生物谷报道：VEGF（血管内皮生长因子）是得到最好定性的肿瘤血管形成诱发因子，阻断VEGF的功能已经成为癌症治疗中的一个重要工具。但VEGF的阻断并不是对所有肿瘤都有效，所以寻找替代方法的工作在继续。两个小组在本期Nature上报告，其中的一个这种替代方法可能是DLL4（即Delta-like ligand 4）的阻断。该跨膜分子是Notch信号作用通道的一部分。过去人们知道它是胚胎中血管正常发育所必需的，而新的研究工作表明，肿瘤血管形成也需要它。它可能是患有对抗VEGF疗法有抵抗力的固体肿瘤的患者的一种可行的、耐受性可能比较好的替代疗法。
FIGURE 1. Dll4-mediated Notch signalling regulates endothelial cell proliferation.
Anti-Dll4 antibodies or DBZ caused enhanced sprouting (a) and proliferation (b) of HUVECs in co-culture with skin fibroblasts, or in the presence of skin fibroblast-conditioned medium (c). d, Immobilized Dll4 inhibited HUVEC proliferation (left) through Notch activation (right). WB, western blot. NICD, Notch intracellular domain. e, f, Systemic delivery of anti-Dll4 antibodies caused massive accumulation (e) and increased proliferation (f) of endothelial cells in neonatal retinas. g, Anti-VEGF antibodies inhibited HUVEC sprouting. h, Changes in VEGFR2 mRNA expression in response to Notch blockade in three-dimensional fibrin gel culture (left), or Notch activation by Dll4 in two-dimensional culture (right). Bars represent the mean s.e.m. (n = 4).
原文出处：
Nature Volume 444 Number 7122 21 December 2006
Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis p1083
John Ridgway, Gu Zhang, Yan Wu, Scott Stawicki, Wei-Ching Liang, Yvan Chanthery, Joe Kowalski, Ryan J. Watts, Christopher Callahan, Ian Kasman, Mallika Singh, May Chien, Christine Tan, Jo-Anne S. Hongo, Fred de Sauvage, Greg Plowman and Minhong Yan
doi:10.1038/nature05313
First paragraph | Full Text | PDF (779K) | Supplementary information
See also: Editor's summary
相关基因：
VEGFA
Official Symbol: VEGFA and Name: vascular endothelial growth factor A [Homo sapiens]
Other Aliases: MGC70609, VEGF, VEGF-A, VPF
Other Designations: vascular permeability factor
Chromosome: 6; Location: 6p12
MIM: 192240
GeneID: 7422
DLL4
Official Symbol: DLL4 and Name: delta-like 4 (Drosophila) [Homo sapiens]
Other Aliases: MGC126344, hdelta2
Other Designations: delta 4 precursor; delta ligand 4 precursor; delta-like 4 homolog (Drosophila); delta-like 4 protein; notch ligand DLL4 precursor; notch ligand delta-2 precursor
Chromosome: 15; Location: 15q14
MIM: 605185
GeneID: 54567
作者简介：
Greg Plowman
Senior Director: Tumor Biology and Angiogenesis
Profile | Education/Background | Top Scientific Papers
Top Scientific Papers
· Lackner MR, Kindt RM, Carroll PM, Brown K, Cancilla MR, Chen C, Franke Y, Guan B, Heuer T, Hung T, Keegan K, Lee JM, Manne V, O?Brien C, Parry D, Perez-Villar JJ, Reddy RK, Xiao H, Zhan H, Cockett M, Plowman GD, Fitzgerald K, Costa, M, Ross-Macdonald, P. Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors. Cancer Cell 2005 7(4):325-336. View Abstract on PubMed
· Manning G, Plowman GD, Hunter T, Sudarsanam S. Evolution of protein kinase signaling from yeast to man. Trends Biochem Sci 2002 Oct;27(10):514-20. View Abstract on PubMed
· Plowman GD, Sudarsanam S, Bingham J, Whyte D, Hunter T. The protein kinases of Caenorhabditis elegans: a model for signal transduction in multicellular organisms. Proc Natl Acad Sci U S A 1999 Nov 23;96(24):13603-10. View Abstract on PubMed
· Bischoff JR, Plowman GD. The Aurora/Ipl1p kinase family: regulators of chromosome segregation and cytokinesis. Trends Cell Biol 1999 Nov;9(11):454-9. View Abstract on PubMed
· Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C, Chan CS, Novotny M, Slamon DJ, Plowman GD. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 1998 Jun 1;17(11):3052-65. View Abstract on PubMed
· Elenius K, Corfas G, Paul S, Choi CJ, Rio C, Plowman GD, Klagsbrun M. A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester. J Biol Chem 1997 Oct 17;272(42):26761-8. View Abstract on PubMed
· Peles E, Nativ M, Lustig M, Grumet M, Schilling J, Martinez R, Plowman GD, Schlessinger J. Identification of a novel contactin-associated transmembrane receptor with multiple domains implicated in protein-protein interactions. EMBO J 1997 Mar 3;16(5):978-88. View Abstract on PubMed
· Shawver LK, Lipson KE, Fong AT, McMahon G, Plowman GD. Strawn,LM. Receptor tyrosine kinases as targets for inhibition of angiogenesis. Drug Discovery Today 1997 2(2), 50-63.
