & Cotran, R. S. Tumor angiogenesis. Rapid induction of endothelial mitoses demonstrated by autoradiography. J. Cell Biol. 54, 408–420 (1972).
Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004).
Boucher, Y., Leunig, M. & Jain, R. K. Tumor angiogenesis and interstitial hypertension. Cancer Res. 56, 4264–4266 (1996).
Hall, A. P. The role of angiogenesis in cancer. Comp. Clin. Path. 13, 95–99 (2005).
Ide, A. G., Baker, N. H., Warren, S. L. Vascularization of the brown Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am. J. Roentgenol. 42, 891–899 (1939).
Algire, G. H., Chalkley, H. W., Legallais, F. Y. & Park, H. D. Vascular reactions of normal and malignant tumors in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic transplants. J. Natl Cancer Inst. 6, 73–85 (1945).
Greenblatt, M. & Shubi, P. Tumor angiogenesis: transfilter diffusion studies in the hamster by the transparent chamber technique. J. Natl Cancer Inst. 41, 111–124 (1968).
Ehrmann, R. L. & Knoth, M. Choriocarcinoma. Transfilter stimulation of vasoproliferation in the hamster cheek pouch. Studied by light and electron microscopy. J. Natl Cancer Inst. 41, 1329–1341 (1968).
Cavallo, T., Sade, R., Folkman, J. & Cotran, R. S. Ultrastructural autoradiographic studies of the early vasoproliferative response in tumor angiogenesis. Am. J. Pathol. 70, 345–362 (1973).
Gimbrone, M. A. Jr, Leapman, S. B., Cotran, R. S. & Folkman, J. Tumor angiogenesis: iris neovascularization at a distance from experimental intraocular tumors. J. Natl Cancer Inst. 50, 219–228 (1973).
Gimbrone, M. A. Jr, Cotran, R. S., Leapman, S. B. & Folkman, J. Tumor growth and neovascularization: an experimental model using the rabbit cornea. J. Natl Cancer Inst. 52, 413–427 (1974).
Folkman, J. & Long, D. M. The use of silicone rubber as a carrier for prolonged drug therapy. J. Surg. Res. 4, 139–142 (1964).
Langer, R. & Folkman, J. Polymers for the sustained release of proteins and other macromolecules. Nature 263, 797–800 (1976).
Auerbach, R., Kubai, L., Knighton, D. & Folkman, J. A simple procedure for the long-term cultivation of chicken embryos. Dev. Biol. 41, 391–394 (1974).
Sade, R. M., Folkman, J. & Cotran, R. S. DNA synthesis in endothelium of aortic segments in vitro. Exp. Cell Res. 74, 297–306 (1972).
Gimbrone, M. A. Jr, Cotran, R. S. & Folkman, J. Endothelial regeneration: studies with human endothelial cells in culture. Ser. Haematol. 6, 453–455 (1973).
Gimbrone, M. A. Jr, Cotran, R. S. & Folkman, J. Human vascular endothelial cells in culture. Growth and DNA synthesis. J. Cell Biol. 60, 673–684 (1974).
Folkman, J., Haudenschild, C. C. & Zetter, B. R. Long-term culture of capillary endothelial cells. Proc. Natl Acad. Sci. USA 76, 5217–5221 (1979).
Folkman, J. & Haudenschild, C. Angiogenesis in vitro. Nature 288, 551–556 (1980).
Folkman, J. What is the evidence that tumors are angiogenesis dependent? J. Natl Cancer Inst. 82, 4–6 (1990).
Ausprunk, D. H., Falterman, K. & Folkman, J. The sequence of events in the regression of corneal capillaries. Lab. Invest. 38, 284–294 (1978).
Brem, S., Brem, H., Folkman, J., Finkelstein, D. & Patz, A. Prolonged tumor dormancy by prevention of neovascularization in the vitreous. Cancer Res. 36, 2807–2812 (1976).
Folkman, J., Merler, E., Abernathy, C. & Williams, G. Isolation of a tumor factor responsible for angiogenesis. J. Exp. Med. 133, 275–288 (1971).
Shing, Y. et al. Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science 223, 1296–1299 (1984).
Klagsbrun, M., Sasse, J., Sullivan, R. & Smith, J. A. Human tumor cells synthesize an endothelial cell growth factor that is structurally related to basic fibroblast growth factor. Proc. Natl Acad. Sci. USA 83, 2448–2452 (1986).
Gospodarowicz, D. Localisation of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth. Nature 249, 123–127 (1974).
Gospodarowicz, D., Brown, K. D., Birdwell, C. R. & Zetter, B. R. Control of proliferation of human vascular endothelial cells. Characterization of the response of human umbilical vein endothelial cells to fibroblast growth factor, epidermal growth factor, and thrombin. J. Cell Biol. 77, 774–788 (1978).
Relf, M. et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor b-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 57, 963–969 (1997).
Langer, R., Conn, H., Vacanti, J., Haudenschild, C. & Folkman, J. Control of tumor growth in animals by infusion of an angiogenesis inhibitor. Proc. Natl Acad. Sci. USA 77, 4331–4335 (1980).
Moses, M. A., Sudhalter, J. & Langer, R. Identification of an inhibitor of neovascularization from cartilage. Science 248, 1408–1410 (1990).
Roy, R., Zhang, B. & Moses, M. A. Making the cut: protease-mediated regulation of angiogenesis. Exp. Cell Res. 312, 608–622 (2006).
Taylor, S. & Folkman, J. Protamine is an inhibitor of angiogenesis. Nature 297, 307–312 (1982).
Crum, R., Szabo, S. & Folkman, J. A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment. Science 230, 1375–1378 (1985).
Ingber, D. et al. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348, 555–557 (1990).
