Neural signaling modulates metabolism of gastric cancer

Rabben, Hanne-Line; Andersen, Gøran; Olsen, Magnus Kringstad; Øverby, Anders; Ianevski, Aleksandr; Kainov, Denis E.; Wang, Yichen; Lundgren, Steinar; Grönbech, Jon Erik; Chen, Duan; Zhao, Chun‐Mei

doi:10.1016/j.isci.2021.102091

Cited by 18 publications

(22 citation statements)

References 87 publications

(99 reference statements)

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“…However, limited evidence exists from preclinical studies showing an effect of devimistat on the TME or specific immune cell populations. One recent study from a gastroadenocarcinoma model highlighted improved survival in deinnervated gastric cancer treated with devimistat in combination with the mTOR inhibitor RAD001, highlighting a possible role for nervous tissue in the TME of these tumors ( 104 ). As a single agent, devimistat has been evaluated in multiple phase I studies, including in combination with modified FOLFIRINOX (mFOLFIRINOX) for pancreatic cancer ( 105 , 106 ) and in combination with cytarabine/mitoxantrone for relapsed/refractory AML.…”

Section: Metabolic Inhibitors In Clinical Trialsmentioning

confidence: 99%

Clinical development of metabolic inhibitors for oncology

Lemberg¹,

Gori²,

Tsukamoto³

et al. 2022

Journal of Clinical Investigation

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Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.

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Section: Metabolic Inhibitors In Clinical Trialsmentioning

confidence: 99%

Clinical development of metabolic inhibitors for oncology

Lemberg¹,

Gori²,

Tsukamoto³

et al. 2022

Journal of Clinical Investigation

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“…In addition to its neurological aspects, SNAP25 research in oncology has received considerable attention in recent years. Recent studies have claimed that neural signalling is of great importance in regulating tumour metabolism and have validated the role of this biological function in regulating SNAP25 expression in gastric cancer metabolism [19]. Therefore, we performed a clinical relevance analysis of the SNAP25 gene in prostate cancer patients using the TCGA database.…”

Section: Discussionmentioning

confidence: 99%

“…SNAP25 has been seen as potentially important for normal vesicle fusion and lysosomal tra cking [17,18]. In recent years, a growing number of studies have identi ed an association between SNAP25 levels and gastric cancer [19], colon cancer [20], hepatocellular carcinoma [21], lung cancer [22] and papillary thyroid cancer [23]. However, the functions and mechanisms associated with SNAP25 activity in the immunologic and pathogenetic progression of prostate cancer remain to be explored.…”

Section: Introductionmentioning

confidence: 99%

SNAP25 Is a Potential Prognostic Biomarker for Prostate Cancer

Maoli

et al. 2021

Preprint

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Background Prostate cancer is one of the most lethal cancers in male individuals. The Synaptosome associated protein 25 (SNAP25) gene is a key mediator of multiple biological functions in tumours. However, its significant impact on the prognosis in prostate cancer remains to be elucidated.Methods We performed a comprehensive analysis of the Cancer Genome Atlas dataset (TCGA) to identify the differentially expressed genes between prostate cancer and normal prostate tissue. We subjected the differentially expressed genes to gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes functional analysis, and constructed a protein-protein interaction network. We then screened for pivotal genes to identify the hub genes of prognostic significance by performing Cox regression analysis. We identified SNAP25 as one such gene and analysed the relationship between its expression in prostate cancer to poor prognosis using Studio R. Results TCGA database demonstrated that SNAP25 was significantly downregulated in prostate cancer, and that its expression was significantly correlated with the Gleason score and pathological TNM stage of patients. The association between SNAP25 expression and tumour-infiltrating immune cells was evaluated using the Tumour Immune Estimation Resource site. Gene set enrichment and gene ontology analyses were used to analyse the function of SNAP25. We found that SNAP25 expression strongly correlated with overall survival in the Gleason score. In addition, SNAP25 was involved in the activation, differentiation, and migration of immune cells, and its expression was positively correlated with immune infiltration, including of B cells, CD8+ T cells, CD4+ T cells, neutrophils, dendritic cells, macrophages, and natural killer cells. SNAP25 expression was also positively correlated with chemokines/chemokine receptors, suggesting that SNAP25 might regulate the migration of immune cells. These molecular experiment results validate the low expression of SNAP25 seen in prostate cancer cells.Conclusion Our findings indicate a relationship between SNAP25 expression and prostate cancer, demonstrating that SNAP25 is a potential prognostic biomarker due to its vital role in immune infiltration.

