, Volume 15, Issue 3, pp 391–407 | Cite as

Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression

  • Hua Zhou
  • Nada O. Binmadi
  • Ying-Hua Yang
  • Patrizia Proia
  • John R. BasileEmail author
Original Paper


The semaphorins and plexins comprise a family of cysteine-rich proteins implicated in control of nerve growth and development and regulation of the immune response. Our group and others have found that Semaphorin 4D (SEMA4D) and its receptor, Plexin-B1, play an important role in tumor-induced angiogenesis, with some neoplasms producing SEMA4D in a manner analogous to vascular endothelial growth factor (VEGF) in order to attract Plexin-B1-expressing endothelial cells into the tumor for the purpose of promoting growth and vascularity. While anti-VEGF strategies have been the focus of most angiogenesis inhibition research, such treatment can lead to upregulation of pro-angiogenic factors that can compensate for the loss of VEGF, eventually leading to failure of therapy. Here, we demonstrate that SEMA4D cooperates with VEGF to promote angiogenesis in malignancies and can perform the same function in a setting of VEGF blockade. We also show the potential value of inhibiting SEMA4D/Plexin-B1 signaling as a complementary mechanism to anti-VEGF treatment, particularly in VEGF inhibitor–resistant tumors, suggesting that this may represent a novel treatment for some cancers.


Semaphorin 4D Plexin-B1 VEGF Head and neck squamous cell carcinoma Tumor-induced angiogenesis 



The authors would like to thank Ernest Smith and Maurice Zauderer of Vaccinex, Inc., for providing the anti-SEMA4D antibody and offering technical support and Daniel Martin and Silvio Gutkind of the National Institute of Dental and Craniofacial Research, NIH, for contributing the head and neck cancer cell lines and assisting in the generation of shRNA lentiviruses. This work was supported by the National Cancer Institute grant R01-CA133162 to J.R.B.


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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Hua Zhou
    • 1
  • Nada O. Binmadi
    • 1
    • 2
  • Ying-Hua Yang
    • 1
  • Patrizia Proia
    • 1
    • 3
  • John R. Basile
    • 1
    • 4
    Email author
  1. 1.Department of Oncology and Diagnostic SciencesUniversity of Maryland Dental SchoolBaltimoreUSA
  2. 2.Department of Oral Basic and Clinical SciencesKing Abdulaziz UniversityJeddahSaudi Arabia
  3. 3.Department of Sports Science (DISMOT)University of PalermoPalermoItaly
  4. 4.Greenebaum Cancer CenterBaltimoreUSA

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