Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion

Julia V. Cockle, Anke Brüning-Richardson, Karen J. Scott, Jill Thompson, Timothy Kottke, Ewan Morrison, Azam Ismail, Angel M. Carcaboso, Ailsa Rose, Peter Selby, Joe Conner, Susan Picton, Susan Short, Richard Vile, Alan Melcher, Elizabeth Ilett

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are invasive tumors with poor survival. Oncolytic virotherapy, initially devised as a direct cytotoxic treatment, is now also known to act via immune-mediated mechanisms. Here we investigate a previously unreported mechanism of action: the inhibition of migration and invasion in pediatric brain tumors. We evaluated the effect of oncolytic herpes simplex virus 1716 (HSV1716) on the migration and invasion of pHGG and DIPG both in vitro using 2D (scratch assay, live cell imaging) and 3D (spheroid invasion in collagen) assays and in vivo using an orthotopic xenograft model of DIPG invasion. HSV1716 inhibited migration and invasion in pHGG and DIPG cell lines. pHGG cells demonstrated reduced velocity and changed morphology in the presence of virus. HSV1716 altered pHGG cytoskeletal dynamics by stabilizing microtubules, inhibiting glycogen synthase kinase-3, and preventing localized clustering of adenomatous polyposis coli (APC) to the leading edge of cells. HSV1716 treatment also reduced tumor infiltration in a mouse orthotopic xenograft DIPG model. Our results demonstrate that HSV1716 targets the migration and invasion of pHGG and DIPG and indicates the potential of an oncolytic virus (OV) to be used as a novel anti-invasive treatment strategy for pediatric brain tumors.

Original languageEnglish
Pages (from-to)75-86
Number of pages12
JournalMolecular Therapy - Oncolytics
Volume5
Early online date2 May 2017
DOIs
Publication statusPublished - 16 Jun 2017
Externally publishedYes

Fingerprint

Oncolytic Viruses
Simplexvirus
Brain Neoplasms
Glioma
Pediatrics
Heterografts
Oncolytic Virotherapy
Glycogen Synthase Kinase 3
Adenomatous Polyposis Coli
Microtubules
Cluster Analysis

Cite this

Cockle, Julia V. ; Brüning-Richardson, Anke ; Scott, Karen J. ; Thompson, Jill ; Kottke, Timothy ; Morrison, Ewan ; Ismail, Azam ; Carcaboso, Angel M. ; Rose, Ailsa ; Selby, Peter ; Conner, Joe ; Picton, Susan ; Short, Susan ; Vile, Richard ; Melcher, Alan ; Ilett, Elizabeth. / Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion. In: Molecular Therapy - Oncolytics. 2017 ; Vol. 5. pp. 75-86.
@article{f34b74720daa42d3bd65877447146ac4,
title = "Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion",
abstract = "Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are invasive tumors with poor survival. Oncolytic virotherapy, initially devised as a direct cytotoxic treatment, is now also known to act via immune-mediated mechanisms. Here we investigate a previously unreported mechanism of action: the inhibition of migration and invasion in pediatric brain tumors. We evaluated the effect of oncolytic herpes simplex virus 1716 (HSV1716) on the migration and invasion of pHGG and DIPG both in vitro using 2D (scratch assay, live cell imaging) and 3D (spheroid invasion in collagen) assays and in vivo using an orthotopic xenograft model of DIPG invasion. HSV1716 inhibited migration and invasion in pHGG and DIPG cell lines. pHGG cells demonstrated reduced velocity and changed morphology in the presence of virus. HSV1716 altered pHGG cytoskeletal dynamics by stabilizing microtubules, inhibiting glycogen synthase kinase-3, and preventing localized clustering of adenomatous polyposis coli (APC) to the leading edge of cells. HSV1716 treatment also reduced tumor infiltration in a mouse orthotopic xenograft DIPG model. Our results demonstrate that HSV1716 targets the migration and invasion of pHGG and DIPG and indicates the potential of an oncolytic virus (OV) to be used as a novel anti-invasive treatment strategy for pediatric brain tumors.",
keywords = "oncolytic virus paediatric brain tumor invasion migration",
author = "Cockle, {Julia V.} and Anke Br{\"u}ning-Richardson and Scott, {Karen J.} and Jill Thompson and Timothy Kottke and Ewan Morrison and Azam Ismail and Carcaboso, {Angel M.} and Ailsa Rose and Peter Selby and Joe Conner and Susan Picton and Susan Short and Richard Vile and Alan Melcher and Elizabeth Ilett",
year = "2017",
month = "6",
day = "16",
doi = "10.1016/j.omto.2017.04.002",
language = "English",
volume = "5",
pages = "75--86",
journal = "Molecular Therapy - Oncolytics",
issn = "2372-7705",
publisher = "Nature Publishing Group",

