DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Frequency

• Published in: Cell stem cell Vol. 5; no. 2; pp. 168 - 177
• Main Authors: Hoey, Timothy, Yen, Wan-Ching, Axelrod, Fumiko, Basi, Jesspreet, Donigian, Lucas, Dylla, Scott, Fitch-Bruhns, Maureen, Lazetic, Sasha, Park, In-Kyung, Sato, Aaron, Satyal, Sanjeev, Wang, Xinhao, Clarke, Michael F., Lewicki, John, Gurney, Austin
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 07.08.2009; Cell Press
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents, Phytogenic - therapeutic use; Apoptosis Regulatory Proteins - metabolism; Biological and medical sciences; Camptothecin - analogs & derivatives; Camptothecin - therapeutic use; Cell differentiation, maturation, development, hematopoiesis; Cell Line, Tumor; Cell physiology; Cell Proliferation - drug effects; CELLCYCLE; Chaperonin 60 - agonists; Chaperonin 60 - metabolism; Drug Synergism; Fundamental and applied biological sciences. Psychology; Humans; Inhibitor of Apoptosis Proteins - metabolism; Intercellular Signaling Peptides and Proteins - immunology; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Membrane Proteins - antagonists & inhibitors; Mice; Molecular and cellular biology; Neoplasms - pathology; Neoplasms - therapy; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - immunology; Neovascularization, Pathologic - metabolism; Receptors, Notch - metabolism; Secondary Prevention; STEMCELL; Xenograft Model Antitumor Assays; STEMCELL; CELLCYCLE; Frequency; Inhibition; Malignant tumor; Tumor cell; Cancer
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2009.05.019

Previous 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 in vivo tumorigenicity studies.