Our previous research has demonstrated that the oncolytic vaccinia virus encoding Aphrocallistes vastus lectin (oncoVV-AVL), an oncolytic vaccinia virus engineered to carry the AVL, exhibits potent cytotoxic effects on colorectal and hepatocellular cancer cells. Based on this foundation, we undertook a series of experiments to explore its efficacy on gastric cancer (GC) cells. Our findings revealed that oncoVV-AVL significantly increased reactive oxygen species levels and suppressed the expression of nuclear factor erythroid 2-related factor 2, thereby enhancing viral replication and disrupting the cellular redox balance, ultimately leading to the demise of cancer cells. Additionally, our investigations uncovered that oncoVV-AVL reprogrammed the metabolic microenvironment to favor viral replication, culminating in the lysis of cancer cells. Furthermore, we observed that oncoVV-AVL not only regressed tumor growth but also induced tumor tissue necrosis. These promising results suggest potential new avenues for the therapeutic management of GC.
Get full access to this article
View all access options for this article.
References
1.
BrayF, FerlayJ, SoerjomataramI, et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018; 68(6):394–424; doi: 10.3322/caac.21492
2.
LópezMJ, CarbajalJ, AlfaroAL, et al.Characteristics of gastric cancer around the world. Crit Rev Oncol Hematol, 2023; 181:103841; doi: 10.1016/j.critrevonc.2022.103841
3.
SolimanH, HogueD, HanH, et al.Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: A phase 2 trial. Nat Med, 2023; 29(2):450–457; doi: 10.1038/s41591-023-02210-0
4.
LingAL, SolomonIH, LandivarAM, et al.Clinical trial links oncolytic immunoactivation to survival in glioblastoma. Nature, 2023; 623(7985):157–166; doi: 10.1038/s41586-023-06623-2
5.
TsunemitsuY, KagawaS, TokunagaN, et al.Molecular therapy for peritoneal dissemination of xenotransplanted human MKN-45 gastric cancer cells with adenovirus mediated Bax gene transfer. Gut, 2004; 53(4):554–560; doi: 10.1136/gut.2003.021683
6.
JhawarSR, ThandoniA, BommareddyPK, et al.Oncolytic viruses-natural and genetically engineered cancer immunotherapies. Front Oncol, 2017; 7:202; doi: 10.3389/fonc.2017.00202
7.
LiM, ZhangM, YeQ, et al.Preclinical and clinical trials of oncolytic vaccinia virus in cancer immunotherapy: A comprehensive review. Cancer Biol Med, 2023; 20(9):646–661; doi: 10.20892/j.issn.2095-3941.2023.0202
8.
ZhuZ, McGrayAJR, JiangW, et al.Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways. Mol Cancer, 2022; 21(1):196; doi: 10.1186/s12943-022-01664-z
9.
FramptonJE. Teserpaturev/G47Δ: First approval. BioDrugs, 2022; 36(5):667–672; doi: 10.1007/s40259-022-00553-7
10.
AndtbackaRH, KaufmanHL, CollichioF, et al.Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol, 2015; 33(25):2780–2788; doi: 10.1200/jco.2014.58.3377
11.
ChengG, DongH, YangC, et al.A review on the advances and challenges of immunotherapy for head and neck cancer. Cancer Cell Int, 2021; 21(1):406; doi: 10.1186/s12935-021-02024-5
12.
AlbertsP, TilgaseA, RasaA, et al.The advent of oncolytic virotherapy in oncology: The Rigvir® story. Eur J Pharmacol, 2018; 837:117–126; doi: 10.1016/j.ejphar.2018.08.042
13.
BuijsPR, VerhagenJH, van EijckCH, et al.Oncolytic viruses: From bench to bedside with a focus on safety. Hum Vaccin Immunother, 2015; 11(7):1573–1584; doi: 10.1080/21645515.2015.1037058
14.
ThorneSH, KirnDH. Future directions for the field of oncolytic virotherapy: A perspective on the use of vaccinia virus. Expert Opin Biol Ther, 2004; 4(8):1307–1321; doi: 10.1517/14712598.4.8.1307
15.
GuoZS, LuB, GuoZ, et al.Vaccinia virus-mediated cancer immunotherapy: Cancer vaccines and oncolytics. J Immunother Cancer, 2019; 7(1):6; doi: 10.1186/s40425-018-0495-7
16.
PelinA, BoultonS, TammingLA, et al.Engineering vaccinia virus as an immunotherapeutic battleship to overcome tumor heterogeneity. Expert Opin Biol Ther, 2020; 20(9):1083–1097; doi: 10.1080/14712598.2020.1757066
17.
ZhangZ, DongL, ZhaoC, et al.Vaccinia virus-based vector against infectious diseases and tumors. Hum Vaccin Immunother, 2021; 17(6):1578–1585; doi: 10.1080/21645515.2020.1840887
18.
MuthukuttyP, YooSY. Oncolytic virus engineering and utilizations: Cancer immunotherapy perspective. Viruses, 2023; 15(8):1645; doi: 10.3390/v15081645
19.
JunKH, GholamiS, SongTJ, et al.A novel oncolytic viral therapy and imaging technique for gastric cancer using a genetically engineered vaccinia virus carrying the human sodium iodide symporter. J Exp Clin Cancer Res, 2014; 33(1):2; doi: 10.1186/1756-9966-33-2
20.
WangM, LuoY, SunT, et al.The ectopic expression of survivinT34A and FilC can enhance the oncolytic effects of vaccinia virus in murine gastric cancer. Onco Targets Ther, 2020; 13:1011–1025; doi: 10.2147/ott.S230902
21.
