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Macrophage depletion using clodronate liposomes decreases tumorigenesis and alters gut microbiota in the AOM/DSS mouse model of colon cancer
- Source :
- American Journal of Physiology-Gastrointestinal and Liver Physiology. 314:G22-G31
- Publication Year :
- 2018
- Publisher :
- American Physiological Society, 2018.
-
Abstract
- We examined the role of macrophages in inflammation associated with colorectal cancer (CRC). Given the emerging evidence on immune-microbiota interactions in CRC, we also sought to examine the interaction between macrophages and gut microbiota. To induce CRC, male C57BL/6 mice ( n = 32) received a single injection of azoxymethane (AOM), followed by three cycles of dextran sodium sulfate (DSS)-supplemented water in weeks 1, 4, and 7. Prior to the final DSS cycle ( week 7) and twice weekly until euthanasia, mice ( n = 16/group) received either 200 μl ip of clodronate-filled liposomes (CLD) or phosphate-buffered saline (PBS) encapsulated liposomes to deplete macrophages. Colon tissue was analyzed for polyp burden, macrophage markers, transcription factors, and inflammatory mediators. Stool samples were collected, and DNA was isolated and subsequently sequenced for 16S rRNA. Clodronate liposomes decreased tumor number by ∼36% and specifically large (≥1 mm) tumors by ∼36% ( P < 0.05). This was consistent with a decrease in gene expression of EMR1 in the colon tissue and polyp tissue as well as expression of select markers associated with M1 (IL-6) and M2 macrophages (IL-13, IL-10, TGFβ, CCL17) in the colon tissue ( P < 0.05). Similarly, there was a decrease in STAT3 and p38 MAPK and ERK signaling in colon tissue. Clodronate liposomes increased the relative abundance of the Firmicutes phylum ( P < 0.05) and specifically Lactobacillaceae and Clostridiaceae families, which have been associated with reduced CRC risk. Overall, these data support the development of therapeutic strategies to target macrophages in CRC and provide support for further evaluation of immune-microbiota interactions in CRC. NEW & NOTEWORTHY We found that macrophage depletion during late-stage tumorigenesis is effective at reducing tumor growth. This was associated with a decrease in macrophage markers and chemokines in the colon tissue and a decrease in transcription factors that are linked to colorectal cancer. The macrophage-depleted group was found to have an increased abundance of Firmicutes, a phylum with documented anti-tumorigenic effects. Overall, these data support the development of therapeutic strategies to target macrophages in colorectal cancer.
- Subjects :
- Male
0301 basic medicine
Chemokine
Time Factors
Physiology
Colorectal cancer
Gut flora
medicine.disease_cause
chemistry.chemical_compound
0302 clinical medicine
Macrophage
Liposome
biology
Dextran Sulfate
Gastroenterology
Tumor Burden
Cell Transformation, Neoplastic
030220 oncology & carcinogenesis
Host-Pathogen Interactions
Cytokines
Inflammation Mediators
Colorectal Neoplasms
Signal Transduction
Research Article
Colon
Azoxymethane
Colonic Polyps
03 medical and health sciences
Physiology (medical)
Biomarkers, Tumor
medicine
Animals
Anticarcinogenic Agents
Macrophage depletion
Hepatology
Macrophages
medicine.disease
biology.organism_classification
digestive system diseases
Gastrointestinal Microbiome
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
chemistry
Liposomes
Immunology
biology.protein
Cancer research
Clodronic Acid
Carcinogenesis
Subjects
Details
- ISSN :
- 15221547 and 01931857
- Volume :
- 314
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Accession number :
- edsair.doi.dedup.....7ae8ea02cca55fb1a0cc3c6fa057b56d