Molecular effects of stromal-selective targeting by uPAR-retargeted oncolytic virus in breast cancer

Yuqi Jing, Valery Chavez, Yuguang Ban, Nicolas Acquavella, Dorraya El-Ashry, Alexey Pronin, Xi Chen, Jaime R Merchan

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The tumor microenvironment (TME) is a relevant target for novel biological therapies. MV-m-uPA and MV-h-uPA are fully retargeted, species-specific, oncolytic measles viruses (MV) directed against murine or human urokinase receptor (PLAUR/uPAR), expressed in tumor and stromal cells. The effects of stromal-selective targeting by uPAR-retargeted MVs were investigated. In vitro infection, virus-induced GFP expression, and cytotoxicity by MV-h-uPA and MV-m-uPA were demonstrated in human and murine cancer cells and cancer-associated fibroblasts in a species-specific manner. In a murine fibroblast/human breast cancer 3D coculture model, selective fibroblast targeting by MV-m-uPA inhibited breast cancer cell growth. Systemic administration of murine-specific MV-m-uPA in mice bearing human MDA-MB-231 xenografts was associated with a significant delay in tumor progression and improved survival compared with controls. Experiments comparing tumor (MV-h-uPA) versus stromal (MV-m-uPA) versus combined virus targeting showed that tumor and stromal targeting was associated with improved tumor control over the other groups. Correlative studies confirmed in vivo viral targeting of tumor stroma by MV-m-uPA, increased apoptosis, and virus-induced differential regulation of murine stromal genes associated with inflammatory, angiogenesis, and survival pathways, as well as indirect regulation of human cancer pathways, indicating viral-induced modulation of tumor–stroma interactions. These data demonstrate the feasibility of stromal-selective targeting by an oncolytic MV, virus-induced modulation of tumor–stroma pathways, and subsequent tumor growth delay. These findings further validate the critical role of stromal uPAR in cancer progression and the potential of oncolytic viruses as antistromal agents.

Original languageEnglish (US)
Pages (from-to)1410-1420
Number of pages11
JournalMolecular Cancer Research
Volume15
Issue number10
DOIs
StatePublished - Oct 1 2017

Fingerprint

Oncolytic Viruses
Measles virus
Breast Neoplasms
Neoplasms
Viruses
Fibroblasts
Oncogenic Viruses
Biological Therapy
Tumor Microenvironment
Survival
Urokinase-Type Plasminogen Activator
Stromal Cells
Growth
Coculture Techniques
Heterografts

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Molecular effects of stromal-selective targeting by uPAR-retargeted oncolytic virus in breast cancer. / Jing, Yuqi; Chavez, Valery; Ban, Yuguang; Acquavella, Nicolas; El-Ashry, Dorraya; Pronin, Alexey; Chen, Xi; Merchan, Jaime R.

In: Molecular Cancer Research, Vol. 15, No. 10, 01.10.2017, p. 1410-1420.

Research output: Contribution to journalArticle

Jing, Yuqi ; Chavez, Valery ; Ban, Yuguang ; Acquavella, Nicolas ; El-Ashry, Dorraya ; Pronin, Alexey ; Chen, Xi ; Merchan, Jaime R. / Molecular effects of stromal-selective targeting by uPAR-retargeted oncolytic virus in breast cancer. In: Molecular Cancer Research. 2017 ; Vol. 15, No. 10. pp. 1410-1420.
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