The Role of Semaphorin 4D and Plexin-B1 in Tumor-Induced Angiogenesis.

Summary

Principal Investigator: John R Basile
Abstract: DESCRIPTION (provided by applicant): Oral cancer is common among men in the developed world and among the most difficult neoplasms to treat. The growth and metastasis of all solid tumors requires induction of angiogenesis, the creation and remodeling of new blood vessels, to meet the increasing metabolic demands of rapidly dividing transformed cells, thus making the development of anti-angiogenic agents an appealing treatment strategy. Recent studies have identified increased expression of hypoxia- inducible factor (HIF)-1, a transcription factor that promotes angiogenesis, in many different primary and metastatic tumors, suggesting that its activation is common in human cancer (1). We now know that proteins involved in transmitting axonal guidance cues can also play a role in tumor-induced angiogenesis. For example, we were the first to show that Plexin-B1, a protein previously identified as a regulator of neuron growth cone progression and migration and nerve bundle fasciculation, is also highly expressed in endothelial cells and promotes a pro-angiogenic response when bound by its ligand Semaphorin 4D (Sema4D) (3), a protein expressed in head and neck squamous cell carcinomas (HNSCC) and many other solid tumors that enhances their growth and vascularity (4). The broad, long-term objectives of this application are to elucidate the mechanisms of regulation of Sema4D and the implications for tumor- induced angiogenesis. The hypothesis to be tested is that Sema4D is upregulated in hypoxia due to HIF-1- mediated pathways, and that its expression acts with other HIF-1-regulated gene products such as membrane type 1-matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor (VEGF) to induce a more vascular and consequently a more aggressive tumor phenotype. The specific aims are: 1) to establish the mechanism of transcriptional regulation of Sema4D and its biological relevance in hypoxia- mediated tumorigenesis. This will be accomplished by analyzing Sema4D protein and message levels in normoxic and hypoxic cells expressing reduced or constitutively active HIF, thorough promoter analysis of the Sema4D gene and through in vitro and in vivo angiogenesis assays and tumor xenograft experiments;2) to determine the importance of hypoxia-mediated induction of MT1-MMP on the ability of Sema4D to induce angiogenesis. This will be studied through analysis of MT1-MMP levels in cells with altered HIF activity and the biological significance of MT1-mediated processing of Sema4D in a tumor xenograft model, and;3) to determine VEGF and Sema4D contributions to HNSCC-induced angiogenesis through retroviral-mediated gene transfer directly into tumor cells in a conditional knockout mouse model. I believe that these investigations into Sema4D/Plexin-B1-mediated angiogenesis will support a newly emerging model of tumor-induced angiogenesis and present possible new targets for cancer therapy.
Funding Period: 2009-09-21 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc Plexin-B1 activates NF-κB and IL-8 to promote a pro-angiogenic response in endothelial cells
    Ying Hua Yang
    Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
    PLoS ONE 6:e25826. 2011
  2. pmc Plexin-B1 and semaphorin 4D cooperate to promote perineural invasion in a RhoA/ROK-dependent manner
    Nada O Binmadi
    Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland 21201, USA
    Am J Pathol 180:1232-42. 2012
  3. pmc Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression
    Hua Zhou
    Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 West Baltimore Street, 7 North, Baltimore, MD 21201, USA
    Angiogenesis 15:391-407. 2012
  4. pmc The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma
    Hua Zhou
    Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, MD 21201, USA
    Exp Cell Res 318:1685-98. 2012
  5. pmc The Semaphorin 4D-Plexin-B1-RhoA signaling axis recruits pericytes and regulates vascular permeability through endothelial production of PDGF-B and ANGPTL4
    Hua Zhou
    Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 West Baltimore Street, 7 North, Baltimore, MD, 21201, USA
    Angiogenesis 17:261-74. 2014

Detail Information

Publications5

  1. pmc Plexin-B1 activates NF-κB and IL-8 to promote a pro-angiogenic response in endothelial cells
    Ying Hua Yang
    Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
    PLoS ONE 6:e25826. 2011
    ....
  2. pmc Plexin-B1 and semaphorin 4D cooperate to promote perineural invasion in a RhoA/ROK-dependent manner
    Nada O Binmadi
    Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland 21201, USA
    Am J Pathol 180:1232-42. 2012
    ..We also demonstrate that nerves are attracted to tumors through this same system of proteins, suggesting that both plexin-B1 and semaphorin 4D are important in the promotion of PNI...
  3. pmc Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression
    Hua Zhou
    Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 West Baltimore Street, 7 North, Baltimore, MD 21201, USA
    Angiogenesis 15:391-407. 2012
    ....
  4. pmc The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma
    Hua Zhou
    Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, MD 21201, USA
    Exp Cell Res 318:1685-98. 2012
    ..We use blocking antibodies to show that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of OSCC and other solid tumors...
  5. pmc The Semaphorin 4D-Plexin-B1-RhoA signaling axis recruits pericytes and regulates vascular permeability through endothelial production of PDGF-B and ANGPTL4
    Hua Zhou
    Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 West Baltimore Street, 7 North, Baltimore, MD, 21201, USA
    Angiogenesis 17:261-74. 2014
    ....

Research Grants30

  1. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  2. Targeting Ovarian Tumor Associated Myeloid Cells with Nanoparticles Therapeutics
    Ronald J Buckanovich; Fiscal Year: 2013
    ..We will test these using in vitro sphere assays with primary human ovarian CSC as well as in mouse models of ovarian cancer stem cells, and human CSC xenografts. ..
  3. Chicago Prevention and Intervention Epicenter (Chicago PIE)
    ROBERT ALAN WEINSTEIN; Fiscal Year: 2013
    ..The impact on ICU infection and prescribing characteristics of doctors will be assessed. To further assess the interventions, costs of averted outcomes and of the interventions will be compared. OPRIONAL OBEJCTIVE SCORE: 2 ..
  4. The Role of HIF-1alpha in Breast Cancer Stem Cell Activity
    TIFFANY NICOLE SEAGROVES; Fiscal Year: 2013
    ....
  5. Hypoxia and HIF in Tumor-Associated Macrophage Driven Tumor Progression
    JESSICA ELIZABETH STEWART SHAY; Fiscal Year: 2013
    ..abstract_text> ..
  6. Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia
    Carlo M Croce; Fiscal Year: 2013
    ..abstract_text> ..
  7. INTEGRATIVE PATHOPHYSIOLOGY OF SOLID TUMORS
    Rakesh K Jain; Fiscal Year: 2013
    ..abstract_text> ..
  8. The Biology of Prostate Cancer Skeletal Metastases
    EVAN TODD KELLER; Fiscal Year: 2013
    ..This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research on PCa bone metastases. ..
  9. Indiana University Center for Pediatric Pharmacology
    Jamie L Renbarger; Fiscal Year: 2013
    ..The direct outcome of these studies will be new biomarkers and predictive signatures that will increase the precision of the existing dosing schemas used in the treatment of childhood cancer. ..
  10. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..