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Iron accelerates Fusobacterium nucleatum-induced CCL8 expression in macrophages and is associated with colorectal cancer progression.

ABSTRACT: Accumulating evidence suggests that high levels of Fusobacterium nucleatum in colorectal tumor tissues can be associated with poor prognosis in patients with colorectal cancer (CRC); however, data regarding distinct prognostic subgroups in F. nucleatum-positive CRC remain limited. Herein, we demonstrate that high-iron status was associated with a worse prognosis in patients with CRC with F. nucleatum. Patients with CRC presenting elevated serum transferrin saturation exhibited preferential iron deposition in macrophages in the tumor microenvironment. In addition, F. nucleatum induced CCL8 expression in macrophages via the TLR4/NF-κB signaling pathway, which was inhibited by iron deficiency. Mechanistically, iron attenuated the inhibitory phosphorylation of NF-κB p65 by activating serine/threonine phosphatases, augmenting tumor-promoting chemokine production in macrophages. Our observations indicate a key role for iron in modulating the NF-κB signaling pathway and suggest its prognostic potential as a determining factor for interpatient heterogeneity in F. nucleatum-positive CRC.

SUBMITTER: Yamane T

PROVIDER: S-EPMC9675438 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Iron accelerates Fusobacterium nucleatum-induced CCL8 expression in macrophages and is associated with colorectal cancer progression.

Yamane Taishi T Kanamori Yohei Y Sawayama Hiroshi H Yano Hiromu H Nita Akihiro A Ohta Yudai Y Hinokuma Hironori H Maeda Ayato A Iwai Akiko A Matsumoto Takashi T Shimoda Mayuko M Niimura Mayumi M Usuki Shingo S Yasuda-Yoshihara Noriko N Niwa Masato M Baba Yoshifumi Y Ishimoto Takatsugu T Komohara Yoshihiro Y Sawa Tomohiro T Hirayama Tasuku T Baba Hideo H Moroishi Toshiro T

JCI insight 20221108 21

Accumulating evidence suggests that high levels of Fusobacterium nucleatum in colorectal tumor tissues can be associated with poor prognosis in patients with colorectal cancer (CRC); however, data regarding distinct prognostic subgroups in F. nucleatum-positive CRC remain limited. Herein, we demonstrate that high-iron status was associated with a worse prognosis in patients with CRC with F. nucleatum. Patients with CRC presenting elevated serum transferrin saturation exhibited preferential iron ...[more]

PMID: 36136589

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Project description:BackgroundFusobacterium nucleatum (Fn) acts as a procarcinogenic bacterium in colorectal carcinoma (CRC) by regulating the inflammatory tumor microenvironment (TME). Neutrophil extracellular traps (NETs), which can be generated by persistent inflammation, have been recently considered to be significant contributors in promoting cancer progression. However, whether NETs are implicated in Fn-related carcinogenesis is still poorly characterized. Here, we explored the role of NETs in Fn-related CRC as well as their potential clinical significance.MethodsFn was measured in tissue specimens and feces samples from CRC patients. The expression of NET markers were also detected in tissue specimens, freshly isolated neutrophils and blood serum from CRC patients, and the correlation of circulating NETs levels with Fn was evaluated. Cell-based experiments were conducted to investigate the mechanism by which Fn modulates NETs formation. In addition, we clarified the functional mechanism of Fn-induced NETs on the growth and metastasis of CRC in vitro and in vivo experiments.ResultsTissue and blood samples from CRC patients, particularly those from Fn-infected CRC patients, exhibited greater neutrophil infiltration and higher NETs levels. Fn infection induced abundant NETs production in in vitro studies. Subsequently, we demonstrated that Fn-induced NETs indirectly accelerated malignant tumor growth through angiopoiesis, and facilitated tumor metastasis, as manifested by epithelial-mesenchymal transition (EMT)-related cell migration, matrix metalloproteinase (MMP)-mediated basement membrane protein degradation, and trapping of CRC cells. Mechanistically, the Toll-like receptor (TLR4)-reactive oxygen species (ROS) signaling pathway and NOD-like receptor (NOD1/2)-dependent signaling were responsible for Fn-stimulated NETs formation. More importantly, circulating NETs combined with carcinoembryonic antigen (CEA) could predict CRC occurrence and metastasis, with areas under the ROC curves (AUCs) of 0.92 and 0.85, respectively.ConclusionsOur findings indicated that Fn-induced NETs abundance by activating TLR4-ROS and NOD1/2 signalings in neutrophils facilitated CRC progression. The combination of circulating NETs and CEA was identified as a novel screening strategy for predicting CRC occurrence and metastasis.

Project description:ImportanceEvidence indicates a complex link between gut microbiome, immunity, and intestinal tumorigenesis. To target the microbiota and immunity for colorectal cancer prevention and therapy, a better understanding of the relationship between microorganisms and immune cells in the tumor microenvironment is needed. Experimental evidence suggests that Fusobacterium nucleatum may promote colonic neoplasia development by downregulating antitumor T cell-mediated adaptive immunity.ObjectiveTo test the hypothesis that a greater amount of F nucleatum in colorectal carcinoma tissue is associated with a lower density of T cells in tumor tissue.Design, setting, and participantsA cross-sectional analysis was conducted on 598 rectal and colon carcinoma cases in 2 US nationwide prospective cohort studies with follow-up through 2006, the Nurses' Health Study (participants enrolled in 1976) and the Health Professionals Follow-up Study (participants enrolled in 1986). Tissue collection and processing were performed from 2002 through 2008, and immunity assessment, 2008 through 2009. From 2013 through 2014, the amount of F nucleatum in colorectal carcinoma tissue was measured by quantitative polymerase chain reaction assay; we equally dichotomized positive cases (high vs low). Multivariable ordinal logistic regression analysis was conducted in 2014 to assess associations of the amount of F nucleatum with densities (quartiles) of T cells in tumor tissue, controlling for clinical and tumor molecular features, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 (LINE-1) methylation, and KRAS, BRAF, and PIK3CA mutation status. We adjusted the 2-sided α level to .013 for multiple hypothesis testing.Main outcomes and measuresDensities of CD3+, CD8+, CD45RO (protein tyrosine phosphatase receptor type C [PTPRC])+, and FOXP3+ T cells in tumor tissue, determined by means of tissue microarray immunohistochemical analysis and computer-assisted image analysis.ResultsF nucleatum was detected in colorectal carcinoma tissue in 76 (13%) of 598 cases. Compared with F nucleatum-negative cases, F nucleatum-high cases were inversely associated with the density of CD3+ T cells (for a unit increase in quartile categories of CD3+ T cells as an outcome: multivariable odds ratio, 0.47 [95% CI, 0.26-0.87]; P for trend = .006). The amount of F nucleatum was not significantly associated with the density of CD8+, CD45RO+, or FOXP3+ T cells (P fortrend = .24, .88, and .014, respectively).Conclusions and relevanceThe amount of tissue F nucleatum is inversely associated with CD3+ T-cell density in colorectal carcinoma tissue. On validation, our human population data may provide an impetus for further investigations on potential interactive roles of Fusobacterium and host immunity in colon carcinogenesis.

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Iron accelerates Fusobacterium nucleatum-induced CCL8 expression in macrophages and is associated with colorectal cancer progression.

Publications

Iron accelerates Fusobacterium nucleatum-induced CCL8 expression in macrophages and is associated with colorectal cancer progression.

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