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Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis.

ABSTRACT: 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.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.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.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.

SUBMITTER: Hernandez SL

PROVIDER: S-EPMC3849070 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis.

Hernandez Sonia L SL Banerjee Debarshi D Garcia Alejandro A Kangsamaksin Thaned T Cheng Wei-Yi WY Anastassiou Dimitris D Funahashi Yasuhiro Y Kadenhe-Chiweshe Angela A Shawber Carrie J CJ Kitajewski Jan K JK Kandel Jessica J JJ Yamashiro Darrell J DJ

Vascular cell 20130925 1

<h4>Background</h4>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.<h4>Methods</h4>We asked whether combining Notch and VEGF blockade would enhance suppression of ...[more]

PMID: 24066611

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Project description:Continued gambling to recover losses--'loss chasing'--is a prominent feature of social and pathological gambling. However, little is known about the neuromodulators that influence this behavior. In three separate experiments, we investigated the role of serotonin activity, D(2)/D(3) receptor activity, and beta-adrenoceptor activity on the loss chasing of age and IQ-matched healthy adults randomized to treatment or an appropriate control/placebo. In Experiment 1, participants consumed amino-acid drinks that did or did not contain the serotonin precursor, tryptophan. In Experiment 2, participants received a single 176 ?g dose of the D(2)/D(3) receptor agonist, pramipexole, or placebo. In Experiment 3, participants received a single 80 mg dose of the beta-adrenoceptor blocker, propranolol, or placebo. Following treatment, participants completed a computerized loss-chasing game. Mood and heart rate were measured at baseline and following treatment. Tryptophan depletion significantly reduced the number of decisions made to chase losses, and the number of consecutive decisions to chase, in the absence of marked changes in mood. By contrast, pramipexole significantly increased the value of losses chased and diminished the value of losses surrendered. Propranolol markedly reduced heart rate, but produced no significant changes in loss-chasing behavior. Loss chasing can be thought of as an aversively motivated escape behavior controlled, in part, by the marginal value of continued gambling relative to the value of already accumulated losses. Serotonin and dopamine appear to play dissociable roles in the tendency of individuals to gamble to recover, or to seek to 'escape' from, previous losses. Serotonergic activity seems to promote the availability of loss chasing as a behavioral option, whereas D(2)/D(3) receptor activity produces complex changes in the value of losses judged worth chasing. Sympathetic arousal, at least as mediated by beta-adrenoceptors, does not play a major role in laboratory-based loss-chasing choices.

Dataset Information

Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis.

Publications

Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis.

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