Transcriptional profiling provides insights into metronomic cyclophosphamide-activated, innate immune-dependent regression of brain tumor xenografts

BMC Cancer

Research Article

David J Waxman¹  Joshua C Doloff¹ 

[1] Department of Biology, Division of Cell and Molecular Biology, Boston University, Boston, USA;

关键词: Immunogenic chemotherapy;    Microarray;    Mouse tumor models;    U251 glioblastoma;    Innate immunity;   

DOI  :  10.1186/s12885-015-1358-y

 received in 2014-11-18, accepted in 2015-04-23,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundCyclophosphamide treatment on a six-day repeating metronomic schedule induces a dramatic, innate immune cell-dependent regression of implanted gliomas. However, little is known about the underlying mechanisms whereby metronomic cyclophosphamide induces innate immune cell mobilization and recruitment, or about the role of DNA damage and cell stress response pathways in eliciting the immune responses linked to tumor regression.MethodsUntreated and metronomic cyclophosphamide-treated human U251 glioblastoma xenografts were analyzed on human microarrays at two treatment time points to identify responsive tumor cell-specific factors and their upstream regulators. Mouse microarray analysis across two glioma models (human U251, rat 9L) was used to identify host factors and gene networks that contribute to the observed immune and tumor regression responses.ResultsMetronomic cyclophosphamide increased expression of tumor cell-derived DNA damage, cell stress, and cell death genes, which may facilitate innate immune activation. Increased expression of many host (mouse) immune networks was also seen in both tumor models, including complement components, toll-like receptors, interferons, and cytolysis pathways. Key upstream regulators activated by metronomic cyclophosphamide include members of the interferon, toll-like receptor, inflammatory response, and PPAR signaling pathways, whose activation may contribute to anti-tumor immunity. Many upstream regulators inhibited by metronomic cyclophosphamide, including hypoxia-inducible factors and MAP kinases, have glioma-promoting activity; their inhibition may contribute to the therapeutic effectiveness of the six-day repeating metronomic cyclophosphamide schedule.ConclusionsLarge numbers of responsive cytokines, chemokines and immune regulatory genes linked to innate immune cell recruitment and tumor regression were identified, as were several immunosuppressive factors that may contribute to the observed escape of some tumors from metronomic CPA-induced, immune-based regression. These factors may include useful biomarkers that facilitate discovery of clinically effective immunogenic metronomic drugs and treatment schedules, and the selection of patients most likely to be responsive to immunogenic drug scheduling.

【 授权许可】

CC BY   
© Doloff and Waxman; licensee BioMed Central. 2015