Correspondence to: Judah Folkman, M.D., Children's Hospital, Hunnewell 103, 300 Longwood Ave., Boston, MA 02115 (e-mail: Judah.Folkman{at}tch.harvard.edu).
The switch to the angiogenic phenotype (1) is under genetic and epigenetic regulation. An example of genetic regulation of the angiogenic switch is expression of the HER-2/neu oncogene, which increases expression of vascular endothelial growth factor (VEGF), a positive regulator of angiogenesis in human breast cancer (2). Another example is expression of the ras oncogene, which increases expression of VEGF and decreases expression of thrombospondin-1, a negative regulator of angiogenesis. At least 13 other oncogenes are known to encode proteins that drive tumor angiogenesis (2). By contrast, certain tumor suppressor genes override the angiogenic switch; e.g., p53 normally maintains thrombospondin-1 production (3). Epigenetic regulation of the angiogenic switch is illustrated by increased VEGF expression in tumor cells by hypoxic induction of hypoxia-inducible factor-1 (4) or by triggering angiogenesis by matrix metalloproteinase-9 during carcinogenesis (5).
Overexpression of VEGF by ovarian cancer cells is a major mediator of angiogenesis in this tumor type. In the ascites fluid of human OVCAR-5 ovarian cancer in mice, we have found VEGF levels of more than 6000 pg/mL and, in the same mice, serum levels in the range of only 30 pg/mL (Wen W, Panigrahy D, Butterfield C: personal communication, unpublished data). When OVCAR-5 cells were grown in vitro, VEGF levels in the conditioned medium reached greater than 1400 pg/mL compared with less than 30 pg/mL for control medium without the tumor cells. In a patient with ovarian cancer, VEGF levels in the ascites fluid were greater than 13 000 pg/mL.
In a report in this issue of the Journal, Hu et al. (6), working with Napoleone Ferrara, a leading figure in angiogenesis research, have unraveled a novel pathway for VEGF expression in ovarian cancer. They show that lysophosphatidic acid (LPA) in ovarian cancer ascites fluid binds to a receptor for the endothelial differentiation gene (Edg4), which is expressed in ovarian cancer cells but not in normal ovarian epithelial cells. The result of ligand binding is increased VEGF expression by the cancer cells. Activation of the Edg4 receptor increased expression of the VEGF promoter by a mechanism that is mediated through c-Jun and c-Fos and differs qualitatively from hypoxia-mediated increased VEGF expression through increases in the half-life of VEGF messenger RNA.
As the authors emphasize (6), these results suggest that Edg4 may provide a new target for therapy in ovarian cancer. This report is of great interest because it suggests the possible development of a novel angiogenesis inhibitor that could shut off the angiogenic switch in ovarian cancer or at least control one aspect of this switch. Antiangiogenic therapy could also reduce ascites, as has been demonstrated previously in animals (7,8). Because LPA is mitogenic for ovarian cancer cells, an Edg4 inhibitor could also directly block cancer cell proliferation.
There are two general classes of angiogenesis inhibitors, indirect and direct. A drug that would decrease VEGF expression in ovarian cancer by blockade of Edg4 would belong to the former class.
An indirect angiogenesis inhibitor decreases a tumor cell's production of an angiogenic factor, neutralizes the angiogenic factor itself, or blocks its receptor on endothelial cells. Examples are 1) the farnesyl transferase inhibitors, developed to target the ras oncogene, which also result in decreased VEGF production by tumor cells; 2) Herceptin, which blocks the HER-2/neu (erbB2) oncogene and also decreases VEGF production by breast cancer cells; and 3) C225, a monoclonal antibody, which blocks the epidermal growth factor receptor tyrosine kinase, also resulting in inhibition of VEGF, basic fibroblast growth factor, and interleukin 8 (IL-8) production by tumor cells (2). STI571 (also known as Glivec), recently discovered to block the Bcr-Abl oncogene in chronic myelogenous leukemia (9), also acts as an indirect angiogenesis inhibitor against human prostate cancer growing in murine bone by blocking the platelet-derived growth factor (PDGF) receptor on microvascular endothelial cells in the tumor bed (10). The PDGF receptor on endothelial cells is expressed when it is in the presence of tumor cells that secrete PDGF.
A direct angiogenesis inhibitor prevents endothelial cells from responding (by proliferation or locomotion) to a wide range of positive regulators of angiogenesis. Some examples are thrombospondin-1, angiostatin, endostatin, and pigment epithelium-derived factor (PEDF) (11). PEDF inhibited endothelial cell locomotion toward every angiogenic factor tested by Dawson et al. (11), including PDGF, VEGF, IL-8, acidic fibroblast growth factor, and LPA, but it did not inhibit locomotion by nonendothelial cells.
The distinction between direct and indirect angiogenesis inhibitors is important in understanding how these agents can be used in patients. Direct angiogenesis inhibitors induce little or no drug resistance in their endothelial cell targets (12,13) and, therefore, can be administered for prolonged periods of time without disease relapse. The very low mutation rate of endothelial cells may account for their lack of resistance to antiangiogenic therapy, in contrast with the high mutation rate of most cancer cells. Because an indirect angiogenesis inhibitor blocks a tumor cell product, such as VEGF, the emergence of a mutant tumor cell that produces a different angiogenic protein, such as IL-8, may eventually nullify the effectiveness of the angiogenesis inhibitor. Therefore, the relapse that can occur after prolonged administration of an indirect angiogenesis inhibitor may differ from the classical acquired drug resistance that emerges after prolonged administration of a cytotoxic agent and may be bypassed by the administration of a direct angiogenesis inhibitor or made to occur less frequently.
Angiogenesis is a general property of virtually all tumors and is critical for tumor growth. An important contribution of the report by Hu et al. (6) is that the angiogenic pathway for a given tumor type may depend on unique mechanisms, which, when elucidated, can lead to the discovery of novel antiangiogenic therapies.
REFERENCES
1 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:35364.[Medline]
2 Rak J, Yu JL, Klement G, Kerbel RS. Oncogenes and angiogenesis: signaling three-dimensional tumor growth. J Investig Dermatol Symp Proc 2000;5:2433.[Medline]
3 Dameron KM, Volpert OV, Tainsky MA, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994;265:15824.[Medline]
4 Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis [erratum appears in Nature 1998;395:525]. Nature 1998;394:48590.[Medline]
5 Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000;2:73744.[Medline]
6
Hu YL, Tee MK, Goetzl EJ, Auersperg N, Mills GB, Ferrara N, et al. Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells. J Natl Cancer Inst 2001;93:7628.
7 Heuser LS, Taylor SH, Folkman J. Prevention of carcinomatosis and bloody malignant ascites in the rat by an inhibitor of angiogenesis. J Surg Res 1984;36:24450.[Medline]
8
Mesiano S, Ferrara N, Jaffe RB. Role of vascular endothelial growth factor in ovarian cancer: inhibition of ascites formation by immunoneutralization. Am J Pathol 1998;153:124956.
9
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:10317.
10 Uehara H, Kim SJ, Karashima T, Zheng L, Fidler IJ. Blockade of PDGF-R signaling by STI571 inhibits angiogenesis and growth of human prostate cancer cells in the bone of nude mice [abstract]. Proc Am Assoc Cancer Res 2001;42:abst 2192.
11
Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 1999;285:2458.
12 Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent resistance to anti-cancer therapeutic agents. Bioessays 1991;13:316.[Medline]
13 Boehm T, Folkman J, Browder T, O'Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 1997;390:4047.[Medline]
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