Tumor and vascular targeting of a novel oncolytic measles virus retargeted against the urokinase receptor

Yuqi Jing, Caili Tong, Jin Zhang, Takafumi Nakamura, Ianko Iankov, Stephen J. Russell, Jaime R Merchan

Research output: Contribution to journalArticle

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Abstract

Oncolytic measles virus (MV) induces cell fusion and cytotoxicity in a CD46-dependent manner. Development of fully retargeted oncolytic MVs would improve tumor selectivity. The urokinase-type plasminogen activator receptor (uPAR) is a tumor and stromal target overexpressed in multiple malignancies. MV-H glycoproteins fully retargeted to either human or murine uPAR were engineered and their fusogenic activity was determined. Recombinant human (MV-h-uPA) and murine (MV-m-uPA) uPAR-retargeted MVs expressing enhanced green fluorescent protein (eGFP) were rescued and characterized. Viral expression of chimeric MV-H was shown by reverse transcription-PCR and Western blot. In vitro viral replication was comparable to MV-GFP control. The receptor and species specificity of MV-uPAs was shown in human and murine cells with different levels of uPAR expression. Removal of the NH 2-terminal fragment ligand from MV-uPA by factor X(a) treatment ablated the MV-uPA functional activity. Cytotoxicity was shown in uPAR-expressing human and murine cells. MV-h-uPA efficiently infected human endothelial cells and capillary tubes in vitro. I.v. administration of MV-h-uPA delayed tumor growth and prolonged survival in the MDA-MB-231 breast cancer xenograft model. Viral tumor targeting was confirmed by immunohistochemistry. MV-m-uPA transduced murine mammary tumors (4T1) in vivo after intratumor administration. MV-m-uPA targeted murine tumor vasculature after systemic administration, as shown by dual (CD31 and MV-N) staining of tumor capillaries in the MDA-MB-231 model. In conclusion, MV-uPA is a novel oncolytic MV associated with potent and specific antitumor effects and tumor vascular targeting. This is the first retargeted oncolytic MV able to replicate in murine cells and target tumor vasculature in a uPAR-dependent manner.

Original languageEnglish
Pages (from-to)1459-1468
Number of pages10
JournalCancer Research
Volume69
Issue number4
DOIs
StatePublished - Feb 15 2009

Fingerprint

Oncolytic Viruses
Measles virus
Urokinase-Type Plasminogen Activator
Blood Vessels
Urokinase Plasminogen Activator Receptors
Neoplasms
Breast Neoplasms
Species Specificity
Factor X

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tumor and vascular targeting of a novel oncolytic measles virus retargeted against the urokinase receptor. / Jing, Yuqi; Tong, Caili; Zhang, Jin; Nakamura, Takafumi; Iankov, Ianko; Russell, Stephen J.; Merchan, Jaime R.

In: Cancer Research, Vol. 69, No. 4, 15.02.2009, p. 1459-1468.

Research output: Contribution to journalArticle

Jing, Yuqi ; Tong, Caili ; Zhang, Jin ; Nakamura, Takafumi ; Iankov, Ianko ; Russell, Stephen J. ; Merchan, Jaime R. / Tumor and vascular targeting of a novel oncolytic measles virus retargeted against the urokinase receptor. In: Cancer Research. 2009 ; Vol. 69, No. 4. pp. 1459-1468.
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abstract = "Oncolytic measles virus (MV) induces cell fusion and cytotoxicity in a CD46-dependent manner. Development of fully retargeted oncolytic MVs would improve tumor selectivity. The urokinase-type plasminogen activator receptor (uPAR) is a tumor and stromal target overexpressed in multiple malignancies. MV-H glycoproteins fully retargeted to either human or murine uPAR were engineered and their fusogenic activity was determined. Recombinant human (MV-h-uPA) and murine (MV-m-uPA) uPAR-retargeted MVs expressing enhanced green fluorescent protein (eGFP) were rescued and characterized. Viral expression of chimeric MV-H was shown by reverse transcription-PCR and Western blot. In vitro viral replication was comparable to MV-GFP control. The receptor and species specificity of MV-uPAs was shown in human and murine cells with different levels of uPAR expression. Removal of the NH 2-terminal fragment ligand from MV-uPA by factor X(a) treatment ablated the MV-uPA functional activity. Cytotoxicity was shown in uPAR-expressing human and murine cells. MV-h-uPA efficiently infected human endothelial cells and capillary tubes in vitro. I.v. administration of MV-h-uPA delayed tumor growth and prolonged survival in the MDA-MB-231 breast cancer xenograft model. Viral tumor targeting was confirmed by immunohistochemistry. MV-m-uPA transduced murine mammary tumors (4T1) in vivo after intratumor administration. MV-m-uPA targeted murine tumor vasculature after systemic administration, as shown by dual (CD31 and MV-N) staining of tumor capillaries in the MDA-MB-231 model. In conclusion, MV-uPA is a novel oncolytic MV associated with potent and specific antitumor effects and tumor vascular targeting. This is the first retargeted oncolytic MV able to replicate in murine cells and target tumor vasculature in a uPAR-dependent manner.",
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