D'Amato, R. J., Lin, C. M., Flynn, E., Folkman, J. & Hamel, E. 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc. Natl Acad. Sci. USA 91, 3964–3968 (1994).
Voest, E. E. et al. Inhibition of angiogenesis in vivo by interleukin 12. J. Natl Cancer Inst. 87, 581–586 (1995).
O'Reilly, M. S., Pirie-Shepherd, S., Lane, W. S. & Folkman, J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science 285, 1926–1928 (1999).
Kisker, O. et al. Vitamin D binding protein-macrophage activating factor (DBP-maf) inhibits angiogenesis and tumor growth in mice. Neoplasia 5, 32–40 (2003).
Beecken, W. D. et al. An endogenous inhibitor of angiogenesis derived from a transitional cell carcinoma: clipped 2-glycoprotein-I. Ann. Surg. Oncol. 13, 1241–1251 (2006).
Folkman, J. Endogenous angiogenesis inhibitors. APMIS 112, 496–507 (2004).
D'Amato, R. J., Loughnan, M. S., Flynn, E. & Folkman, J. Thalidomide is an inhibitor of angiogenesis. Proc. Natl Acad. Sci. USA 91, 4082–4085 (1994).
Kumar, S. & Rajkumar, S. V. Thalidomide and lenalidomide in the treatment of multiple myeloma. Eur. J. Cancer 42, 1612–1622 (2006).
Folkman, J. In Tumor Angiogenesis (eds Marme, D. & Fusenig, N.) 1–28 (Springer, Berlin, 2008).
O'Reilly, M. S. et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79, 315–328 (1994).
O'Reilly, M. S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).
Folkman, J. Antiangiogenesis in cancer therapy — endostatin and its mechanisms of action. Exp. Cell Res. 312, 594–607 (2006).
Wen, W., Moses, M. A., Wiederschain, D., Arbiser, J. L. & Folkman, J. The generation of endostatin is mediated by elastase Cancer Res. 59, 6052–6056 (1999).
Holmgren, L., O'Reilly, M. S. & Folkman, J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med. 1, 149–153 (1995).
O'Reilly, M. S., Holmgren, L., Chen, C. & Folkman, J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nature Med. 2, 689–692 (1996).
Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60, 1878–1886 (2000).
Klement, G. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105, R15–R24 (2000).
Emmenegger, U. & Kerbel, R. S. Five years of clinical experience with metronomic chemotherapy: achievements and perspectives. Onkologie 30, 606–608 (2007).
Kerbel, R. & Folkman, J. Clinical translation of angiogenesis inhibitors. Nature Rev. Cancer 2, 727–739 (2002).
Kieran, M. W. et al. A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J. Pediatr. Hematol. Oncol. 27, 573–581 (2005).
Bottini, A. et al. Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J. Clin. Oncol. 24, 3623–3628 (2006).
Garcia, A. A. et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J. Clin. Oncol. 26, 76–82 (2008).
Tapper, D., Langer, R., Bellows, A. R. & Folkman, J. Angiogenesis capacity as a diagnostic marker for human eye tumors. Surgery 86, 36–40 (1979).
Chodak, G. W., Haudenschild, C., Gittes, R. F. & Folkman, J. Angiogenic activity as a marker of neoplastic and preneoplastic lesions of the human bladder. Ann. Surg. 192, 762–771 (1980).
Chodak, G. W., Scheiner, C. J. & Zetter, B. R. Urine from patients with transitional-cell carcinoma stimulates migration of capillary endothelial cells. N. Engl. J. Med. 305, 869–874 (1981).
Nguyen, M., Watanabe, H., Budson, A. E., Richie, J. P. & Folkman, J. Elevated levels of the angiogenic peptide basic fibroblast growth factor in urine of bladder cancer patients. J. Natl Cancer Inst. 85, 241–242 (1993).
Weidner, N., Semple, J. P., Welch, W. R. & Folkman, J. Tumor angiogenesis and metastasis — correlation in invasive breast carcinoma. N. Engl. J. Med. 324, 1–8 (1991).
Weidner, N., Carroll, P. R., Flax, J., Blumenfeld, W. & Folkman, J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am. J. Pathol. 143, 401–409 (1993).
Vermeulen, P. B. et al. Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours. Eur. J. Cancer 38, 1564–1579 (2002).
Italiano, J. E. Jr et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 111, 1227–1233 (2008).
Cervi, D. et al. Platelet-associated PF-4 as a biomarker of early tumor growth. Blood 111, 1201–1207 (2008).
Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nature Rev. Drug Discov. 6, 273–286 (2007).
Shojaei, F. & Ferrara, N. Antiangiogenesis to treat cancer and intraocular neovascular disorders. Lab. Invest. 87, 227–230 (2007).
Folkman, J. Is angiogensis an organizing principle in biology and medicine? J. Pediatr. Surg. 42, 1–11 (2007).
Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).
Ausprunk, D. H., Knighton, D. R. & Folkman, J. Vascularization of normal and neoplastic tissues grafted to the chick chorioallantois. Role of host and preexisting graft blood vessels. Am. J. Pathol. 79, 597–618 (1975).
Ribatti, D. The first evidence of the tumor-induced angiogenesis in vivo by using the chorioallantoic membrane dated 1913. Leukemia 18, 1350–1351 (2004).
Satchi-Fainaro, R. et al. Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nature Med. 10, 255–261 (2004).
Benny, O. et al. An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. Nature Biotech. 29 Jun 2008 (doi:10.1038/nbt1415).
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Zetter, B. The scientific contributions of M. Judah Folkman to cancer research. Nat Rev Cancer 8, 647–654 (2008). https://doi.org/10.1038/nrc2458
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DOI: https://doi.org/10.1038/nrc2458
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