title: Delta-like 4/Notch pathway is differentially regulated in benign and malignant thyroid tissues.
abstract: BACKGROUND
  Angiogenesis plays an essential role in embryonic and tumoral developments. Vascular endothelial growth factor (VEGF), one of the best known proangiogenic factors, is increased in thyroid cancers, especially in papillary carcinomas (PC). However, other regulating mechanisms refine VEGF-induced cellular changes, such as the Notch family of ligands and receptors. Their role has not yet been investigated in the thyroid. The purpose of our study was to analyze the expression of Notch1, Notch4, and Delta-like 4 (DLL4) in benign and malignant thyroid lesions.
  
  
  METHODS
  The expression of Notch1, Notch4, and DLL4 was analyzed by immunohistochemistry, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), and Western-blot in normal thyroids (NTs), hyperplasic thyroids from patients with Graves' disease (GD), microcarcinomas, PC, and follicular carcinomas.
  
  
  RESULTS
  The immunohistochemical expression of Notch1, Notch4, and DLL4 was highly variable in thyrocytes from NTs and GD. In contrast, the staining in tumors was homogeneous and often intense. The increased expression of Notch1, Notch4, and DLL4 in carcinomas compared with the neighboring normal tissue was confirmed by qRT-PCR and Western-blot. However, only capillary endothelial cells from GD samples were positive for DLL4, the expression being restricted to large vessels in carcinomas and NTs.
  
  
  CONCLUSIONS
  The detection of Notch1, Notch4, and DLL4 in thyrocytes and their regulation in various pathologies suggest that this pathway may play a role in thyroid carcinogenesis and angiogenesis.
authors: Department of Pathology, University Hospital (UZ) Brussels, Vrij University of Brussels, Brussels, Belgium.
authors: Caroline
authors: C
authors: Geers
authors: Ides M
authors: IM
authors: Colin
authors: Anne-Catherine
authors: AC
authors: Gérard
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D018263:Adenocarcinoma, Follicular; D000704:Analysis of Variance; D001530:Belgium; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D002277:Carcinoma; D002291:Carcinoma, Papillary; D006111:Graves Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000032:analysis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051881:Receptor, Notch1 / Q000032:analysis* / Q000235:genetics; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000032:analysis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000737:chemistry* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C497761:NOTCH1 protein, human; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D051880:Receptors, Notch