title: High NOTCH activity induces radiation resistance in non small cell lung cancer.
abstract: OBJECTIVE
  Patients with advanced NSCLC have survival rates <15%. The NOTCH pathway plays an important role during lung development and physiology but is often deregulated in lung cancer, making it a potential therapeutic target. We investigated NOTCH signaling in NSCLC and hypothesized that high NOTCH activity contributes to radiation resistance.
  
  
  METHODS
  NOTCH signaling in NSCLC patient samples was investigated using quantitative RT-PCR. H460 NSCLC cells with either high or blocked NOTCH activity were generated and their radiation sensitivity monitored using clonogenic assays. In vivo, xenograft tumors were irradiated and response assessed using growth delay. Microenvironmental parameters were analyzed by immunohistochemistry.
  
  
  RESULTS
  Patients with high NOTCH activity in tumors showed significantly worse disease-free survival. In vitro, NOTCH activity did not affect the proliferation or intrinsic radiosensitivity of NSCLC cells. In contrast, xenografts with blocked NOTCH activity grew slower than wild type tumors. Tumors with high NOTCH activity grew significantly faster, were more hypoxic and showed a radioresistant phenotype.
  
  
  CONCLUSIONS
  We demonstrate an important role for NOTCH in tumor growth and correlate high NOTCH activity with poor prognosis and radioresistance. Blocking NOTCH activity in NSCLC might be a promising intervention to improve outcome after radiotherapy.
authors.affiliation: Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+).
authors.forename: Jan
authors.initials: J
authors.lastname: Theys
authors.affiliation: Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+).
authors.forename: Sanaz
authors.initials: S
authors.lastname: Yahyanejad
authors.affiliation: Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+).
authors.forename: Roger
authors.initials: R
authors.lastname: Habets
authors.affiliation: Department of Radiation Oncology, Radboud University Medical Center, Nijmegen.
authors.forename: Paul
authors.initials: P
authors.lastname: Span
authors.affiliation: Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+).
authors.forename: Ludwig
authors.initials: L
authors.lastname: Dubois
authors.affiliation: Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+).
authors.forename: Kim
authors.initials: K
authors.lastname: Paesmans
authors.affiliation: Department of Radiation Oncology, Radboud University Medical Center, Nijmegen.
authors.forename: Bo
authors.initials: B
authors.lastname: Kattenbeld
authors.affiliation: Department of Pathology, Maastricht University Medical Center (MUMC+).
authors.forename: Jack
authors.initials: J
authors.lastname: Cleutjens
authors.affiliation: Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+).
authors.forename: Arjan J
authors.initials: AJ
authors.lastname: Groot
authors.affiliation: Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Olga C J
authors.initials: OCJ
authors.lastname: Schuurbiers
authors.affiliation: Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+).
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
authors.affiliation: Department of Radiation Oncology, Radboud University Medical Center, Nijmegen.
authors.forename: Jan
authors.initials: J
authors.lastname: Bussink
authors.affiliation: Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+).
authors.forename: Marc
authors.initials: M
authors.lastname: Vooijs
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D011836:Radiation Tolerance; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051880:Receptors, Notch
keywords: Hypoxia; NOTCH; NSCLC; Radiation
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