title: Hes4: A potential prognostic biomarker for newly diagnosed patients with high-grade osteosarcoma.
abstract: Prognostic biomarkers for osteosarcoma (OS) at the time of diagnosis are lacking. Necrotic response of OS to preoperative chemotherapy correlates with survival and is determined 3-4 months after diagnosis. The purpose of this study is to identify biomarkers that will stratify patients into good or poor responders to chemotherapy at diagnosis and determine the role of potential biomarkers in OS pathogenesis.
  
  
  
  Because OS may be caused by disruptions of osteogenic differentiation, and the Notch pathway is one regulator of bone development, we examined the link between Notch effectors, OS differentiation, and OS outcome. We probed the R2: Genomics Analysis and Visualization Platform for RNA expression levels of Notch targets in mixed high-grade OS pretreatment biopsies. We used human OS cell lines in vitro and in mice to determine the role of the Notch target hairy/enhancer of split 4 (Hes4) in OS.
  
  
  
  We found that in OS patients, high expression of Hes4 is correlated with decreased metastasis-free and overall survival. Human OS cells that overexpress Hes4 are more immature and have an increased invasive capacity in vitro. This was not universal to all Notch effectors, as Hes1 overexpression induced opposing effects. When injected into NSG mice, Hes4-overexpressing OS cells produced significantly larger, more lytic tumors and significantly more metastases than did control cells.
  
  
  
  Hes4 overexpression promotes a more aggressive tumor phenotype by preventing osteoblastic differentiation of OS cells. Hes4 expression may allow for the stratification of patients into good or poor responders to chemotherapy at diagnosis.
authors: Division of Pediatrics, Department of Pediatric Research, MD Anderson Cancer Center, Houston, Texas.
authors: Madonna
authors: M
authors: McManus
authors: Division of Pediatrics, Department of Pediatric Research, MD Anderson Cancer Center, Houston, Texas.
authors: Eugenie
authors: E
authors: Kleinerman
authors: Division of Pediatrics, Department of Pediatric Research, MD Anderson Cancer Center, Houston, Texas.
authors: Yanwen
authors: Y
authors: Yang
authors: Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: John Andrew
authors: JA
authors: Livingston
authors: Division of Pediatrics, Department of Pediatric Research, MD Anderson Cancer Center, Houston, Texas.
authors: Jared
authors: J
authors: Mortus
authors: Division of Pediatrics, Department of Pediatric Research, MD Anderson Cancer Center, Houston, Texas.
authors: Rocio
authors: R
authors: Rivera
authors: Division of Pediatrics, Department of Pediatric Research, MD Anderson Cancer Center, Houston, Texas.
authors: Patrick
authors: P
authors: Zweidler-McKay
authors: Division of Pediatrics, Department of Pediatric Research, MD Anderson Cancer Center, Houston, Texas.
authors: Keri
authors: K
authors: Schadler
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics; D001859:Bone Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D010012:Osteogenesis / Q000502:physiology*; D012516:Osteosarcoma / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000096:biosynthesis; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D050659:Core Binding Factor Alpha 1 Subunit; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors; C000604917:Hes4 protein, human; C493709:RUNX2 protein, human; C478163:SP7 protein, human
keywords: Hes4; Notch; osteogenic differentiation; osteosarcoma; prognostic factor