VEGF and Notch Signaling

Hellström, Mats; Phng, Li-Kun; Gerhardt, Holger

doi:10.4161/cam.1.3.4978

Cited by 144 publications

(66 citation statements)

References 28 publications

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“…However, NOTCH1 has been associated with VEGFR1 in previous studies [19]. Moreover, a discussion on NOTCH and VEGF signaling proposes a model where NOTCH1 and VEGFR2 may play symbiotic roles in angiogenesis [20]. This indicates that there might also be an association of NOTCH1 and VEGFR2 in combined development towards angiogenesis which strengthens our results.…”

Section: Discussionsupporting

confidence: 79%

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

Jauhri¹,

Gupta²,

Shokeen³

et al. 2017

Next Generat Sequenc & Applic

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Aim: This study aims to find out the frequency of KDR mutation in colorectal cancer patients and if any correlation exists between KDR mutation and demographical features or with other common and uncommon gene mutations occurring in colon cancer.Methods: FFPE samples of 112 patients were analyzed using next generation sequencing.Results: KDR gene was found to be mutated most frequently (19.6%) as compared to other uncommon gene mutations occurring among patients. 21/22 patients had the p.Q472H type of KDR mutation. It was significantly associated with mutations in PTEN (p=0.003), KRAS (p=0.026), APC (p=0.033), EGFR (p=0.036), NOTCH1 (p=0.029) and ERBB4 (p=0.008) mutations. More number of males (22.06%) harbored KDR mutations than the number of females (15.9%). A higher number of KDR mutations in Stage III (31%) as compared to other stages -I-II (19.23%) and IV (7.31%) was reported. KDR mutations were found to be in greater number in patients with lymph node metastasis (27.3%) as compared to liver metastasis (8%). However, a statistically significant association of any clinical parameter was not found. Conclusion:Our results suggest that although KDR is a rare somatic mutation in CRC, it plays a pivotal role in the development of colon cancer via angiogenesis pathway.

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Section: Discussionsupporting

confidence: 79%

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

Jauhri¹,

Gupta²,

Shokeen³

et al. 2017

Next Generat Sequenc & Applic

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“…NCID acts as a transcription factor and co-activator of Mastermind-like (MAML). In retinal endothelial cells, the transcription factor NF-E2- related factor 2 (Nrf2) promotes angiogenic sprouting by suppressing Dll4/Notch signaling (Wei, Gong et al 2013), as a consequence, tip cell markers, including VEGFR2 are overexpressed (Hellstrom, Phng et al 2007, Lobov, Renard et al 2007, Suchting, Freitas et al 2007), thus supporting the role of Notch signaling in cell fate determination. Finally, the vasculature is remodeled in a leukocyte dependent manner by the induction of endothelial apoptosis in a Fas ligand (or CD18)-dependent process (Ishida, Yamashiro et al 2003) endosialin (Simonavicius, Ashenden et al 2012).…”

Section: Development Of the Inner Blood-retinal Barriermentioning

confidence: 99%

The inner blood-retinal barrier: Cellular basis and development

2017

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“…We describe the pre-existing vasculature on this grid-like network in which sprouts can be generated from and fuse into, analogous to [McDougall et al , 2002, Stephanou et al , 2005, McDougall et al , 2006, Bartha & Rieger, 2006, Lee et al , 2006,Welter et al , 2008,Welter et al , 2009,Welter et al , 2010]. During angiogenesis, the sprouting pattern along stimulated vessels can be mediated by Notch-Delta signaling between adjacent endothelial cells (ECs) that ensures no adjacent ECs sprout simultaneously under the TAF stimulation [Hellstrom et al , 2007, Jakobsson et al , 2009]. We incorporate this sprouting pattern analogously to [Welter et al , 2009] (investigated in detail in [Bentley et al , 2008]).…”

Section: The Coupled Mathematical Modelmentioning

confidence: 99%

The effect of interstitial pressure on therapeutic agent transport: Coupling with the tumor blood and lymphatic vascular systems

Frieboes

Chaplain

et al. 2014

Journal of Theoretical Biology

101

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Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but leads to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the response slows down as the tumor shrinks due to the heterogeneity and low concentration of agents in the tumor interior compared with the cases where other pathological effects may combine to flatten the IFP and thus reduce the heterogeneity. We conclude that dual normalizations of the micronevironment - both the vasculature and the interstitium - are needed to maximize the effects of chemotherapy, while normalization of only one of these may be insufficient to overcome the physical resistance and thus leads to sub-optimal outcomes.

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VEGF and Notch Signaling

Cited by 144 publications

References 28 publications

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

The inner blood-retinal barrier: Cellular basis and development

The effect of interstitial pressure on therapeutic agent transport: Coupling with the tumor blood and lymphatic vascular systems

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