Premium
Emodin Administration Depolarizes Tumor Associated M2‐Type Macrophages in the Colorectal Cancer Tumor Microenvironment
Author(s) -
Sougiannis Alexander,
VanderVeen Brandon,
Chatzistamou Ioulia,
Testerman Traci,
Kubinak Jason,
Nagarkatti Mitzi,
Fan Daping,
Murphy E. Angela
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03894
Subject(s) - emodin , colorectal cancer , bone marrow , medicine , monocyte , cytokine , tumor microenvironment , cancer , immunology , pharmacology , chemistry , chromatography
Natural anthraquinone emodin has been shown to have anti‐inflammatory and anti‐tumorigenic properties and may be an effective therapy for colorectal cancer (CRC). We evaluated the efficacy of emodin to be used as a preventative therapy in the AOM/DSS (n=20/group) mouse model of CRC cancer. Emodin successfully reduced tumor count (p<0.05) and size (p<0.05) in the Apcmin/+ mouse model and reduced tumor count (p<0.05) and size (p<0.05) in the AOM/DSS mouse model. AOM/DSS mice treated with 80mg/kg emodin had reduced circulating monocyte counts (p<0.05) and increased platelet counts (p<0.05) compared to vehicle treated controls. We further analyzed the colon microenvironment of AOM/DSS mice and observed decreased CD206‐expressing M2‐type macrophages in mice receiving both 40mg/kg (p<0.05) and 80mg/kg (p<0.05) emodin. Interestingly, when analyzing colon polyps, we discovered that despite reducing M2‐type macrophages, 40mg/kg emodin did not significantly change local pro‐or anti‐inflammatory cytokine levels compared to control mice. Of note, only mice treated with 80mg/kg emodin had increased NOS2 expression (p<0.05) compared to control mice. We therefore investigated the bone marrow environment to attempt to explain our immunological findings. In the tibial bone marrow, we revealed that AOM/DSS mice had increased M1‐type macrophages (p<0.05) compared to healthy controls, a phenotype that was completely reversed with both 40mg/kg (p<0.05) and 80mg/kg (p<0.05) emodin treatment. Analyzing the protein expression of the bone we discovered decreased P2X7 receptor expression (p<0.05) and reduced STAT3 phosphorylation (p<0.05) in AOM/DSS mice treated with both 40mg/kg and 80mg/kg emodin compared to controls. To observe the effect of emodin on macrophages; we isolated and cultured bone marrow derived macrophages and treated with tumor conditioned media from C‐26 cells for 24hrs and then 50uM of emodin for another 24hrs. Utilizing flow‐cytometry we discovered emodin treatment increased CD11c+/CD206‐ (M1‐type macrophages) (p<0.05) and decreased CD11c‐/CD206+ (M2‐type macrophages) (p<0.05). Taken together, emodin treatment may work to ameliorate chronic inflammation present during CRC and improve CRC prognosis. Future investigations will interrogate the role of the P2X7 receptor to elucidate the mechanism of action of emodin on tumor conditioned macrophages.