Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis.
BACKGROUND
Anti-angiogenesis is a validated strategy to treat cancer, with efficacy in controlling both primary tumor growth and metastasis. The role of the Notch family of proteins in tumor angiogenesis is still emerging, but recent data suggest that Notch signaling may function in the physiologic response to loss of VEGF signaling, and thus participate in tumor adaptation to VEGF inhibitors.


METHODS
We asked whether combining Notch and VEGF blockade would enhance suppression of tumor angiogenesis and growth, using the NGP neuroblastoma model. NGP tumors were engineered to express a Notch1 decoy construct, which restricts Notch signaling, and then treated with either the anti-VEGF antibody bevacizumab or vehicle.


RESULTS
Combining Notch and VEGF blockade led to blood vessel regression, increasing endothelial cell apoptosis and disrupting pericyte coverage of endothelial cells. Combined Notch and VEGF blockade did not affect tumor weight, but did additively reduce tumor viability.


CONCLUSIONS
Our results indicate that Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis, and show that concurrent blockade disrupts primary tumor vasculature and viability further than inhibition of either pathway alone.
Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
Sonia L
SL
Hernandez
Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
Debarshi
D
Banerjee
Department of Surgery, Columbia University Medical Center, New York, NY, USA.
Alejandro
A
Garcia
Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA.
Thaned
T
Kangsamaksin
Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.
Wei-Yi
WY
Cheng
Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.
Dimitris
D
Anastassiou
Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA.
Yasuhiro
Y
Funahashi
Department of Surgery, Columbia University Medical Center, New York, NY, USA.
Angela
A
Kadenhe-Chiweshe
Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA.
Carrie J
CJ
Shawber
Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA.|Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
Jan K
JK
Kitajewski
Department of Surgery, Columbia University Medical Center, New York, NY, USA.
Jessica J
JJ
Kandel
Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.|Department of Surgery, Columbia University Medical Center, New York, NY, USA.|Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
Darrell J
DJ
Yamashiro