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UNVEILING THE ROLE OF MFSD2A IN CONTRIBUTING TO THE RESOLUTION OF COLORECTAL CANCER-ASSOCIATED INFLAMMATION
Date
May 21, 2024
BACKGROUND
The intrinsic connection between inflammation and tumor promotion is well characterized and is a key pathogenic event in patients with colorectal cancer (CRC). A small fraction of patients with CRC suffers from genetic predisposition, however environmental factors and chronic inflammation, such as ulcerative colitis (UC), represent the major causes of intestinal carcinogenesis. A few years ago, our laboratory described that the intestinal endothelium isolated from actively inflamed UC patients displayed defective production of inflammation-resolving DHA-derived metabolites, by comparison with healthy controls and tissues in remission. We also reported that the Major Facilitator Superfamily Domain containing 2A (MFSD2A) participated in the production of the inflammation-resolving DHA-derived metabolites by the intestinal endothelium of patients with UC in remission, ameliorating colonic inflammation.
Therefore, we hypothesized that the endothelial MFSD2A also has a role in preventing and/or counteracting cancer-associated inflammation.
METHODS
Human Intestinal Microvascular Endothelial Cells (HIMEC) isolated from CRC and healthy samples were transduced with MFSD2A protein-encoding lentiviral vectors (MFSD2A) or GFP as control, and MFSD2A targeting shRNA or the scramble as control, and were analyzed by lipidomics.
Furthermore, to assess if endothelial MFSD2A shapes CRC growth, Colon-adenocarcinoma cell line (Caco-2) co-cultured with HIMEC-MFSD2A were analyzed by FACS, evaluating their proliferation.
Moreover, an orthotopic model of CRC was made intrarectally injecting CD1 nude mice with a cell mixture of Caco-2 and Human Umbelical Vascular Endothelial Cell (HUVEC) overexpressing MFSD2A or GFP as control. Mice were gavaged twice a week with 1 mg/g DHA-ethyl-ester of PBS. FACS analysis were performed on tumor and colonic samples.
RESULTS
Lipidomic analysis revealed that the loss of MFSD2A in CRC is detrimental because there is a reduced production of pro-resolving lipids confirming that MFSD2A is important for the maintenance of an adequate balance between pro-resolving and pro-inflammatory phenotype. Moreover, the enhancement of MFSD2A expression at endothelial level limits Caco-2 cell proliferation, supporting its beneficial role. Furthermore, DHA administration in mice overexpressing endothelial MFSD2A ameliorates the inflammation, suggesting that the resolution phase through DHA-derived metabolites is due to the presence of MFSD2A.
CONCLUSION
Tumor-associated inflammation remains a crucial hallmark of CRC. Our study seeks to identify the role of MFSD2A in the resolution phase of inflammation, pointing out alternative therapies for CRC treatment. These data suggested that MFSD2A might contrast the tumor-associated inflammation and ensure the correct balance between pro-inflammatory and pro-resolving milieu.
The intrinsic connection between inflammation and tumor promotion is well characterized and is a key pathogenic event in patients with colorectal cancer (CRC). A small fraction of patients with CRC suffers from genetic predisposition, however environmental factors and chronic inflammation, such as ulcerative colitis (UC), represent the major causes of intestinal carcinogenesis. A few years ago, our laboratory described that the intestinal endothelium isolated from actively inflamed UC patients displayed defective production of inflammation-resolving DHA-derived metabolites, by comparison with healthy controls and tissues in remission. We also reported that the Major Facilitator Superfamily Domain containing 2A (MFSD2A) participated in the production of the inflammation-resolving DHA-derived metabolites by the intestinal endothelium of patients with UC in remission, ameliorating colonic inflammation.
Therefore, we hypothesized that the endothelial MFSD2A also has a role in preventing and/or counteracting cancer-associated inflammation.
METHODS
Human Intestinal Microvascular Endothelial Cells (HIMEC) isolated from CRC and healthy samples were transduced with MFSD2A protein-encoding lentiviral vectors (MFSD2A) or GFP as control, and MFSD2A targeting shRNA or the scramble as control, and were analyzed by lipidomics.
Furthermore, to assess if endothelial MFSD2A shapes CRC growth, Colon-adenocarcinoma cell line (Caco-2) co-cultured with HIMEC-MFSD2A were analyzed by FACS, evaluating their proliferation.
Moreover, an orthotopic model of CRC was made intrarectally injecting CD1 nude mice with a cell mixture of Caco-2 and Human Umbelical Vascular Endothelial Cell (HUVEC) overexpressing MFSD2A or GFP as control. Mice were gavaged twice a week with 1 mg/g DHA-ethyl-ester of PBS. FACS analysis were performed on tumor and colonic samples.
RESULTS
Lipidomic analysis revealed that the loss of MFSD2A in CRC is detrimental because there is a reduced production of pro-resolving lipids confirming that MFSD2A is important for the maintenance of an adequate balance between pro-resolving and pro-inflammatory phenotype. Moreover, the enhancement of MFSD2A expression at endothelial level limits Caco-2 cell proliferation, supporting its beneficial role. Furthermore, DHA administration in mice overexpressing endothelial MFSD2A ameliorates the inflammation, suggesting that the resolution phase through DHA-derived metabolites is due to the presence of MFSD2A.
CONCLUSION
Tumor-associated inflammation remains a crucial hallmark of CRC. Our study seeks to identify the role of MFSD2A in the resolution phase of inflammation, pointing out alternative therapies for CRC treatment. These data suggested that MFSD2A might contrast the tumor-associated inflammation and ensure the correct balance between pro-inflammatory and pro-resolving milieu.
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