Abstract:The interplay between gut microbiota and the host immune system is emerging as a factor in the pathogenesis of colorectal cancer. Here, we set out to identify the effect of Akkermansia muciniphila (A. muciniphila) on colorectal cancer pathogenesis. A. muciniphila abundance was significantly reduced in patients with colorectal cancer from two independent clinical cohorts and the GMrepo dataset. Supplementation with A. muciniphila suppressed colonic tumorigenesis in ApcMin/+ mice and the growth of implanted HCT1… Show more
“…Moreover, we established an AOM/DSS-induced CRC model accompanying with gavage treatment of F. nucleatum , E. coli or PBS control as previously described (Supplementary Figure 5a-b). 27 , 30 Quantitative RT-PCR analysis revealed a significant upregulation of ALPK1 and ICAM1 levels in orthotopic tumor tissues from mice receiving F. nucleatum treatment compared with E. coli or PBS control (Supplementary Figure 5c-d). These results confirm that the overabundance of F. nucleatum in mouse colon tissues leads to the upregulation of ALPK1 and ICAM1 in vivo .…”
Section: Resultsmentioning
confidence: 99%
“…F. nucleatum strain 10953 treatment, similar with F. nucleatum strain 25586, obviously promoted CRC cell-endothelial cell adhesion and CRC cells migration (Supplementary Figure 1b-c), suggesting that this may be a general property of F. nucleatum . Interestingly, when we employed a Gram-negative bacteria Akkermansia muciniphila ( A. muciniphila ) 27 and a Gram-positive bacteria Bifidobacterium adolescentis ( B. adolescentis ) 28 to identify the specific phenotype of F. nucleatum , we found that F. nucleatum treatment dramatically promoted CRC cells adhesion to endothelial cells, as well as the migration ability, but not A. muciniphila or B. adolescentis (Supplementary Figure 1d-e). Figure 1.…”
Metastasis is the leading cause of death for colorectal cancer (CRC) patients, and the spreading tumor cells adhesion to endothelial cells is a critical step for extravasation and further distant metastasis. Previous studies have documented the important roles of gut microbiota-host interactions in the CRC malignancy, and
Fusobacterium nucleatum
(
F. nucleatum
) was reported to increase proliferation and invasive activities of CRC cells. However, the potential functions and underlying mechanisms of
F. nucleatum
in the interactions between CRC cells and endothelial cells and subsequent extravasation remain unclear. Here, we uncovered that
F. nucleatum
enhanced the adhesion of CRC cells to endothelial cells, promoted extravasation and metastasis by inducing ICAM1 expression. Mechanistically, we identified that
F. nucleatum
induced a new pattern recognition receptor ALPK1 to activate NF-κB pathway, resulting in the upregulation of ICAM1. Interestingly, the abundance of
F. nucleatum
in tumor tissues of CRC patients was positively associated with the expression levels of ALPK1 and ICAM1. Moreover, high expression of ALPK1 or ICAM1 was significantly associated with a shorter overall survival time of CRC patients. This study provides a new insight into the role of gut microbiota in engaging into the distant metastasis of CRC cells.
“…Moreover, we established an AOM/DSS-induced CRC model accompanying with gavage treatment of F. nucleatum , E. coli or PBS control as previously described (Supplementary Figure 5a-b). 27 , 30 Quantitative RT-PCR analysis revealed a significant upregulation of ALPK1 and ICAM1 levels in orthotopic tumor tissues from mice receiving F. nucleatum treatment compared with E. coli or PBS control (Supplementary Figure 5c-d). These results confirm that the overabundance of F. nucleatum in mouse colon tissues leads to the upregulation of ALPK1 and ICAM1 in vivo .…”
Section: Resultsmentioning
confidence: 99%
“…F. nucleatum strain 10953 treatment, similar with F. nucleatum strain 25586, obviously promoted CRC cell-endothelial cell adhesion and CRC cells migration (Supplementary Figure 1b-c), suggesting that this may be a general property of F. nucleatum . Interestingly, when we employed a Gram-negative bacteria Akkermansia muciniphila ( A. muciniphila ) 27 and a Gram-positive bacteria Bifidobacterium adolescentis ( B. adolescentis ) 28 to identify the specific phenotype of F. nucleatum , we found that F. nucleatum treatment dramatically promoted CRC cells adhesion to endothelial cells, as well as the migration ability, but not A. muciniphila or B. adolescentis (Supplementary Figure 1d-e). Figure 1.…”
Metastasis is the leading cause of death for colorectal cancer (CRC) patients, and the spreading tumor cells adhesion to endothelial cells is a critical step for extravasation and further distant metastasis. Previous studies have documented the important roles of gut microbiota-host interactions in the CRC malignancy, and
Fusobacterium nucleatum
(
F. nucleatum
) was reported to increase proliferation and invasive activities of CRC cells. However, the potential functions and underlying mechanisms of
F. nucleatum
in the interactions between CRC cells and endothelial cells and subsequent extravasation remain unclear. Here, we uncovered that
F. nucleatum
enhanced the adhesion of CRC cells to endothelial cells, promoted extravasation and metastasis by inducing ICAM1 expression. Mechanistically, we identified that
F. nucleatum
induced a new pattern recognition receptor ALPK1 to activate NF-κB pathway, resulting in the upregulation of ICAM1. Interestingly, the abundance of
F. nucleatum
in tumor tissues of CRC patients was positively associated with the expression levels of ALPK1 and ICAM1. Moreover, high expression of ALPK1 or ICAM1 was significantly associated with a shorter overall survival time of CRC patients. This study provides a new insight into the role of gut microbiota in engaging into the distant metastasis of CRC cells.
