Paracrine signaling through MYCN enhances tumor-vascular interactions in neuroblastoma.
Neuroblastoma, a tumor of peripheral neural crest origin, numbers among the most common childhood cancers. Both amplification of the proto-oncogene MYCN and increased neoangiogenesis mark high-risk disease. Because angiogenesis is regulated by phosphatidylinositol 3-kinase (PI3K), we tested a clinical PI3K inhibitor, NVP-BEZ235, in MYCN-dependent neuroblastoma. NVP-BEZ235 decreased angiogenesis and improved survival in both primary human (highly pretreated recurrent MYCN-amplified orthotopic xenograft) and transgenic mouse models for MYCN-driven neuroblastoma. Using both gain- and loss-of-function approaches, we demonstrated that the antiangiogenic efficacy of NVP-BEZ235 depended critically on MYCN in vitro and in vivo. Thus, clinical PI3K/mammalian target of rapamycin inhibitors drove degradation of MYCN in tumor cells, with secondary paracrine blockade of angiogenesis. Our data demonstrated significantly improved survival in treated animals and suggest that NVP-BEZ235 should be tested in children with high-risk, MYCN-amplified neuroblastoma.
Biomedical Science Graduate Program, University of California, San Francisco, 1450 Third Street, MC0520, San Francisco, CA 94158-9001, USA.
Yvan H
YH
Chanthery
W Clay
WC
Gustafson
Melissa
M
Itsara
Anders
A
Persson
Christopher S
CS
Hackett
Matt
M
Grimmer
Elise
E
Charron
Slava
S
Yakovenko
Grace
G
Kim
Katherine K
KK
Matthay
William A
WA
Weiss
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009447:Neuroblastoma / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D015513:Oncogene Proteins / Q000096:biosynthesis*; D019899:Paracrine Communication; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction
D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011804:Quinolines; C000715470:MAS1 protein, human; C459801:MYCN protein, human; C571825:MYCN protein, mouse; C531198:dactolisib