title: Cross-talk between endothelial cells and tumor via delta-like ligand 4/Notch/PTEN signaling inhibits lung cancer growth.
abstract: Lung cancer is a leading cause of cancer death in many countries. Notch signaling has been demonstrated to frequently participate in the process of lung carcinogenesis. Delta-like ligand 4 (Dll4) is a vascular-specific ligand of Notch, and has a critical role in the angiogenesis of numerous cancers. However, the role of Dll4 in the cross-talk between endothelial cells (ECs) and tumor cells remains obscure. Herein, our study revealed that Dll4-expressing ECs (EC-Dll4) significantly suppressed the proliferation of neighboring non-small cell lung cancer (NSCLC) cells and attenuated the growth of NSCLC xenograft in nude mice. On the contrary, silencing endothelial Dll4 by its specific interference RNA reversed these effects of Dll4 on NSCLC cell proliferation and tumor formation. Furthermore, activation of Notch1, but not Notch2 or Notch3, was enhanced in NSCLC cells cultured with EC-Dll4, as well as in xenografts induced by a mixture of NSCLC cells and EC-Dll4. Interference of Notch1 significantly attenuated Dll4-mediated suppression of NSCLC cell proliferations, indicating that Dll4/Notch1 signaling negatively modulates the NSCLC growth. Moreover, PTEN expression in NSCLC cells was increased by EC-Dll4 or rhDll4 (recombinant human-Dll4 protein), and the induction was impaired by Notch1 interference suggesting that Dll4 could upregulate PTEN expression by Notch1. Taken together, we conclude that the cross-talk between ECs and NSCLC cells by Dll4/Notch1/PTEN signaling pathway inhibits the growth of NSCLC.
authors: Department of Thoracic and Cardiovascular Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors: X-Y
authors: XY
authors: Ding
authors: J
authors: J
authors: Ding
authors: K
authors: K
authors: Wu
authors: W
authors: W
authors: Wen
authors: C
authors: C
authors: Liu
authors: H-X
authors: HX
authors: Yan
authors: C
authors: C
authors: Chen
authors: S
authors: S
authors: Wang
authors: H
authors: H
authors: Tang
authors: C-K
authors: CK
authors: Gao
authors: L-N
authors: LN
authors: Guo
authors: D
authors: D
authors: Cao
authors: Z
authors: Z
authors: Li
authors: G-S
authors: GS
authors: Feng
authors: H-Y
authors: HY
authors: Wang
authors: Z-F
authors: ZF
authors: Xu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002450:Cell Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human