“…This plasticity is a characteristic of the monocyte-macrophage system and reflects the particularity of these cells (11). CC is a malignant tumor with abundant macrophage infiltration (36,37). However, the role of macrophages in the progression of CC is still controversial.…”
Section: Discussionmentioning
confidence: 99%
“…CC is a malignant tumor with abundant macrophage infiltration ( 36 , 37 ). However, the role of macrophages in the progression of CC is still controversial.…”
BackgroundMacrophage extracellular traps (METs) and tumor-infiltrating macrophages contribute to the progression of several diseases. But the role of METs and tumor-infiltrating macrophages in colon cancer (CC) has not been illuminated. In this study, we aimed to clarify the prognostic value of METs for CC patients and to explore the interaction between CC cells and METs in vitro and in vivo.MethodsA training cohort consisting of 116 patients and a validation cohort of 94 patients were enrolled in this study. Immunofluorescence (IF) staining was conducted to determine METs formation in CC patients. Cox regression was used to perform prognostic analysis and screen out the best prognostic model. A nomogram was established to predict 5-year overall survival (OS). The correlation between METs with clinicopathological features and inflammatory markers was analyzed. The formation of METs in vitro was detected by SYTOX® green and IF staining, and the effect of METs on CC cells was detected by transwell assays. PAD2-IN-1, a selective inhibitor of peptidylarginine deiminase 2 (PAD2), was introduced to destroy the crosstalk between CC cells and METs in vitro and in vivo.ResultsMETs levels were higher in CC tissues and were an independent prognostic factor for CC patients. The prognostic model consisting of age, tumors local invasion, lymph node metastasis and METs were confirmed to be consistent and accurate for predicting the 5-year OS of CC patients. Besides, METs were correlated with distant metastasis and inflammation. Through in vitro experiments, we confirmed that there was a positive feedback loop between CC cells and METs, in that METs promoted the invasion of CC cells and CC cells enhanced the production of METs, in turn. This interaction could be blocked by PAD2-IN-1 inhibitors. More importantly, animal experiments revealed that PAD2-IN-1 inhibited METs formation and CC liver metastasis in vivo.ConclusionsMETs were the potential biomarker of CC patient prognosis. PAD2-IN-1 inhibited the crosstalk between CC cells and METs in vitro and in vivo, which should be emphasized in CC therapy.
“…[ 53 ] A. muciniphila can induce M1-like macrophage activation and that is mediated via TLR2/NLRP3-dependent signaling. [ 54 ] Immunotherapy has become relatively mature and has applications in many diseases, including CRC. However, in some conditions, ICIs are often ineffective.…”
Section: Specific Bacteria Correlated With Crcmentioning
Colorectal cancer (CRC) is one of the most prevalent, most lethal cancers in the world. Increasing evidence suggests that the intestinal microbiota is closely related to the pathogenesis and prognosis of CRC. The normal microbiota plays an essential role in maintaining gut barrier function and the immune microenvironment. Recent studies have identified carcinogenic bacteria such as
enterotoxigenic Bacteroides fragilis
(
ETBF
) and
Streptococcus gallolyticus
(
S. gallolyticus
), as well as protective bacterial such as
Akkermansia muciniphila
(
A. muciniphila
), as potential targets of CRC treatment. Gut microbiota modulation aims to restore gut dysbiosis, regulate the intestinal immune system and prevent from pathogen invasion, all of which are beneficial for CRC prevention and prognosis. The utility of probiotics, prebiotics, postbiotics, fecal microbiota transplantation and dietary inventions to treat CRC makes them novel microbe-based management tools. In this review, we describe the mechanisms involved in bacteria-derived colorectal carcinogenesis and summarized novel bacteria-related therapies for CRC. In summary, we hope to facilitate clinical applications of intestinal bacteria for preventing and treating CRC.
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