Abstract
BackgroundGallbladder 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.MethodsWe 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.ResultsMYXV + 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.ConclusionsUnlike 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.
Highlights
Gallbladder carcinoma (GBC) remains the most common biliary tract malignancy characterized by its high lethality, aggressive nature, and dismal prognosis [1]
Novelty & impact statements Myxoma virus (MYXV), a rabbit-specific poxvirus, is characterized by its narrow host tropism and efficient tumor killing, which has not been studied in Gallbladder carcinoma (GBC), the most common biliary tract malignancy featured by its high lethality, aggressive nature, and dismal prognosis
It was indicated that extracellular tissue collagen IV hinders MYXV dissemination implanted GBC tumors
Summary
Gallbladder carcinoma (GBC) remains the most common biliary tract malignancy characterized by its high lethality, aggressive nature, and dismal prognosis [1]. Oncolytic viruses that selectively infect and kill tumors exhibit modest clinical success [3]. Myxoma virus (MYXV), a rabbit-specific poxvirus, exhibits narrow host tropism likely as a consequence of protective induced-interferon (IFN) responses in other species [4]. MYXV can infect and kill over 70% of tested human tumor cell lines by exploiting the same cellular defects such as IFN-mediated mutations [5]. 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
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