A1 F4/80+LY6CHI MACROPHAGES ARE KEY TO CANCER INITIATION IN COLITIS
Bibliographic record
Abstract
Abstract Background Colorectal cancer (CRC) is the third leading cause of cancer death, with a major risk factor being chronic inflammation. Thus, patients with inflammatory bowel disease (IBD) are at an increased risk of CRC. Despite the clear association between inflammation and cancer, the mechanism by which colitis leads to CRC is still not well understood. Aims In this study, we aim to explore the mechanism by which inflammation contributes to the initiation of colitis-associated cancer (CAC). We hypothesize that dextran sodium sulfate (DSS)-induced colitis leads to the infiltration of a specific immune cell type associated with tumorigenesis. Methods Following an injection of azoxymethane (AOM), mice were treated with the colitis-inducing agents DSS, trinitrobenzene sulfonic acid (TNBS), oxazolone (oxa), Citrobacter rodentium, or Doxorubicin (Doxo). The tumor studies were repeated using our published Cre-dependent murine model of CAC. To generate tamoxifen-inducible Cre transgenic mice that allow for Dclk1+ cell lineage tracing and cell-specific knock-out of the tumor suppressor adenomatous polyposis coli (APC), we crossed our Dclk1CreERT2 mice to both ROSA26tdTomato and APCfl/fl mice (Dclk1/APCfl/fl). Results Treatment with DSS, TNBS, oxa, C. rodentium, or Doxo induced colonic inflammation as detected by increased myeloperoxidase (MPO) activity and histologic analysis. DSS administration led to colonic tumors, whereas TNBS, oxa, C. rodentium, or Doxo did not lead to tumorigenesis up to 52 weeks following colitis induction. Upon flow cytometric analysis of several types of immune cells in the colonic tissue, we observed no difference in the number of T and B cells between mice treated with various colitis inducing agents. We did, however, detect significantly increased levels of Ly6G+ neutrophils and F4/80+Ly6Chi macrophages in the DSS-treated mice when compared to mice in the other models of colitis. mRNA and protein array analyses of the colonic tissue, as well as analysis of the RNA-seq data from 206 UC patients (GSE109142), revealed upregulated expression of genes associated with macrophages and neutrophils. Addition of macrophage-produced cytokines, such as IL-1β, TNF-α, or IL-6, induced lineage tracing of Dclk1+ tuft cells in intestinal organoids. Clodronate liposome-mediated depletion of F4/80+Ly6Chi macrophages significantly reduced the number of colonic tumors but did not affect tumor size in Dclk1/APCfl/fl mice. Conclusions Our data suggest that infiltration of F4/80+Ly6Chi macrophages, unique to DSS-induced colitis, leads to colonic tumor formation. This demonstrates that specific immune cell types, rather than the presence of colonic inflammation, plays an important role in the initiation of CAC. Funding Agencies CAG, CIHR
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".