Back to Search
Start Over
Apoptotic Cancer Cells Suppress 5-Lipoxygenase in Tumor-Associated Macrophages
- Source :
- Journal of immunology (Baltimore, Md. : 1950). 200(2)
- Publication Year :
- 2017
-
Abstract
- The enzyme 5-lipoxygenase (5-LO) is key in the synthesis of leukotrienes, which are potent proinflammatory lipid mediators involved in chronic inflammatory diseases including cancer. 5-LO is expressed in immune cells but also found in cancer cells. Although the role of 5-LO in tumor cells is beginning to emerge, with the notion that tumor-promoting functions are attributed to its products, the function of 5-LO in the tumor microenvironment remains unclear. To understand the role of 5-LO and its products in the tumor microenvironment, we analyzed its expression and function in tumor-associated macrophages (TAMs). TAMs were generated by coculturing primary human macrophages (MΦ) with human MCF-7 breast carcinoma cells, which caused cell death of cancer cells followed by phagocytosis of cell debris by MΦ. Expression and activity of 5-LO in TAMs were reduced upon coculture with cancer cells. Downregulation of 5-LO in TAMs required tumor cell death and the direct contact between MΦ and dying cancer cells via Mer tyrosine kinase. Subsequently, upregulation of proto-oncogene c-Myb in TAMs induced a stable transcriptional repression of 5-LO. Reduced 5-LO expression in TAMs was mechanistically coupled to an attenuated T cell recruitment. In primary TAMs from human and murine breast tumors, 5-LO expression was absent or low when compared with monocyte-derived MΦ. Our data reveal that 5-LO, which is required for leukotriene production and subsequent T cell recruitment, is downregulated in TAMs through Mer tyrosine kinase–dependent recognition of apoptotic cancer cells. Mechanistically, we noticed transcriptional repression of 5-LO by proto-oncogene c-Myb and conclude that loss of stromal 5-LO expression favors tumor progression.
- Subjects :
- 0301 basic medicine
Stromal cell
Transcription, Genetic
T cell
T-Lymphocytes
Immunology
Gene Expression
Apoptosis
Breast Neoplasms
Proto-Oncogene Mas
Proinflammatory cytokine
03 medical and health sciences
Mice
Proto-Oncogene Proteins c-myb
Immune system
Downregulation and upregulation
Cell Line, Tumor
Neoplasms
medicine
Immunology and Allergy
Animals
Humans
skin and connective tissue diseases
Cells, Cultured
Tumor microenvironment
Arachidonate 5-Lipoxygenase
Chemistry
Macrophages
Enzyme Activation
Gene Expression Regulation, Neoplastic
Chemotaxis, Leukocyte
030104 developmental biology
medicine.anatomical_structure
Tumor progression
Cancer cell
Cancer research
Female
Subjects
Details
- ISSN :
- 15506606
- Volume :
- 200
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Accession number :
- edsair.doi.dedup.....493f0ef42fa301110fd6a3832e8d02e8