Oncolytic Vaccinia Virus Expressing White-Spotted Charr Lectin Regulates Antiviral Response in Tumor Cells and Inhibits Tumor Growth In Vitro and In Vivo.
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ABSTRACT:
SUBMITTER: Wang X
PROVIDER: S-EPMC8224321 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Coldwater-adapted freshwater fishes, especially their populations along warm-range margins, are most vulnerable to the climate oscillations associated with global warming. Stocking is a major strategy for avoiding the extinction of these species. However, while stocking can reverse the decline of isolated populations, it may also result in a loss of genetic diversity in the native local population due to the introgressive replacement of hatchery genes. To plan an adequate strategy for conserving locally adapted populations, the genetic impacts of stocking on native lineages should be evaluated from small river branches to wide-ranging drainage areas. We investigated the population genetic structure of white-spotted charr (Salvelinus leucomaenis) within its southern range (Lake Biwa basin, Japan). By applying genome-wide SNP analysis to the population's genetic structure, we assessed the extent of genetic introgression resulting from stocking. White-spotted charr in the Lake Biwa watershed constitutes a distinctive genetic group, within which apparent genetic differentiation was observed. The hatchery-reared fish line commonly used for supplementation stocking in the catchment was discernable from the native population, enabling us to analyze genetic introgression across the entire drainage area. Admixed individuals resulting from hatchery introgression were observed in most of the stocked sites that showed relatively high heterozygosity and nucleotide diversity. However, their genetic differentiation was much lower than that of native populations. The supplementation history as well as the road availability contributed substantially to the introgression of hatchery genes. Populations with the native genetic structure remained in the upstream regions of the tested rivers. However, their heterozygosity and nucleotide diversity were low when compared with that of the populations with hatchery supplementation. Our results shed light on the genetic impacts of stocking on isolated native populations and suggest that conventional supplementation methods cannot preserve a unique biodiversity in the distribution margin.
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Project description:White-spotted charr (Salvelinus leucomaenis, S. I.) is an anadromous cold water-adapted fish, distributed in the Far East. We have previously reported the complete mitochondrial DNA sequences of white-spotted chars (S. l. imbrius and S. l. pluvius) in Japan. In general, fish hepatocytes are useful for cellular and biochemical studies of fish. In this study, we isolated hepatocytes from the liver of white-spotted charr and used basic methods, such as enzyme digestion and low centrifugation, to analyze the molecular mechanisms involved in specific cellular responses. The isolated hepatocytes could be cultured at 5-20 °C but not 37 °C. The morphology of hepatocytes was altered in a temperature-dependent manner. The properties of hepatocyte were similar to those of living fish. Moreover, the proliferation rate and damage of isolated hepatocytes depended on the concentration of fetal bovine serum in the culture medium. Taken together, this study demonstrates that this simple method for isolation and culture of hepatocytes from white-spotted charr may be useful for other biochemical and cellular studies.
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Project description:Oncolytic viruses are a promising class of anti-tumor agents; however, concerns regarding uncontrolled viral replication have led to the development of a replication-controllable oncolytic vaccinia virus (OVV). The engineering involves replacing the native thymidine kinase (VV-tk) gene, in a Wyeth strain vaccinia backbone, with the herpes simplex virus thymidine kinase (HSV-tk) gene, which allows for viral replication control via ganciclovir (GCV, an antiviral/cytotoxic pro-drug). Adding the wild-type HSV-tk gene might disrupt the tumor selectivity of VV-tk deleted OVVs; therefore, only engineered viruses that lacked tk activity were selected as candidates. Ultimately, OTS-412, which is an OVV containing a mutant HSV-tk, was chosen for characterization regarding tumor selectivity, sensitivity to GCV, and the influence of GCV on OTS-412 anti-tumor effects. OTS-412 demonstrated comparable replication and cytotoxicity to VVtk- (control, a VV-tk deleted OVV) in multiple cancer cell lines. In HCT 116 mouse models, OTS-412 replication in tumors was reduced by >50% by GCV (p = 0.004); additionally, combination use of GCV did not compromise the anti-tumor effects of OTS-412. This is the first report of OTS-412, a VV-tk deleted OVV containing a mutant HSV-tk transgene, which demonstrates tumor selectivity and sensitivity to GCV. The HSV-tk/GCV combination provides a safety mechanism for future clinical applications of OTS-412.
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Project description:Oncolytic vaccinia virus (VACV) therapy is an alternative treatment option for glioblastoma multiforme. Here, we used a comparison of different tumor locations and different immunologic and genetic backgrounds to determine the replication efficacy and oncolytic potential of the VACV LIVP 1.1.1, an attenuated wild-type isolate of the Lister strain, in murine GL261 glioma models. With this approach, we expected to identify microenvironmental factors, which may be decisive for failure or success of oncolytic VACV therapy. We found that GL261 glioma cells implanted subcutaneously or orthotopically into Balb/c athymic, C57BL/6 athymic, or C57BL/6 wild-type mice formed individual tumors that respond to oncolytic VACV therapy with different outcomes. Surprisingly, only Balb/c athymic mice with subcutaneous tumors supported viral replication. We identified intratumoral IFN-γ expression levels that upregulate MHCII expression on GL261 cells in C57BL/6 wild-type mice associated with a non-permissive status of the tumor cells. Moreover, this IFN-γ-induced tumor cell phenotype was reversible.
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