title: Targeting gallbladder cancer: oncolytic virotherapy with myxoma virus is enhanced by rapamycin in vitro and further improved by hyaluronan in vivo.
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.
authors.forename: Mingzhe
authors.initials: M
authors.lastname: Weng
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.forename: Mingzhe
authors.initials: M
authors.lastname: Ma
authors.forename: Bingfeng
authors.initials: B
authors.lastname: Chu
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Qin
authors.forename: Mingdi
authors.initials: M
authors.lastname: Zhang
authors.forename: Xueqing
authors.initials: X
authors.lastname: Lun
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.forename: Peter
authors.initials: P
authors.lastname: Forsyth
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200092, China. Yangyong@hotmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Quan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy* / Q000821:virology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage; D066298:In Vitro Techniques; D051379:Mice; D009233:Myxoma virus / Q000235:genetics; D050130:Oncolytic Virotherapy; D020123:Sirolimus / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D006820:Hyaluronic Acid; D020123:Sirolimus
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