OmokawaY, MiyazakiT, WaldeP, et al.In vitro and in vivo anti-tumor effects of novel Span 80 vesicles containing immobilized Eucheuma serra agglutinin. Int J Pharm, 2010; 389(1–2):157–167; doi: 10.1016/j.ijpharm.2010.01.033
22.
TatsutaT, SatoS, SatoT, et al.Sialic acid-binding lectin from bullfrog eggs exhibits an anti-tumor effect against breast cancer cells including triple-negative phenotype cells. Molecules, 2018; 23(10):2714; doi: 10.3390/molecules23102714
23.
ZhouY, WangQ, YingQ, et al.Effects of oncolytic vaccinia viruses harboring different marine lectins on hepatocellular carcinoma cells. Int J Mol Sci, 2023; 24(4):3823; doi: 10.3390/ijms24043823
24.
ZhengX, XuW, YingQ, et al.Oncolytic vaccinia virus carrying aphrocallistes vastus lectin (oncoVV-AVL) enhances inflammatory response in hepatocellular carcinoma cells. Mar Drugs, 2022; 20(11):667; doi: 10.3390/md20110667
25.
WuT, XiangY, LiuT, et al.Oncolytic vaccinia virus expressing aphrocallistes vastus lectin as a cancer therapeutic agent. Mar Drugs, 2019; 17(6):363; doi: 10.3390/md17060363
26.
JiangBH, LiuLZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res, 2009; 102:19–65; doi: 10.1016/s0065-230x(09)02002-8
27.
Álvarez-GarciaV, TawilY, WiseHM, et al.Mechanisms of PTEN loss in cancer: It’s all about diversity. Semin Cancer Biol, 2019; 59:66–79; doi: 10.1016/j.semcancer.2019.02.001
28.
FangL, TengH, WangY, et al.SET1A-Mediated mono-methylation at K342 Regulates YAP activation by blocking its nuclear export and promotes tumorigenesis. Cancer Cell, 2018; 34(1):103–118.e9; doi: 10.1016/j.ccell.2018.06.002
29.
FooJ, BellotG, PervaizS, et al.Mitochondria-mediated oxidative stress during viral infection. Trends Microbiol, 2022; 30(7):679–692; doi: 10.1016/j.tim.2021.12.011
30.
FerrariM, ZeviniA, PalermoE, et al.Dengue virus targets Nrf2 for NS2B3-Mediated degradation leading to enhanced oxidative stress and viral replication. J Virol, 2020; 94(24):e01551-20; doi: 10.1128/jvi.01551-20
31.
MitsuishiY, MotohashiH, YamamotoM. The Keap1-Nrf2 system in cancers: Stress response and anabolic metabolism. Front Oncol, 2012; 2:200; doi: 10.3389/fonc.2012.00200
32.
BedardK, KrauseKH. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev, 2007; 87(1):245–313; doi: 10.1152/physrev.00044.2005
33.
KennedyBE, SadekM, GujarSA. Targeted metabolic reprogramming to improve the efficacy of oncolytic virus therapy. Mol Ther, 2020; 28(6):1417–1421; doi: 10.1016/j.ymthe.2020.03.014
34.
GoyalP, RajalaMS. Reprogramming of glucose metabolism in virus infected cells. Mol Cell Biochem, 2023; 478(11):2409–2418; doi: 10.1007/s11010-023-04669-4
35.
VorobyevPO, KochetkovDV, ChumakovPM, et al.2-Deoxyglucose, an inhibitor of glycolysis, enhances the oncolytic effect of coxsackievirus. Cancers (Basel), 2022; 14(22):5611; doi: 10.3390/cancers14225611
36.
MengG, LiB, ChenA, et al.Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma. Br J Cancer, 2020; 122(1):111–120; doi: 10.1038/s41416-019-0639-7
37.
SextonRE, Al HallakMN, DiabM, et al.Gastric cancer: A comprehensive review of current and future treatment strategies. Cancer Metastasis Rev, 2020; 39(4):1179–1203; doi: 10.1007/s10555-020-09925-3
38.
JuHQ, LinJF, TianT, et al.NADPH homeostasis in cancer: Functions, mechanisms and therapeutic implications. Signal Transduct Target Ther, 2020; 5(1):231; doi: 10.1038/s41392-020-00326-0
39.
SahooBR, CrookAA, PattnaikA, et al.Redox regulation and metabolic dependency of zika virus replication: Inhibition by Nrf2-Antioxidant response and NAD(H) antimetabolites. J Virol, 2023; 97(2):e0136322; doi: 10.1128/jvi.01363-22
40.
SajadimajdS, KhazaeiM. Oxidative stress and cancer: The role of Nrf2. Curr Cancer Drug Targets, 2018; 18(6):538–557; doi: 10.2174/1568009617666171002144228
41.
JaramilloMC, ZhangDD. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev, 2013; 27(20):2179–2191; doi: 10.1101/gad.225680.113
ThorneSH. Immunotherapeutic potential of oncolytic vaccinia virus. Front Oncol, 2014; 4:155; doi: 10.3389/fonc.2014.00155
44.
WangLC, LynnRC, ChengG, et al.Treating tumors with a vaccinia virus expressing IFNβ illustrates the complex relationships between oncolytic ability and immunogenicity. Mol Ther, 2012; 20(4):736–748; doi: 10.1038/mt.2011.228
45.
YeJ, ChenL, WaltermireJ, et al.Intratumoral delivery of interleukin 9 via oncolytic vaccinia virus elicits potent antitumor effects in tumor models. Cancers (Basel), 2024; 16(5):1021; doi: 10.3390/cancers16051021
