Cargando…
Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy()()
Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (γH2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resectio...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614733/ https://www.ncbi.nlm.nih.gov/pubmed/28954241 http://dx.doi.org/10.1016/j.neo.2017.08.005 |
_version_ | 1783266454002466816 |
---|---|
author | Harryman, William L. Gard, Jaime M.C. Pond, Kelvin W. Simpson, Skyler J. Heppner, Lucas H. Hernandez-Cortes, Daniel Little, Andrew S. Eschbacher, Jennifer M. Cress, Anne E. |
author_facet | Harryman, William L. Gard, Jaime M.C. Pond, Kelvin W. Simpson, Skyler J. Heppner, Lucas H. Hernandez-Cortes, Daniel Little, Andrew S. Eschbacher, Jennifer M. Cress, Anne E. |
author_sort | Harryman, William L. |
collection | PubMed |
description | Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (γH2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resections, 23 patients) to test if blocking cell adhesion sensitizes U-CH1 tumor cells to IR. U-CH1 cells expressed brachyury, YAP, and laminin adhesion receptors (CD49c, CD49f, CD44), and approximately 15% to 20% of U-CH1 cells featured an α6 integrin-dependent (CD49f) cohesive cluster phenotype, which confers therapeutic resistance and aids metastasis. DDR to IR in U-CH1 cells was compared to normal prostate epithelial (PrEC) and tumor cells (DU145). Flow cytometry showed a dose- and time-dependent increase in γH2AX and pKAP1 expression in all cell lines. However, nearly 50% of U-CH1 cells exhibited nonresponsive phenotype to IR (measured by γH2AX and pKAP1) independent of cell cycle status. Immunofluorescence microscopy verified that only 15% of U-CH1 clustered cells were γH2AX or pKAP1 positive (versus 80% of nonclustered cells) 2 hours following 2-Gy IR. Conversely, both tumor cell lines were uniformly defective in pATM response. HYD1, a synthetic ECM ligand, inhibited DDR through an unresolved γH2AX response. β1 integrin-blocking antibody (AIIB2) decreased cell survival 50% itself and approximately doubled the IR-induced cell kill at all IR doses observed at 2 and 4 weeks posttreatment. These results suggest that a heterogeneity of DDR to IR exists within a chordoma population. Blocking integrin function alone and/or as an adjuvant to IR may eradicate chordomas containing the cohesive cluster phenotype. |
format | Online Article Text |
id | pubmed-5614733 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-56147332017-10-02 Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy()() Harryman, William L. Gard, Jaime M.C. Pond, Kelvin W. Simpson, Skyler J. Heppner, Lucas H. Hernandez-Cortes, Daniel Little, Andrew S. Eschbacher, Jennifer M. Cress, Anne E. Neoplasia Original article Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (γH2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resections, 23 patients) to test if blocking cell adhesion sensitizes U-CH1 tumor cells to IR. U-CH1 cells expressed brachyury, YAP, and laminin adhesion receptors (CD49c, CD49f, CD44), and approximately 15% to 20% of U-CH1 cells featured an α6 integrin-dependent (CD49f) cohesive cluster phenotype, which confers therapeutic resistance and aids metastasis. DDR to IR in U-CH1 cells was compared to normal prostate epithelial (PrEC) and tumor cells (DU145). Flow cytometry showed a dose- and time-dependent increase in γH2AX and pKAP1 expression in all cell lines. However, nearly 50% of U-CH1 cells exhibited nonresponsive phenotype to IR (measured by γH2AX and pKAP1) independent of cell cycle status. Immunofluorescence microscopy verified that only 15% of U-CH1 clustered cells were γH2AX or pKAP1 positive (versus 80% of nonclustered cells) 2 hours following 2-Gy IR. Conversely, both tumor cell lines were uniformly defective in pATM response. HYD1, a synthetic ECM ligand, inhibited DDR through an unresolved γH2AX response. β1 integrin-blocking antibody (AIIB2) decreased cell survival 50% itself and approximately doubled the IR-induced cell kill at all IR doses observed at 2 and 4 weeks posttreatment. These results suggest that a heterogeneity of DDR to IR exists within a chordoma population. Blocking integrin function alone and/or as an adjuvant to IR may eradicate chordomas containing the cohesive cluster phenotype. Neoplasia Press 2017-09-24 /pmc/articles/PMC5614733/ /pubmed/28954241 http://dx.doi.org/10.1016/j.neo.2017.08.005 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original article Harryman, William L. Gard, Jaime M.C. Pond, Kelvin W. Simpson, Skyler J. Heppner, Lucas H. Hernandez-Cortes, Daniel Little, Andrew S. Eschbacher, Jennifer M. Cress, Anne E. Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy()() |
title | Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy()() |
title_full | Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy()() |
title_fullStr | Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy()() |
title_full_unstemmed | Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy()() |
title_short | Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy()() |
title_sort | targeting the cohesive cluster phenotype in chordoma via β1 integrin increases ionizing radiation efficacy()() |
topic | Original article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614733/ https://www.ncbi.nlm.nih.gov/pubmed/28954241 http://dx.doi.org/10.1016/j.neo.2017.08.005 |
work_keys_str_mv | AT harrymanwilliaml targetingthecohesiveclusterphenotypeinchordomaviab1integrinincreasesionizingradiationefficacy AT gardjaimemc targetingthecohesiveclusterphenotypeinchordomaviab1integrinincreasesionizingradiationefficacy AT pondkelvinw targetingthecohesiveclusterphenotypeinchordomaviab1integrinincreasesionizingradiationefficacy AT simpsonskylerj targetingthecohesiveclusterphenotypeinchordomaviab1integrinincreasesionizingradiationefficacy AT heppnerlucash targetingthecohesiveclusterphenotypeinchordomaviab1integrinincreasesionizingradiationefficacy AT hernandezcortesdaniel targetingthecohesiveclusterphenotypeinchordomaviab1integrinincreasesionizingradiationefficacy AT littleandrews targetingthecohesiveclusterphenotypeinchordomaviab1integrinincreasesionizingradiationefficacy AT eschbacherjenniferm targetingthecohesiveclusterphenotypeinchordomaviab1integrinincreasesionizingradiationefficacy AT cressannee targetingthecohesiveclusterphenotypeinchordomaviab1integrinincreasesionizingradiationefficacy |