Dataset Information

F4/80⁺Ly6C^high Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis.

ABSTRACT:

Background & aims

Colorectal cancer is a leading cause of cancer death, and a major risk factor is chronic inflammation. Despite the link between colitis and cancer, the mechanism by which inflammation leads to colorectal cancer is not well understood.

Methods

To investigate whether different forms of inflammation pose the same risk of cancer, we compared several murine models of colitis (dextran sodium sulfate [DSS], 2,4,6-trinitrobenzene sulfonic acid, 4-ethoxylmethylene-2-phenyloxazol-5-one, Citrobacter rodentium, Fusobacterium nucleatum, and doxorubicin) with respect to their ability to lead to colonic tumorigenesis. We attempted to correlate the severity of colitis and inflammatory profile with the risk of tumorigenesis in both azoxymethane-dependent and Dclk1/APC^fl/fl murine models of colitis-associated cancer.

Results

DSS colitis reproducibly led to colonic tumors in both mouse models of colitis-associated cancer. In contrast, all other forms of colitis did not lead to cancer. When compared with the colitis not associated with tumorigenesis, DSS colitis was characterized by significantly increased CD11b⁺F4/80⁺Ly6C^high macrophages and CD11b⁺Ly6G⁺ neutrophils. Interestingly, depletion of the CD11b⁺F4/80⁺Ly6C^high macrophages inhibited tumorigenesis, whereas depletion of CD11b⁺Ly6G⁺ neutrophils had no effect on tumorigenesis. Furthermore, the macrophage-derived cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-6 were significantly increased in DSS colitis and promoted stemness of Dclk1⁺ tuft cells that serve as the cellular origin of cancer.

Conclusions

We have identified CD11b⁺F4/80⁺Ly6C^high macrophages as key mediators of cancer initiation in colitis-associated cancer. Development of new therapies that target these cells may provide an effective preventative strategy for colitis-associated cancer.

SUBMITTER: Shin AE

PROVIDER: S-EPMC10038892 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

F4/80<sup>+</sup>Ly6C<sup>high</sup> Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis.

Shin Alice E AE Tesfagiorgis Yodit Y Larsen Frederikke F Derouet Mathieu M Zeng Peter Y F PYF Good Hayley J HJ Zhang Liyue L Rubinstein Mara R MR Han Yiping W YW Kerfoot Steven M SM Nichols Anthony C AC Hayakawa Yoku Y Howlett Christopher J CJ Wang Timothy C TC Asfaha Samuel S

Gastroenterology 20230110 4

<h4>Background & aims</h4>Colorectal cancer is a leading cause of cancer death, and a major risk factor is chronic inflammation. Despite the link between colitis and cancer, the mechanism by which inflammation leads to colorectal cancer is not well understood.<h4>Methods</h4>To investigate whether different forms of inflammation pose the same risk of cancer, we compared several murine models of colitis (dextran sodium sulfate [DSS], 2,4,6-trinitrobenzene sulfonic acid, 4-ethoxylmethylene-2-pheny ...[more]

PMID: 36634827

Similar Datasets

Project description:Lipopolysaccharide (LPS) decreases hepatic CETP (cholesteryl ester transfer protein) expression albeit that the underlying mechanism is disputed. We recently showed that plasma CETP is mainly derived from Kupffer cells (KCs). In this study, we investigated the role of KC subsets in the mechanism by which LPS reduces CETP expression. In CETP-transgenic mice, LPS markedly decreased hepatic CETP expression and plasma CETP concentration without affecting hepatic macrophage number. This was paralleled by decreased expression of the resting KC markers C-type lectin domain family 4, member f (Clec4f) and V-set and immunoglobulin domain containing 4 (Vsig4), while expression of the infiltrating monocyte marker lymphocyte antigen 6 complex locus C (Ly6C) was increased. Simultaneously, the ratio of plasma high-density lipoprotein-cholesterol over non-high-density lipoprotein-cholesterol transiently increased. After ablation hepatic macrophages via injection with liposomal clodronate, the reappearance of hepatic gene and protein expression of CETP coincided with Clec4f and Vsig4, but not Ly6C. Double-immunofluorescence staining showed that CETP co-localized with Clec4f+ KCs and not Ly6C+ monocytes. In humans, microarray gene-expression analysis of liver biopsies revealed that hepatic expression and plasma level of CETP both correlated with hepatic VSIG4 expression. LPS administration decreased the plasma CETP concentration in humans. In vitro experiments showed that LPS reduced liver X receptor-mediated CETP expression. Hepatic expression of CETP is exclusively confined to the resting KC subset (ie, F4/80+Clec4f+Vsig4+Ly6C-). LPS activated resting KCs, leading to reduction of Clec4f and Vsig4 expression and reduction of hepatic CETP expression, consequently decreasing plasma CETP and raising high-density lipoprotein (HDL)-cholesterol. This sequence of events is consistent with the anti-inflammatory role of HDL in the response to LPS and may be relevant as a defense mechanism against bacterial infections.

Dataset Information

F4/80⁺Ly6C^high Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis.

Background & aims

Methods

Results

Conclusions

Publications

F4/80<sup>+</sup>Ly6C<sup>high</sup> Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

F4/80+Ly6Chigh Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis.

Background & aims

Methods

Results

Conclusions

Publications

F4/80<sup>+</sup>Ly6C<sup>high</sup> Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

F4/80⁺Ly6C^high Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis.