This work was supported by funding from an RO3 grant (DE017137-01A1) from the National Institute of Dental and Craniofacial Research/National Institutes of Health (NIDCR/NIH), and from a donation from the Bernard Hemann family. The authors have no other funding, financial relationships, or conflicts of interest to disclose.
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Head and Neck
rhBMP-2 has adverse effects on human oral carcinoma cell lines in vivo†
Article first published online: 13 OCT 2011
DOI: 10.1002/lary.22345
Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.
Additional Information
How to Cite
Kokorina, N. A., Lewis, J. S., Zakharkin, S. O., Krebsbach, P. H. and Nussenbaum, B. (2012), rhBMP-2 has adverse effects on human oral carcinoma cell lines in vivo. The Laryngoscope, 122: 95–102. doi: 10.1002/lary.22345
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Publication History
- Issue published online: 19 DEC 2011
- Article first published online: 13 OCT 2011
- Manuscript Accepted: 9 AUG 2011
- Manuscript Received: 18 JUL 2011
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Keywords:
- Bone morphogenetic protein;
- oral cancer;
- squamous cell carcinoma;
- Level of Evidence: 5.
Abstract
Objectives/Hypothesis:
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.
Study Design:
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.