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Macrophage depletion using clodronate liposomes decreases tumorigenesis and alters gut microbiota in the AOM/DSS mouse model of colon cancer.
Am J Physiol Gastrointest Liver Physiol. 2018 01 01; 314(1):G22-G31.AJ

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.

Authors+Show Affiliations

Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina , Columbia, South Carolina.Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina , Columbia, South Carolina.Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina , Columbia, South Carolina. Department of Exercise Science, School of Public Health, University of South Carolina , Columbia, South Carolina.Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina , Columbia, South Carolina.Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina , Columbia, South Carolina.Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina , Columbia, South Carolina.Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina , Columbia, South Carolina.Department of Exercise Science, School of Public Health, University of South Carolina , Columbia, South Carolina.Department of Exercise Science, School of Public Health, University of South Carolina , Columbia, South Carolina. Center for Colon Cancer Research, University of South Carolina , Columbia, South Carolina.Department of Microbiology, Immunology, and Cell Biology, School of Medicine, West Virginia University , Morgantown, West Virginia.Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina , Columbia, South Carolina. Center for Colon Cancer Research, University of South Carolina , Columbia, South Carolina.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

29025731

Citation

Bader, Jackie E., et al. "Macrophage Depletion Using Clodronate Liposomes Decreases Tumorigenesis and Alters Gut Microbiota in the AOM/DSS Mouse Model of Colon Cancer." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 314, no. 1, 2018, pp. G22-G31.
Bader JE, Enos RT, Velázquez KT, et al. Macrophage depletion using clodronate liposomes decreases tumorigenesis and alters gut microbiota in the AOM/DSS mouse model of colon cancer. Am J Physiol Gastrointest Liver Physiol. 2018;314(1):G22-G31.
Bader, J. E., Enos, R. T., Velázquez, K. T., Carson, M. S., Nagarkatti, M., Nagarkatti, P. S., Chatzistamou, I., Davis, J. M., Carson, J. A., Robinson, C. M., & Murphy, E. A. (2018). Macrophage depletion using clodronate liposomes decreases tumorigenesis and alters gut microbiota in the AOM/DSS mouse model of colon cancer. American Journal of Physiology. Gastrointestinal and Liver Physiology, 314(1), G22-G31. https://doi.org/10.1152/ajpgi.00229.2017
Bader JE, et al. Macrophage Depletion Using Clodronate Liposomes Decreases Tumorigenesis and Alters Gut Microbiota in the AOM/DSS Mouse Model of Colon Cancer. Am J Physiol Gastrointest Liver Physiol. 2018 01 1;314(1):G22-G31. PubMed PMID: 29025731.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Macrophage depletion using clodronate liposomes decreases tumorigenesis and alters gut microbiota in the AOM/DSS mouse model of colon cancer. AU - Bader,Jackie E, AU - Enos,Reilly T, AU - Velázquez,Kandy T, AU - Carson,Meredith S, AU - Nagarkatti,Mitzi, AU - Nagarkatti,Prakash S, AU - Chatzistamou,Ioulia, AU - Davis,J Mark, AU - Carson,James A, AU - Robinson,Cory M, AU - Murphy,E Angela, Y1 - 2017/10/12/ PY - 2017/10/14/pubmed PY - 2019/2/27/medline PY - 2017/10/14/entrez KW - azoxymethane KW - dextran sodium sulfate SP - G22 EP - G31 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 314 IS - 1 N2 - 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. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/29025731/Macrophage_depletion_using_clodronate_liposomes_decreases_tumorigenesis_and_alters_gut_microbiota_in_the_AOM/DSS_mouse_model_of_colon_cancer_ L2 - https://journals.physiology.org/doi/10.1152/ajpgi.00229.2017?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -