Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution
| Autor: | Donna J. Hicks, Andrew Williams, Rebecca S. Cook, Meghan M. Morrison, Jiyeon Lim, Michelle M. Williams, Christian D. Young, Jamie C. Stanford, Justin M. Balko, David B. Vaught, Philip Owens, Debra A. Tonetti, Dana M. Brantley-Sieders, H. Shelton Earp |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Lung Neoplasms Gene Expression Apoptosis Mice Transgenic Biology Metastasis Mammary Glands Animal Phagocytosis Proto-Oncogene Proteins medicine Animals Humans Involution (medicine) Efferocytosis Mammary gland involution Tumor microenvironment Mammary tumor c-Mer Tyrosine Kinase Postpartum Period Mammary Neoplasms Experimental Receptor Protein-Tyrosine Kinases General Medicine MERTK medicine.disease Coculture Techniques Tumor Burden Up-Regulation Gene Expression Regulation Neoplastic MCF-7 Cells Cancer research Cytokines Female Neoplasm Transplantation Postpartum period Signal Transduction Research Article |
| Zdroj: | Journal of Clinical Investigation. 124:4737-4752 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci76375 |
| Popis: | Breast cancers that occur in women 2–5 years postpartum are more frequently diagnosed at metastatic stages and correlate with poorer outcomes compared with breast cancers diagnosed in young, premenopausal women. The molecular mechanisms underlying the malignant severity associated with postpartum breast cancers (ppBCs) are unclear but relate to stromal wound-healing events during postpartum involution, a dynamic process characterized by widespread cell death in milk-producing mammary epithelial cells (MECs). Using both spontaneous and allografted mammary tumors in fully immune–competent mice, we discovered that postpartum involution increases mammary tumor metastasis. Cell death was widespread, not only occurring in MECs but also in tumor epithelium. Dying tumor cells were cleared through receptor tyrosine kinase MerTK–dependent efferocytosis, which robustly induced the transcription of genes encoding wound-healing cytokines, including IL-4, IL-10, IL-13, and TGF-β. Animals lacking MerTK and animals treated with a MerTK inhibitor exhibited impaired efferocytosis in postpartum tumors, a reduction of M2-like macrophages but no change in total macrophage levels, decreased TGF-β expression, and a reduction of postpartum tumor metastasis that was similar to the metastasis frequencies observed in nulliparous mice. Moreover, TGF-β blockade reduced postpartum tumor metastasis. These data suggest that widespread cell death during postpartum involution triggers efferocytosis-induced wound-healing cytokines in the tumor microenvironment that promote metastatic tumor progression. |
| Databáze: | OpenAIRE |
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