Targeting gallbladder cancer: Oncolytic virotherapy with myxoma virus is enhanced by rapamycin in vitro and further improved by hyaluronan in vivo

Mingzhe Weng, Wei Gong, Mingzhe Ma, Bingfeng Chu, Yiyu Qin, Mingdi Zhang, Xueqing Lun, Grant McFadden, Peter Forsyth, Yong Yang, Zhiwei Quan

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Background: Gallbladder carcinoma (GBC) is highly lethal, and effective treatment will require synergistic anti-tumor management. The study is aimed at investigating the oncolytic value of myxoma virus (MYXV) infection against GBC and optimizing MYXV oncolytic efficiency. Methods: We examined the permissiveness of GBC cell lines to MYXV infection and compared the effects of MYXV on cell viability among GBC and control permissive glioma cells in vitro and in vivo after MYXV + rapamycin (Rap) treatment, which is known to enhance cell permissiveness to MYXV by upregulating p-Akt levels. We also assessed MYXV + hyaluronan (HA) therapy efficiency by examinating Akt activation status, MMP-9 expression, cell viability, and collagen distribution. We further compared hydraulic conductivity, tumor area, and survival of tumor-bearing mice between the MYXV + Rap and MYXV + HA therapeutic regimens. Results: MYXV + Rap treatment could considerably increase the oncolytic ability of MYXV against GBC cell lines in vitro but not against GBC xenografts in vivo. We found higher levels of collagen IV in GBC tumors than in glioma tumors. Diffusion analysis demonstrated that collagen IV could physically hinder MYXV intratumoral distribution. HA-CD44 interplay was found to activate the Akt signaling pathway, which increases oncolytic rates. HA was also found to enhance the MMP-9 secretion, which contributes to collagen IV degradation. Conclusions: Unlike MYXV + Rap, MYXV + HA therapy significantly enhanced the anti-tumor effects of MYXV in vivo and prolonged survival of GBC tumor-bearing mice. HA may optimize the oncolytic effects of MYXV on GBC via the HA-CD44 interaction which can promote viral infection and diffusion.

Original languageEnglish (US)
Article number82
JournalMolecular Cancer
Volume13
Issue number1
DOIs
StatePublished - Apr 13 2014

Keywords

  • Collagen IV
  • Gallbladder cancer
  • Myxoma virus
  • Oncolytic virotherapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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