High-Dose Radiation Increases Notch1 in Tumor Vasculature

Autor: Ariela L. Rumeld, Darrell J. Yamashiro, Cherease Street, Sunjay M. Barton, Debarshi Banerjee, Angela Kadenhe-Chiweshe, Shunpei Okochi, Shuobo Boboila, Peter Grabham, Eileen P. Connolly
Rok vydání: 2020
Předmět:
Cancer Research
JAG1
Epithelial-Mesenchymal Transition
medicine.medical_treatment
Notch signaling pathway
Mice
Nude
Radiation Dosage
Article
Umbilical vein
030218 nuclear medicine & medical imaging
Mice
03 medical and health sciences
0302 clinical medicine
Cell Line
Tumor
Neuroblastoma
Basic Helix-Loop-Helix Transcription Factors
Human Umbilical Vein Endothelial Cells
Animals
Humans
Medicine
Radiology
Nuclear Medicine and imaging
Receptor
Notch1
HEY2
HEY1
Radiation
Neovascularization
Pathologic
business.industry
Radiotherapy Dosage
medicine.disease
Gene Expression Regulation
Neoplastic
Repressor Proteins
Endothelial stem cell
Radiation therapy
Cell Transformation
Neoplastic
Oncology
030220 oncology & carcinogenesis
cardiovascular system
Cancer research
Female
business
Jagged-1 Protein
Signal Transduction
Zdroj: International journal of radiation oncology, biology, physics
ISSN: 0360-3016
Popis: Purpose: The aim of this study is to characterize the effects of high-dose radiation therapy (HDRT) on Notch signaling components of the tumor vasculature. Methods and Materials: Human umbilical vein endothelial cells monolayers were exposed to different single fraction doses of irradiation; ribonucleic acid RNA was isolated and polymerase chain reaction was performed for Notch signaling components. The vascular response to radiation therapy was examined in a xenograft model of neuroblastoma. Tumors were treated with 0 Gy, 2 Gy, and 12 Gy single fraction doses and analyzed by double immunofluorescence staining for Notch1, Notch ligands Jagged1 and Dll4, and the endothelial cell (EC) marker endomucin. To assess the role of Notch in vivo, NGP xenograft tumors expressing Fc or Notch1-1–24-decoy (a novel Notch inhibitor) were treated with 0 Gy and 12 Gy. Immunofluorescence staining for endomucin and endomucin/αSMA was performed to analyze the effect of combination treatment on tumor EC and endothelial-to-mesenchymal-transition (EndMT), respectively. Results: In human umbilical vein endothelial cells monolayers doses ≥8 Gy increased expression of NOTCH1, JAG1, and Notch target genes HEY1 and HEY2 as early as 6 hours after irradiation. In vivo, 12 Gy significantly increased Notch1 and Jagged1 in tumor ECs compared with 0 Gy or 2 Gy after 72 hours. Combining HDRT with Notch inhibition using the Notch1-1–24-decoy resulted in a greater loss of EC coverage of tumor vessels than HDRT alone at 6 hours and 72 hours post treatment. Notch inhibition reduced EndMT induced by HDRT, as indicated by diminished αSMA staining in ECs. Conclusions: HDRT induced Notch1 expression and increased Notch1 signaling in the endothelial component of tumor vasculature, which was not observed with lower doses. This increase in Notch1 activation might protect tumor vessels from HDRT induced damage and regulate EndMT process.
Summary High-dose radiation (HDRT) not only has a direct cytotoxic effect on tumor cells but can also effect the tumor vasculature. Our study examined HDRT and Notch signaling in a xenograft model of neuroblastoma. We observed an increased Notch signaling in endothelial cells after HDRT. Notch1 inhibition augments the effect of HDRT on endothelial cell loss and reduces radiation-induced endothelial-to-mesenchymal transition.
Databáze: OpenAIRE
Externí odkaz: