Nature medicine, 2012-08, Vol.18 (8), p.1224-1231
2012
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- Autor(en) / Beteiligte
- Titel
- Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape
- Ist Teil von
- Nature medicine, 2012-08, Vol.18 (8), p.1224-1231
- Ort / Verlag
- New York: Nature Publishing Group US
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The authors identify Irf7 and associated interferon signaling as an important factor suppressing bone metastasis of breast cancers. Irf7 is lost in experimental metastasis and human bone metastastic tissue, and this fosters an immunosuppressive environment that facilitates metastasis. Manipulating this innate immune signaling pathway emerging from tumor cells by interferon administration had beneficial effects in mouse models by reducing bone metastasis and increasing survival time. Breast cancer metastasis is a key determinant of long-term patient survival. By comparing the transcriptomes of primary and metastatic tumor cells in a mouse model of spontaneous bone metastasis, we found that a substantial number of genes suppressed in bone metastases are targets of the interferon regulatory factor Irf7. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. In mice deficient in the interferon (IFN) receptor or in natural killer (NK) and CD8 + T cell responses, metastasis was accelerated, indicating that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7-regulated genes in primary tumors was associated with prolonged bone metastasis–free survival. This gene signature may identify patients that could benefit from IFN-based therapies. Thus, we have identified an innate immune pathway intrinsic to breast cancer cells, the suppression of which restricts immunosurveillance to enable metastasis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-8956eISSN: 1546-170XDOI: 10.1038/nm.2830Titel-ID: cdi_proquest_miscellaneous_1221142149
- Format
- –
- Schlagworte
- 631/80/86, 692/699/67/1347, 692/699/67/322/803, 692/699/67/580, Animals, Biomedical and Life Sciences, Biomedicine, Bone cancer, Bones, Breast cancer, Breast Neoplasms - genetics, Breast Neoplasms - immunology, Cancer cells, Cancer Research, Care and treatment, CD8-Positive T-Lymphocytes - immunology, Development and progression, Female, Gene expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic - drug effects, Gene Silencing, Genetic aspects, Human immunogenetics, Humans, Immune system, Immunologic Surveillance, Infectious Diseases, Interferon Regulatory Factor-7 - antagonists & inhibitors, Interferon Regulatory Factor-7 - biosynthesis, Interferon Regulatory Factor-7 - genetics, Interferon Regulatory Factor-7 - physiology, Interferon-alpha - pharmacology, Interferon-Stimulated Gene Factor 3, gamma Subunit - antagonists & inhibitors, Interferon-Stimulated Gene Factor 3, gamma Subunit - genetics, Interferon-Stimulated Gene Factor 3, gamma Subunit - physiology, Killer Cells, Natural - immunology, Mammary Neoplasms, Experimental - genetics, Mammary Neoplasms, Experimental - immunology, Metabolic Diseases, Metastasis, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, SCID, Molecular Medicine, Neoplasm Metastasis - physiopathology, Neoplasm Proteins - antagonists & inhibitors, Neoplasm Proteins - genetics, Neoplasm Proteins - physiology, Neurosciences, Receptors, Interferon - deficiency, Receptors, Interferon - physiology, Recombinant Proteins - metabolism, Severe Combined Immunodeficiency - genetics, Severe Combined Immunodeficiency - immunology, Signal transduction, Survival, T-Lymphocyte Subsets - immunology, Tumor Escape - genetics, Tumor Escape - physiology, Tumors