Review of relationship between vascular endothelial growth factor family & receptors and tumor angiogenesis

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Julia Alyson Hopkins
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1 hinese Bulletin of Life Sciences Vol. 16, No. 1 Feb., (2004) (vascular endothelial growth factor, ) (vascular permeability factor, VPF), -A -B - -D -E (placenta growth factor, PLGF) R-1(flt-1) R-2(flk-1/KDR) R-3(flt-4) neuropilin(npr1/ NPR2) / R322.1;R732.2 A Review of relationship between vascular endothelial growth factor family & receptors and tumor angiogenesis HEN Shan 1, JIN Wei 1, MIN Ping 1, LU He 2 (1 Shanghai Institute of Materia Medica, hinese Academy of Sciences, Shanghai , hina; 2 Le pôle francochinois du science du vivant et génomique, Ruijin Hospital, Shanghai , hina) Abstract: Vascular endothelial growth factor () also named vascular permeability factor (VPF), is an important positive regulator for angiogenesis. This is one target of the anticancer research. Discovered members of family include: -A, -B, -, -D, -E and placenta growth factor (PLGF). Receptors of are R-1(flt-1), R-2(flk-1/KDR), R-3(flt-4) and neuropilin(npr1/npr2). Members of this family can selectively promote mitosis of vascular endotheial cells or lymphatic endothelial cells, stimulate endothelial cells to proliferate and induce angiogenesis. They also enhance the permeability of microvessels, help to establish capillary vessels net. This article mainly reviewed the structures, functional characteristics, relationship between and its inhibitors and tumor angiogenesis. Key words: vascular endothelial growth factor; vascular endothelial growth factors receptors; angiogenesis (1978 ) (1972 ) 1973 (1957 )

2 A -A 6p kb ~45kD -A 5 -A [1] 5 -A mrna B 167 -B kD 32kD -B 167 -B 186 N -B 167 -B 186 -B 167 B 186 -B (EM) -A 145 -A 165 -A A 189 -A 206 -B A 165 -B A 165 -A -B -A -A [3,4] -B mrna q34 - cdna kD - N -A 4 - -A 3 N - 1 -A 5 [1] - -A -A 1(HIF-1) EGF TGFα/β 1 FGF -A mrna -A Ras -A IL-1α IL-6 -A 1.2 -B -B 11q13 4kb, 7 6 -B 2.4kD 2.0kD - mrna 2.4kD mrna Eichmann [5] - flt-4 PDGF EGF TGF-β - mrna - mrna IL-1β - (TNF) IL-1α - mrna [4,6] 1.4 -D -D Xp kb 7 6 cdna D mrna 2.3kb

21 2.8kb -D - - N N -D -D 3 N- - -D - -D c-fos c-fos -D, TGF-α betacelluin(bt) heregulin-β(hrg-β) -D mrna 1.5 -E -E 20kD -A 121 25 flk-1 -A 165 [6] 1.

3 21 2.8kb -D - - N N -D -D 3 N- - -D - -D c-fos c-fos -D, TGF-α betacelluin(bt) heregulin-β(hrg-β) -D mrna 1.5 -E -E 20kD -A flk-1 -A 165 [6] 1.6 PLGF PLGF 2p ~50kD PLGF-1 PLGF-2 PLGF-2 [6] 2, -A R-1 R-2 7 R-3 - -D -A Neuropilins(NRP1/NRP2) R-1(flt-1) R-1 (RTK) HIF-1 R-1 -A R-1 PIGF -B flt-1 -A R-1 - A, -A Park [7] R-1 2

4 22 R-2 -A PGF R-1 -A [8] R-1 Gille R-1 -PI3 R-1 PL-γ c-rasgap(gtpase activating protein) [9] Fong R-1 -A R-1 R-2 -A PI3-Kinase-Akt R R-3(flt-4) R-3 - R-3 [12] -D R-3 R-1 -A -A R-1 R-1 (MMP9) [10] R-1 PLGF R- 1 R- 1 (HGF) IL-6 R-1 [11] R-3 R-3 R-3 R-3 R-3 R-3 R-3 MAPK RAFTK - -D R-3 SH/Grb2/SOS Ras/MAPK RAFTK 2.2 R-2(KDR/flk-1) R-2 -A flk-1 8.5~9.5 (-A) R-3 R-3 [13] Makinen [14] -D -A, PL-γ PI3 Ras GTP Src -A Raf-Mek-Erk Ras -A R- 2 R Neuropilin(NRP1/NRP2) -A -A Soker NRP1 collapsinsemaphorin R-2 NRP1 NRP1 R-2

5 23 NRP1 -A 165 -A 121 -A 165 NRP1/2 3 R-2 Burkitt 4 T R-1 R-2 Flt-1 mrna mrna KDR mrna Flt-4 Kim [15] R-2 sflt-1 R-2 R-2 R-1/2 [1] Poltorak Z, ohen T, Sivan R, et al. 145, a secreted vascular endothelia growth factor isoform that binds to extracellular matrix. J Biol hem, 1997, 272: 7151~7158 Ferrara N, Gerber H P, Leouter J. The biology of and its receptors. Nat Med, 2003, 9(6): 669~676 [3],. -B -. :, 1999, 19(6): 479~481 [4],,. : -B - -D. :,1999, 19(4): 279~282 [5] Eichmann A, orbel, Jaffredo T, et al. Avian -: cloning, embryonic expression pattern and stimulation of the differentiation of R 2 -expressing endothelial cell precursors. Development, 1998, 125: 743~752 [6],.. :, 2000, 20(3): 187~189 [7] Park J E, hen H H, Winter J, et al. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol hem, 1994, 269: 25646~25654 [8] Gille H, Kowalski J, Yu L L, et al. A repressor sequence in the juxtamembrane domain of Flt-1 (R-1) constitutively inhibits vascular endothelial growth fator-dependent phosphatidylinositol 3 kinase activation and endothelial cell migration. EMBO J, 2000, 19: 4064~4073 [9] Fong G H, Zhang L Y, Bryce D M, et al. Increased hemangioblast commitment, not vascular disorganized, is the primary defect in flt-1 knock-out mice. Development, 1999, 126: 3015~3025 [10] Hiratsuka S, Minowa O, Kuno J, et al. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA, 1998, 4: 9349~9354 [11] Lecouter J, Moritz D R, Li B, et al. Angiogenesis-independent endothelial protection of liver: role of R-1. Science, 2003, 299: 890~893 [12] Adini A, Kornaga T, Firoozbakht F, et al. Placental growth factor is a survival factor for tumor endothelial cells and macrophages. ancer Res, 2002, 62: 2749~2752 [13],. 3., 2002, 30(2): 73~75 [14] Makinen T, Jussila L, Veikkola T, et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble receptor-3. Nat Med, 2001, 7(2): 199~205 [15] Kim K J, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature, 1993, 362: 841~844

Angiogenesis as a therapeutic target

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