}

Cockle, JV, Brüning-Richardson, A, Scott, KJ, Thompson, J, Kottke, T, Morrison, E, Ismail, A, Carcaboso, AM, Rose, A, Selby, P, Conner, J, Picton, S, Short, S, Vile, R, Melcher, A & Ilett, E 2017, 'Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion', Molecular Therapy - Oncolytics, vol. 5, pp. 75-86. https://doi.org/10.1016/j.omto.2017.04.002

Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion. / Cockle, Julia V.; Brüning-Richardson, Anke; Scott, Karen J.; Thompson, Jill; Kottke, Timothy; Morrison, Ewan; Ismail, Azam; Carcaboso, Angel M.; Rose, Ailsa; Selby, Peter; Conner, Joe; Picton, Susan; Short, Susan; Vile, Richard; Melcher, Alan; Ilett, Elizabeth.

In: Molecular Therapy - Oncolytics, Vol. 5, 16.06.2017, p. 75-86.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion

AU - Cockle, Julia V.

AU - Brüning-Richardson, Anke

AU - Scott, Karen J.

AU - Thompson, Jill

AU - Kottke, Timothy

AU - Morrison, Ewan

AU - Ismail, Azam

AU - Carcaboso, Angel M.

AU - Rose, Ailsa

AU - Selby, Peter

AU - Conner, Joe

AU - Picton, Susan

AU - Short, Susan

AU - Vile, Richard

AU - Melcher, Alan

AU - Ilett, Elizabeth

PY - 2017/6/16

Y1 - 2017/6/16

N2 - Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are invasive tumors with poor survival. Oncolytic virotherapy, initially devised as a direct cytotoxic treatment, is now also known to act via immune-mediated mechanisms. Here we investigate a previously unreported mechanism of action: the inhibition of migration and invasion in pediatric brain tumors. We evaluated the effect of oncolytic herpes simplex virus 1716 (HSV1716) on the migration and invasion of pHGG and DIPG both in vitro using 2D (scratch assay, live cell imaging) and 3D (spheroid invasion in collagen) assays and in vivo using an orthotopic xenograft model of DIPG invasion. HSV1716 inhibited migration and invasion in pHGG and DIPG cell lines. pHGG cells demonstrated reduced velocity and changed morphology in the presence of virus. HSV1716 altered pHGG cytoskeletal dynamics by stabilizing microtubules, inhibiting glycogen synthase kinase-3, and preventing localized clustering of adenomatous polyposis coli (APC) to the leading edge of cells. HSV1716 treatment also reduced tumor infiltration in a mouse orthotopic xenograft DIPG model. Our results demonstrate that HSV1716 targets the migration and invasion of pHGG and DIPG and indicates the potential of an oncolytic virus (OV) to be used as a novel anti-invasive treatment strategy for pediatric brain tumors.

AB - Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are invasive tumors with poor survival. Oncolytic virotherapy, initially devised as a direct cytotoxic treatment, is now also known to act via immune-mediated mechanisms. Here we investigate a previously unreported mechanism of action: the inhibition of migration and invasion in pediatric brain tumors. We evaluated the effect of oncolytic herpes simplex virus 1716 (HSV1716) on the migration and invasion of pHGG and DIPG both in vitro using 2D (scratch assay, live cell imaging) and 3D (spheroid invasion in collagen) assays and in vivo using an orthotopic xenograft model of DIPG invasion. HSV1716 inhibited migration and invasion in pHGG and DIPG cell lines. pHGG cells demonstrated reduced velocity and changed morphology in the presence of virus. HSV1716 altered pHGG cytoskeletal dynamics by stabilizing microtubules, inhibiting glycogen synthase kinase-3, and preventing localized clustering of adenomatous polyposis coli (APC) to the leading edge of cells. HSV1716 treatment also reduced tumor infiltration in a mouse orthotopic xenograft DIPG model. Our results demonstrate that HSV1716 targets the migration and invasion of pHGG and DIPG and indicates the potential of an oncolytic virus (OV) to be used as a novel anti-invasive treatment strategy for pediatric brain tumors.

KW - oncolytic virus paediatric brain tumor invasion migration

UR - http://www.scopus.com/inward/record.url?scp=85020523685&partnerID=8YFLogxK

U2 - 10.1016/j.omto.2017.04.002

DO - 10.1016/j.omto.2017.04.002

M3 - Article

VL - 5

SP - 75

EP - 86

JO - Molecular Therapy - Oncolytics

JF - Molecular Therapy - Oncolytics

SN - 2372-7705

ER -