· Hunter T, Plowman GD. The protein kinases of budding yeast: six score and more. Trends Biochem Sci 1997 Jan;22(1):18-22. View Abstract on PubMed
· Riese DJ, Kim ED, Elenius K, Buckley S, Klagsbrun M, Plowman GD, Stern DF. The epidermal growth factor receptor couples transforming growth factor-alpha, heparin-binding epidermal growth factor-like factor, and amphiregulin to Neu, ErbB-3, and ErbB-4. J Biol Chem 1996 Aug 16;271(33):20047-52. View Abstract on PubMed
· Schuger L, Johnson GR, Gilbride K, Plowman GD, Mandel R. Amphiregulin in lung branching morphogenesis: interaction with heparan sulfate proteoglycan modulates cell proliferation. Development 1996 Jun;122(6):1759-67. View Abstract on PubMed
· Riese DJ 2nd, Bermingham Y, van Raaij TM, Buckley S, Plowman GD, Stern DF. Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-beta. Oncogene 1996 Jan 18;12(2):345-53. View Abstract on PubMed
· Riese DJ 2nd, van Raaij TM, Plowman GD, Andrews GC, Stern DF. The cellular response to neuregulins is governed by complex interactions of the erbB receptor family. Mol Cell Biol 1995 Oct;15(10):5770-6. View Abstract on PubMed
· Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio JM, Plowman GD, Rudy B, Schlessinger J. Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature 1995 Aug 31;376(6543):737-45. View Abstract on PubMed
· Peles E, Nativ M, Campbell PL, Sakurai T, Martinez R, Lev S, Clary DO, Schilling J, Barnea G, Plowman GD, et al. The carbonic anhydrase domain of receptor tyrosine phosphatase beta is a functional ligand for the axonal cell recognition molecule contactin. Cell 1995 Jul 28;82(2):251-60. View Abstract on PubMed
· Siegall CB, Bacus SS, Cohen BD, Plowman GD, Mixan B, Chace D, Chin DM, Goetze A, Green JM, Hellstrom I, et al. HER4 expression correlates with cytotoxicity directed by a heregulin-toxin fusion protein. J Biol Chem 1995 Mar 31;270(13):7625-30. View Abstract on PubMed
· Thorne BA, Plowman GD. The heparin-binding domain of amphiregulin necessitates the precursor pro-region for growth factor secretion. Mol Cell Biol 1994 Mar;14(3):1635-46. View Abstract on PubMed
· Plowman GD, Green JM, Culouscou JM, Carlton GW, Rothwell VM, Buckley S. Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Nature 1993 Dec 2;366(6454):473-5. View Abstract on PubMed
· Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG, Shoyab M. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci U S A 1993 Mar 1;90(5):1746-50. View Abstract on PubMed
· Shoyab M, McDonald VL, Byles C, Todaro GJ, Plowman GD. Epithelins 1 and 2: isolation and characterization of two cysteine-rich growth-modulating proteins. Proc Natl Acad Sci U S A 1990 Oct;87(20):7912-6. View Abstract on PubMed
· Plowman GD, Whitney GS, Neubauer MG, Green JM, McDonald VL, Todaro GJ, Shoyab M. Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. Proc Natl Acad Sci U S A 1990 Jul;87(13):4905-9. View Abstract on PubMed
· Plowman GD, Green JM, McDonald VL, Neubauer MG, Disteche CM, Todaro GJ, Shoyab M. The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity. Mol Cell Biol 1990 May;10(5):1969-81. View Abstract on PubMed
· Shoyab M, Plowman GD, McDonald VL, Bradley JG, Todaro GJ. Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science 1989 Feb 24;243(4894 Pt 1):1074-6. View Abstract on PubMed
· Rose TM, Plowman GD, Teplow DB, Dreyer WJ, Hellstrom KE, Brown JP. Primary structure of the human melanoma-associated antigen p97 (melanotransferrin) deduced from the mRNA sequence. Proc Natl Acad Sci U S A 1986 Mar;83(5):1261-5. View Abstract on PubMed
