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PNAS 103 (24): 9017-9022

Copyright © 2006 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis

John R. Basile*, Rogerio M. Castilho*, Vanessa P. Williams{dagger}, and J. Silvio Gutkind*,{ddagger}

*Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; and {dagger}Meharry Medical College, 1005 Dr. D. B. Todd, Jr., Boulevard, Nashville, TN 37208

Edited by Marc T. Tessier-Lavigne, Genentech, Inc., South San Francisco, CA, and approved May 4, 2006

Received for publication October 7, 2005.

Abstract: Tumor progression and metastasis depend on the ability of cancer cells to initiate angiogenesis and ensure delivery of oxygen, nutrients, and growth factors to rapidly dividing transformed cells and provide access to the systemic circulation. In addition to well established growth factors and inflammatory mediators that promote capillary sprouting and endothelial cell growth and migration, an emerging body of evidence supports a previously unrecognized function for axon guidance molecules in regulation of blood vessel development. Here we show that semaphorin 4D (Sema4D), a protein originally shown to regulate axonal growth cone guidance in the developing central nervous system through its receptor, plexin-B1, is highly expressed in cell lines derived from head and neck squamous cell carcinomas (HNSCCs) at both the protein and message level. Immunohistochemical analysis of a large collection of HNSCC specimens revealed high levels of Sema4D in a cell surface pattern in invading islands of transformed epithelial cells, but not in normal and noninvasive dysplastic epithelium. A similar pattern was observed in malignant cells from prostate, colon, breast, and lung cancer tissues. When shed from HNSCC cells, Sema4D stimulates endothelial cell migration, which can be prevented by Sema4D-blocking antibodies and by Sema4D knockdown. Furthermore, knocking down Sema4D by lentiviral expression of Sema4D shRNA reduces dramatically the size and vascularity of HNSCC tumor xenografts. These findings indicate that expression of Sema4D is a frequently used strategy by which a wide variety of carcinomas may promote angiogenesis, and therefore is a possible therapeutic target for the treatment of these malignancies.

Key Words: head and neck cancer • c-Met protein • plexin • chemotaxis • endothelium

Author contributions: J.R.B., R.M.C., V.P.W., and J.S.G. designed research; J.R.B., R.M.C., and V.P.W. performed research; J.R.B. and R.M.C. contributed new reagents/analytic tools; J.R.B., R.M.C., V.P.W., and J.S.G. analyzed data; and J.R.B. and J.S.G. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

{dagger}To whom correspondence should be addressed at: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 211, Bethesda, MD 20892. E-mail: sg39v{at}nih.gov

© 2006 by The National Academy of Sciences of the USA

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