rhBMP-2 has adverse effects on human oral carcinoma cell lines in vivo

Authors

  • Natalia A. Kokorina MD,

    1. Department of Otolaryngology–Head and Neck Surgery , Washington University School of Medicine, St. Louis, Missouri
    Search for more papers by this author
  • James S. Lewis Jr. MD,

    1. Department of Otolaryngology–Head and Neck Surgery , Washington University School of Medicine, St. Louis, Missouri
    2. Department of Pathology , Washington University School of Medicine, St. Louis, Missouri
    Search for more papers by this author
  • Stanislav O. Zakharkin PhD,

    1. Department of Science and Technology , Solae, St. Louis, Missouri
    Search for more papers by this author
  • Paul H. Krebsbach DDS, PhD,

    1. Department of Biologic and Materials Sciences , University of Michigan School of Dentistry, Ann Arbor, Michigan, U.S.A.
    Search for more papers by this author
  • Brian Nussenbaum MD

    Corresponding author
    1. Department of Otolaryngology–Head and Neck Surgery , Washington University School of Medicine, St. Louis, Missouri
    • Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8115, St. Louis, MO 63110
    Search for more papers by this author

  • 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.

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.

Ancillary