High-Dose Radiation Increases Notch1 in Tumor Vasculature

Banerjee, Debarshi; Barton, Sunjay M.; Grabham, Peter; Rumeld, Ariela L.; Okochi, Shunpei; Street, Cherease; Kadenhe-Chiweshe, Angela; Boboila, Shuobo; Yamashiro, Darrell J.; Connolly, Eileen

doi:10.1016/j.ijrobp.2019.11.010

Cited by 13 publications

(12 citation statements)

References 32 publications

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“…HDR increased Notch1 signaling, which was not observed at doses less than 2 Gy. These results suggest that Notch1 activation can protect tumor vessels and control the EndMT process in HDRT 85 .…”

Section: Radiation-induced Tumor Endmtmentioning

confidence: 69%

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

et al. 2020

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Endothelial-to-mesenchymal transition (EndMT) involves the phenotypic conversion of endothelial-to-mesenchymal cells, and was first discovered in association with embryonic heart development. EndMT can regulate various processes, such as tissue fibrosis and cancer. Recent findings have shown that EndMT is related to resistance to cancer therapy, such as chemotherapy, antiangiogenic therapy, and radiation therapy. Based on the known effects of EndMT on the cardiac toxicity of anticancer therapy and tissue damage of radiation therapy, we propose that EndMT can be targeted as a strategy for overcoming tumor resistance while reducing complications, such as tissue damage. In this review, we discuss EndMT and its roles in damaging cardiac and lung tissues, as well as EndMT-related effects on tumor vasculature and resistance in anticancer therapy. Modulating EndMT in radioresistant tumors and radiationinduced tissue fibrosis can especially increase the efficacy of radiation therapy. In addition, we review the role of hypoxia and reactive oxygen species as the main stimulating factors of tissue damage due to vascular damage and EndMT. We consider drugs that may be clinically useful for regulating EndMT in various diseases. Finally, we argue the importance of EndMT as a therapeutic target in anticancer therapy for reducing tissue damage.

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Section: Radiation-induced Tumor Endmtmentioning

confidence: 69%

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

et al. 2020

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“…Previously, reactivation of developmental signaling pathways, including Notch, was sufficient to epigenetically reprogram cardiomyocytes to produce a conductive "Purkinje-like" electrophenotype 33,34 . Furthermore, Notch signaling is known to play a role in the radiation response and radio-resistance of several tissue types 54,55 . Through RNA-seq and transgenic approaches, we identify cardiomyocyte-specific Notch activation as one potential cell signaling mechanism that may contribute to the pro-conductive effect of radiation via upregulation of the cardiac sodium channel.…”

Section: Discussionmentioning

confidence: 99%

“…Here we show that radiation-induced electrical reprogramming can also occur at lower doses in the range of 15-25 Gy in mice. Indeed, Notch signaling has been reported to activate in a variety of tissue types following lower doses of radiation 54,55,57 . These data could warrant future clinical studies of careful downward dose titration to find the lowest effective dose that minimizes risk of late-stage toxicity.…”

Section: Discussionmentioning

confidence: 99%

Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis

et al. 2021

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Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in NaV1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to NaV1.5 upregulation after RT. Clinically, RT was associated with increased NaV1.5 expression in 1 of 1 explanted heart. On electrocardiogram (ECG), post-RT QRS durations were shortened in 13 of 19 patients and lengthened in 5 patients. Collectively, this study provides evidence for radiation-induced reprogramming of cardiac conduction as a potential treatment strategy for arrhythmia management in VT patients.

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“…Additionally, NOTCH activation in ECs promotes lung metastasis, while endothelial NOTCH1 activation in the liver reduces intercellular adhesion molecule-1 expression and endothelial tumor cell adhesion and retention, thereby reducing liver metastasis 528,529 . During radiotherapy, endothelial NOTCH1 activation protects tumor vessels from radiotherapy-induced damage and regulates endothelialmesenchymal transition 530 . Surprisingly, NOTCH3 acts as a receptor-dependent receptor in the endothelium to induce endothelial cell apoptosis and can be blocked by JAG1 526 .…”

Section: Squamous Cell Cancersmentioning

confidence: 99%

Notch signaling pathway: architecture, disease, and therapeutics

Zhou

Wanling

Long

et al. 2022

Sig Transduct Target Ther

475

255

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The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.

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High-Dose Radiation Increases Notch1 in Tumor Vasculature

Cited by 13 publications

References 32 publications

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis

Notch signaling pathway: architecture, disease, and therapeutics

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