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Radiation-induced Notch signaling in breast cancer stem cells.

ABSTRACT: To explore patterns of Notch receptor and ligand expression in response to radiation that could be crucial in defining optimal dosing schemes for ?-secretase inhibitors if combined with radiation.Using MCF-7 and T47D breast cancer cell lines, we used real-time reverse transcription-polymerase chain reaction to study the Notch pathway in response to radiation.We show that Notch receptor and ligand expression during the first 48 hours after irradiation followed a complex radiation dose-dependent pattern and was most pronounced in mammospheres, enriched for breast cancer stem cells. Additionally, radiation activated the Notch pathway. Treatment with a ?-secretase inhibitor prevented radiation-induced Notch family gene expression and led to a significant reduction in the size of the breast cancer stem cell pool.Our results indicate that, if combined with radiation, ?-secretase inhibitors may prevent up-regulation of Notch receptor and ligand family members and thus reduce the number of surviving breast cancer stem cells.

SUBMITTER: Lagadec C

PROVIDER: S-EPMC3788036 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Radiation-induced Notch signaling in breast cancer stem cells.

Lagadec Chann C Vlashi Erina E Alhiyari Yazeed Y Phillips Tiffany M TM Bochkur Dratver Milana M Pajonk Frank F

International journal of radiation oncology, biology, physics 20130827 3

<h4>Purpose</h4>To explore patterns of Notch receptor and ligand expression in response to radiation that could be crucial in defining optimal dosing schemes for γ-secretase inhibitors if combined with radiation.<h4>Methods and materials</h4>Using MCF-7 and T47D breast cancer cell lines, we used real-time reverse transcription-polymerase chain reaction to study the Notch pathway in response to radiation.<h4>Results</h4>We show that Notch receptor and ligand expression during the first 48 hours a ...[more]

PMID: 23992604

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Project description:Dendritic cells (DCs) play critical roles in regulating the innate and adaptive immune responses, and have long been a major focus of cancer immunotherapy. Accumulating evidence suggests that conventional type 1 DCs (cDC1s) excel in cross-presentation of exogenous antigens on MHC-I molecules and induction of antitumor CD8+ T cell immunity; however, obtaining large numbers of cDC1s is difficult. The use of reprogramming and differentiation technology is advantageous for obtaining unlimited numbers of autologous cDC1s especially for therapeutic interventions where repeated vaccinations are required. However, generation of cDC1s from human induced pluripotent stem cells (iPSCs) remains elusive. Human iPSCs established from peripheral blood T cells and monocytes were differentiated to myeloid cells under on-feeder or feeder-free culture conditions in vitro. Phenotype, genomic and transcriptomic signature, and function of human iPSC-derived DCs were analyzed. The role of Notch signaling for the generation of HLA-DR+ cells from human iPSCs was interrogated by a loss- and gain-of-function approach. Flow cytometric analyses and single-cell profiling of HLA-DR+ cells revealed that human iPSCs gave rise to CD141+XCR1+CLEC9A+ cells (cDC1s), CLEC4AhiCLEC10A-CD1c+ cells (cDC2As), CLEC4AloCLEC10A+CD1c+ cells (cDC2Bs), CD163-CD5+CD1c+ cells (CD5+cDC2s), and AXL+SIGLEC6+ cells (AS-DCs) on OP9 feeder cells expressing the Notch ligand delta-like 1 (OP9-DL1) while the majority of iPSC-derived cells differentiated on OP9 cells were CD163+CD5-CD1c+ cells (DC3s) and monocytes. Plasmacytoid DCs were not differentiated from iPSCs on either OP9 or OP9-DL1 cells. Inhibition of Notch signaling during co-culture of iPSC-derived CD34+ hematopoietic progenitor cells with OP9-DL1 cells abrogated generation of cDC1s, cDC2As, cDC2Bs, CD5+cDC2s, and AS-DCs but increased frequency of DC3s. Notch-activated human iPSC-derived XCR1+CLEC9A+HLA-DR+CD11c+ cells exhibited similar gene expression profile with peripheral blood cDC1s. Human iPSC-derived DCs have phagocytic, T-cell proliferative, and cytokine-producing functions. Our study demonstrates a critical role of Notch signaling in regulating developmental pathway of human cDCs. These findings provide insights into the future development of personalized treatment with unlimited numbers of autologous cDCs from human iPSCs.

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Radiation-induced Notch signaling in breast cancer stem cells.

Publications

Radiation-induced Notch signaling in breast cancer stem cells.

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