Tumor-specific cell-cycle decoy by <i>Salmonella typhimurium</i> A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging

Yano, Shuya; Takehara, Kiyoto; Zhao, Ming; Tan, Yuying; Han, Qinghong; Li, Shukuan; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M.

doi:10.1080/15384101.2016.1181240

Cited by 56 publications

(39 citation statements)

References 71 publications

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“…Images were acquired with the FV1000 confocal microscope (Olympus, Tokyo, Japan). In the FUCCI system, the cells in G 0 /G 1 , S, or G 2 /M phases appear red , yellow , or green , respectively [66] …”

Section: Methionine Dependence and Altered Transmethylation In Cancermentioning

confidence: 99%

Is DNA methylation the new guardian of the genome?

Hoffman

2017

Mol Cytogenet

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BackgroundIt has been known for more than 100 years that aneuploidy is an essence of cancer. The question is what keeps the genome stable, thereby preventing aneuploidy. For the past 25 years, it has been proposed that p53 is the “guardian of the genome.” However, it has been shown that inactivation of p53 does not cause aneuploidy. Another essence of cancer is global DNA hypomethylation, which causes destabilization of the genome and subsequent aneupoloidy. Yet, another essence of cancer is excessive use of methionine, resulting in methionine dependence. Methionine dependence is due to possible “metabolic reprogramming” due to carcinogens, including chemical agents and infectious organisms, such as Helicobacter pylori, that result in altered and excessive transmethylation in cancer cells. Cancer cells appear to have a “methyl-sink” whereby methyl groups are diverted from DNA.ConclusionDNA hypomethylation destabilizes the genome, leading to aneuploidy and subsequent selection and speciation into autonomous cancers, leading to the conclusion that DNA methylation is the “guardian of the genome.”Electronic supplementary materialThe online version of this article (doi:10.1186/s13039-017-0314-8) contains supplementary material, which is available to authorized users.

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Section: Methionine Dependence and Altered Transmethylation In Cancermentioning

confidence: 99%

Is DNA methylation the new guardian of the genome?

Hoffman

2017

Mol Cytogenet

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“…1 We have termed this phenomena tumor intrinsic chemoresistance (TIC). 2 The results also suggest that drugs that target quiescent cancer cells are urgently needed. 1 In the present study, we demonstrate that dormant/quiescent cancer cells induce nascent tumor vessels after chemotherapy, allowing tumors to regrow rapidly after cessation of treatment.…”

Section: Introductionmentioning

confidence: 99%

Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging

et al. 2017

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We previously demonstrated that quiescent cancer cells in a tumor are resistant to conventional chemotherapy as visualized with a fluorescence ubiquitination cell cycle indicator (FUCCI). We also showed that proliferating cancer cells exist in a tumor only near nascent vessels or on the tumor surface as visualized with FUCCI and green fluorescent protein (GFP)-expressing tumor vessels. In the present study, we show the relationship between cellcycle phase and chemotherapy-induced tumor angiogenesis using in vivo FUCCI real-time imaging of the cell cycle and nestin-driven GFP to detect nascent blood vessels. We observed that chemotherapy-treated tumors, consisting of mostly of quiescent cancer cells after treatment, had much more and deeper tumor vessels than untreated tumors. These newly-vascularized cancer cells regrew rapidly after chemotherapy. In contrast, formerly quiescent cancer cells decoyed to S/G 2 phase by a telomerase-dependent adenovirus did not induce tumor angiogenesis. The present results further demonstrate the importance of the cancer-cell position in the cell cycle in order that chemotherapy be effective and not have the opposite effect of stimulating tumor angiogenesis and progression.

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“…Carried vascular endothelial growth factor receptor 2 (VEGFR-2) of S. typhi Ty21a delivered VXM01, which is an orally available T-cell vaccine used to activate T-cells to breakdown tumor vasculature [36]. S. typhimurium A1-R combined with chemotherapy can efficiently targeT cells in the S/G2/M phases, rather than in the S/G2 phases, hence making it a promising strategy to suppress tumor growth [37]. Utilizing S. typhimurium A1-R to assess antitumor efficacy in a patient-derived orthotopic xenograft (PDOX) model may be used as an assessment.…”

Section: Discussionmentioning

confidence: 99%

Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

Chen

Pangilinan

Lee

2019

Cancers

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Immunotherapy is becoming a popular treatment modality in combat against cancer, one of the world’s leading health problems. While tumor cells influence host immunity via expressing immune inhibitory signaling proteins, some bacteria possess immunomodulatory activities that counter the symptoms of tumors. The accumulation of Salmonella in tumor sites influences tumor protein expression, resulting in T cell infiltration. However, the molecular mechanism by which Salmonella activates T cells remains elusive. Many tumors have been reported to have high expressions of programmed death-ligand 1 (PD-L1), which is an important immune checkpoint molecule involved in tumor immune escape. In this study, Salmonella reduced the expression of PD-L1 in tumor cells. The expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and the phospho-p70 ribosomal s6 kinase (P-p70s6K) pathway were revealed to be involved in the Salmonella-mediated downregulation of PD-L1. In a tumor-T cell coculture system, Salmonella increased T cell number and reduced T cell apoptosis. Systemic administration of Salmonella reduced the expressions of PD-L-1 in tumor-bearing mice. In addition, tumor growth was significantly inhibited along with an enhanced T cell infiltration following Salmonella treatment. These findings suggest that Salmonella acts upon the immune checkpoint, primarily PD-L1, to incapacitate protumor effects and thereby inhibit tumor growth.

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Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging

Cited by 56 publications

References 71 publications

Is DNA methylation the new guardian of the genome?

Is DNA methylation the new guardian of the genome?

Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging

Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

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