title: rhBMP-2 has adverse effects on human oral carcinoma cell lines in vivo.
abstract: OBJECTIVE
  To establish the relevance of the bone morphogenetic protein (BMP) signaling pathway in human oral squamous cell carcinoma (OSCCA) cell lines and determine if there is a biologic impact of stimulating this pathway with recombinant human (rh) BMP-2.
  
  
  METHODS
  In vitro laboratory investigations and in vivo analysis using an orthotopic animal model for oral cancer.
  
  
  METHODS
  Gene expression profiles for BMP-2 and components of the BMP-signaling pathway were determined using reverse transcriptase-polymerase chain reaction. In vivo effects were evaluated using Kaplan-Meier survival analysis and studying histopathologic changes in established tumor xenografts with or without rhBMP-2 pretreatment. A phosphokinase array was used to detect levels of activation in signaling kinases.
  
  
  RESULTS
  The BMP-2 gene was expressed in 90% of the 30 OSCCA cell lines tested. Gene expression of all components of the BMP-signaling pathway was highly conserved. Tumor xenografts established with rhBMP-2-treated cells showed more rapid local growth that resulted in worse animal survival as compared to the control group. These tumors had a more poorly differentiated morphology. Changes in protein kinases suggested interactions of BMP-2 signaling with the Wnt-β-catenin, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways.
  
  
  CONCLUSIONS
  Human OSCCA cell lines frequently express BMP-2 and all necessary components of the BMP-signaling pathway. Exogenous treatment of human OSCCA cell lines with rhBMP-2 prior to engraftment in an orthotopic animal model caused the subsequent tumors to be more locally aggressive with worse survival. Continued caution should be used for considering rhBMP-2 for reconstruction of bone defects in oral cancer patients.
authors: Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors: Natalia A
authors: NA
authors: Kokorina
authors: James S
authors: JS
authors: Lewis
authors: Stanislav O
authors: SO
authors: Zakharkin
authors: Paul H
authors: PH
authors: Krebsbach
authors: Brian
authors: B
authors: Nussenbaum
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000009:adverse effects* / Q000096:biosynthesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009062:Mouth Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000009:adverse effects; D016212:Transforming Growth Factor beta / Q000009:adverse effects*; D014407:Tumor Cells, Cultured
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2