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“…Previously, we have showed that denervation (surgically, pharmacologically or genetically) suppressed the tumorigenesis of gastric cancer, which was associated with a decrease in WNT/β-catenin signaling, the suppression of stem cell expansion through M3 receptor-mediated cholinergic signaling and the reversion of metabolic reprogramming, and that the combination of denervation and mono-chemotherapy led to an enhanced effect on tumor growth and survival in an animal model of gastric cancer (Zhao et al, 2014;Rabben et al, 2016). Recently, we have further shown that neural signaling modulated metabolism of gastric cancer, reflected by metabolic switch from glutaminolysis to OXPHOS/glycolysis and normalization of the energy metabolism after denervation (Rabben et al, 2021). In the present study, we wanted to explore the potential of a class of anti-cancer agents, isothiocyanates (ITCs) for chemoprevention and enhancement of chemotherapy as they are also shown to interfere with tumor metabolism (Conaway et al, 2002;Lv et al, 2020).…”

Section: Introductionmentioning

confidence: 94%

Chemopreventive Effects of Dietary Isothiocyanates in Animal Models of Gastric Cancer and Synergistic Anticancer Effects With Cisplatin in Human Gastric Cancer Cells

et al. 2021

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Naturally occurring isothiocyanates (ITCs) from edible vegetables have shown potential as chemopreventive agents against several types of cancer. The aims of the present study were to study the potential of ITCs in chemoprevention and in potentiating the efficacy of cytotoxic drugs in gastric cancer treatment. The chemoprevention was studied in chemically induced mouse model of gastric cancer, namely N-methyl-N-nitrosourea (MNU) in drinking water, and in a genetically engineered mouse model of gastric cancer (the so-called INS-GAS mice). The pharmacological effects of ITCs with or without cisplatin were studied in human gastric cell lines MKN45, AGS, MKN74 and KATO-III, which were derived from either intestinal or diffused types of gastric carcinoma. The results showed that dietary phenethyl isothiocyanate (PEITC) reduced the tumor size when PEITC was given simultaneously with MNU, but neither when administrated after MNU nor in INS-GAS mice. Treatments of gastric cancer cells with ITCs resulted in a time- and concentration-dependent inhibition on cell proliferation. Pretreatment of gastric cancer cells with ITCs enhanced the inhibitory effects of cisplatin (but not 5-fluorouracil) in time- and concentration-dependent manners. Treatments of gastric cancer cells with PEITC plus cisplatin simultaneously at different concentrations of either PEITC or cisplatin exhibited neither additive nor synergetic inhibitory effect. Furthermore, PEITC depleted glutathione and induced G2/M cell cycle arrest in gastric cancer cells. In conclusion, the results of the present study showed that PEITC displayed anti-cancer effects, particularly when given before the tumor initiation, suggesting a chemopreventive effect in gastric cancer, and that pretreatment of PEITC potentiated the anti-cancer effects of cisplatin, possibly by reducing the intracellular pool of glutathione, suggesting a possible combination strategy of chemotherapy with pretreatment with PEITC.

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Neural signaling modulates metabolism of gastric cancer

Cited by 18 publications

References 87 publications

Clinical development of metabolic inhibitors for oncology

Clinical development of metabolic inhibitors for oncology

SNAP25 Is a Potential Prognostic Biomarker for Prostate Cancer

Chemopreventive Effects of Dietary Isothiocyanates in Animal Models of Gastric Cancer and Synergistic Anticancer Effects With Cisplatin in Human Gastric Cancer Cells

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