Chemopreventive Strategies for Inflammation-Related Carcinogenesis: Current Status and Future Direction

Kanda, Yusuke; Osaki, Mitsuhiko; Okada, Futoshi

doi:10.3390/ijms18040867

Cited by 27 publications

(19 citation statements)

References 273 publications

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“…In addition to the balance of Th1/Th2 ratio, AOM/DSS treatment causes colon tissue damage and it induces cytokine productions by neutrophil, monocyte, and macrophage. 42 After colon tissue damage, like T and B cells, these cells produce cytokines including TNF-α, IL-1β, and IL-6, causing inflammatory cell infiltration. Therefore, total cytokines are produced from T cell, B cell, and these three other cells.…”

Section: Discussionmentioning

confidence: 99%

Cancer-protective effect of a synbiotic combination between Lactobacillus gasseri 505 and a Cudrania tricuspidata leaf extract on colitis-associated colorectal cancer

et al. 2020

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Previously, a synbiotic combination of probiotic Lactobacillus gasseri 505 (LG) and a new prebiotic, Cudrania tricuspidata leaf extract (CT) in fermented milk, designated FCT, showed an in vitro immunomodulatory effect and antioxidant activity. Although synbiotic combination might have cancer-protective effects, these activities have not been fully validated in vivo. Ten-week treatment of LG, CT, or FCT to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated colorectal cancer (CAC) mouse model reduced both the incidence of colonic tumors and damage to the colonic mucosa effectively, suggesting a cancer-protective effect. To understand these, biomarkers associated with inflammation, colon barrier, apoptosis, and cancer cell proliferation were monitored in AOM/DSS group versus LG/CT/FCT groups. A synbiotic combination (FCT) downregulated pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-6) and inflammation-associated enzymes (iNOS and COX-2), and up-regulated anti-inflammatory cytokines (IL-4 and IL-10). In addition, colon barrier experiment revealed that biomarkers of mucus layer (MUC-2 and TFF3) and tight junction (occludin and ZO-1) were up-regulated. Subsequent apoptosis experiment showed that pro-apoptotic factors (p53, p21, and Bax) were up-regulated and anti-apoptotic factors (Bcl-2 and Bcl-xL) were down-regulated. Furthermore, comparative metagenome analysis of gut microbiota revealed that Staphylococcus decreased but Lactobacillus, Bifidobacterium, and Akkermansia increased, supporting their protective effects, accompanied by increased short-chain fatty acids (SCFAs). Taken together, the FCT administration showed cancer-protective effects by reducing the risk of colitis-associated colon cancer via regulation of inflammation, carcinogenesis, and compositional change of gut microbiota. Consequently, the synbiotic combination (FCT) could be a novel potential health-protective natural agent against CAC.

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Section: Discussionmentioning

confidence: 99%

Cancer-protective effect of a synbiotic combination between Lactobacillus gasseri 505 and a Cudrania tricuspidata leaf extract on colitis-associated colorectal cancer

et al. 2020

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“…ROS participate in neutrophils’ cytotoxic activity against cancer cells [ 35 , 74 ]. Nevertheless, enhanced ROS production by neutrophils limits the NK cell–mediated antibody-dependent cytotoxicity against leukemic cells during anti-CD20 treatment, induces DNA mutations and genotoxicity, and favors drug resistance and systemic T-cell and NK-cell dysfunction [ 77 , 78 , 79 ]. Collectively, these findings suggest that neutrophil-derived ROS can exert a protumorigenic action.…”

Section: Discussionmentioning

confidence: 99%

Potential involvement of neutrophils in human thyroid cancer

et al. 2018

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BackgroundNeutrophil functions have long been regarded as limited to acute inflammation and the defense against microbes. The role(s) of neutrophils in cancer remain poorly understood. Neutrophils infiltrate tumors and are key effector cells in the orchestration of inflammatory responses. Thyroid cancer (TC) is the most recurrent endocrine malignant tumor and is responsible for 70% of deaths due to endocrine cancers. No studies are so far available on the role of neutrophils in TC.ObjectiveOur purpose was to study the involvement of tumor-associated neutrophils in TC.MethodsHighly purified human neutrophils (>99%) from healthy donors were stimulated in vitro with conditioned media derived from TC cell lines TPC1 and 8505c (TC-CMs). Neutrophil functions (e.g., chemotaxis, activation, plasticity, survival, gene expression, and protein release) were evaluated.ResultsTC-derived soluble factors promoted neutrophil chemotaxis and survival. Neutrophil chemotaxis toward a TC-CM was mediated, at least in part, by CXCL8/IL-8, and survival was mediated by granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, each TC-CM induced morphological changes and activation of neutrophils (e.g., CD11b and CD66b upregulation and CD62L shedding) and modified neutrophils’ kinetic properties. Furthermore, each TC-CM induced production of reactive oxygen species, expression of proinflammatory and angiogenic mediators (CXCL8/IL-8, VEGF-A, and TNF-α), and a release of matrix metalloproteinase 9 (MMP-9). Moreover, in TC patients, tumor-associated neutrophils correlated with larger tumor size.ConclusionsTC cell lines produce soluble factors able to “educate” neutrophils toward an activated functional state. These data will advance the understanding of the molecular and cellular mechanisms of innate immunity in TC.

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“…Studies to date have focused on the roles of DNA mutations as drivers of carcinogenesis. Nevertheless, many studies have established that DNA methylation changes are associated with chronic inflammation and cancer progression (Kanda et al, 2017;Zaware and Zhou, 2017). Although the presence of a small number of highfrequency CNVs in the field effect complicates the interpretation, our data suggest that early epigenetic changes involving DNA methylation could in fact cause the subsequent genomic alterations.…”

Section: Discussionmentioning

confidence: 67%

Whole-Organ Genomic Characterization of Mucosal Field Effects Initiating Bladder Carcinogenesis

et al. 2019

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Graphical AbstractHighlights d Field change in DNA methylation is the initiator of bladder carcinogenesis d The methylation changes suppressed immunity and dysregulated Ras-related pathways d Founder ACIN1 mutation in normal mucosa clonally expanded in progression to carcinoma d Cells with mutations of 22 genes expanded clonally with progression to carcinoma SUMMARYWe used whole-organ mapping to study the locoregional molecular changes in a human bladder containing multifocal cancer. Widespread DNA methylation changes were identified in the entire mucosa, representing the initial field effect. The field effect was associated with subclonal low-allele frequency mutations and a small number of DNA copy alterations. A founder mutation in the RNA splicing gene, ACIN1, was identified in normal mucosa and expanded clonally with an additional 21 mutations in progression to carcinoma. The patterns of mutations and copy number changes in carcinoma in situ and foci of carcinoma were almost identical, confirming their clonal origins. The pathways affected by the DNA copy alterations and mutations, including the Kras pathway, were preceded by the field changes in DNA methylation, suggesting that they reinforced mechanisms that had already been initiated by methylation. The results demonstrate that DNA methylation can serve as the initiator of bladder carcinogenesis.

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Chemopreventive Strategies for Inflammation-Related Carcinogenesis: Current Status and Future Direction

Cited by 27 publications

References 273 publications

Cancer-protective effect of a synbiotic combination between Lactobacillus gasseri 505 and a Cudrania tricuspidata leaf extract on colitis-associated colorectal cancer

Cancer-protective effect of a synbiotic combination between Lactobacillus gasseri 505 and a Cudrania tricuspidata leaf extract on colitis-associated colorectal cancer

Potential involvement of neutrophils in human thyroid cancer

Whole-Organ Genomic Characterization of Mucosal Field Effects Initiating Bladder Carcinogenesis

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