Article:DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Fr

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Table of Contents for Cell Stem Cell,
# v' C7 u4 ~% z, P9 F4 sVolume 5, Issue 2. August 2009) \% A) I9 D& A$ ]9 z3 k2 q
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1 L4 C/ A! ]- g. _9 v. y1 jDLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Frequency
. I$ y) A7 [: b& r$ U. F# v& eTimothy Hoey1,,,Wan-Ching Yen1,Fumiko Axelrod1,Jesspreet Basi1,Lucas Donigian1,Scott Dylla1,Maureen Fitch-Bruhns1,Sasha Lazetic1,In-Kyung Park1,Aaron Sato1,Sanjeev Satyal1,Xinhao Wang1,Michael F. Clarke2,John Lewicki1andAustin Gurney1$ Y) B" {- e1 n
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1 OncoMed Pharmaceuticals Inc., Redwood City, CA 94063, USA
/ C5 E2 g, t/ G2 Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94063, USA
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Corresponding author
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+ d% y( ~* @! d: Z0 V% eSummary
4 |1 P& T  Q$ s" r0 G4 O7 oPrevious studies have shown that blocking DLL4 signaling reduced tumor growth by disrupting productive angiogenesis. We developed selective anti-human and anti-mouse DLL4 antibodies to dissect the mechanisms involved by analyzing the contributions of selectively targeting DLL4 in the tumor or in the host vasculature and stroma in xenograft models derived from primary human tumors. We found that each antibody inhibited tumor growth and that the combination of the two antibodies was more effective than either alone. Treatment with anti-human DLL4 inhibited the expression of Notch target genes and reduced proliferation of tumor cells. Furthermore, we found that specifically inhibiting human DLL4 in the tumor, either alone or in combination with the chemotherapeutic agent irinotecan, reduced cancer stem cell frequency, as shown by flow cytometric and invivo tumorigenicity studies.