Ly6G + inflammatory cells enable the conversion of cancer cells to cancer stem cells in an irradiated glioblastoma model

Hee Young Jeon, Seok Won Ham, Jun Kyum Kim, Xiong Jin, Seon Yong Lee, Yong Jae Shin, Chang Yong Choi, Jason K. Sa, Se Hoon Kim, Taehoon Chun, Xun Jin, Do Hyun Nam, Hyunggee Kim

Research output: Contribution to journalArticle

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Abstract

Most glioblastomas frequently recur at sites of radiotherapy, but it is unclear if changes in the tumor microenvironment due to radiotherapy influence glioblastoma recurrence. Here, we demonstrate that radiation-induced senescent glioblastoma cells exhibit a senescence-associated secretory phenotype that functions through NFκB signaling to influence changes in the tumor microenvironment, such as recruitment of Ly6G + inflammatory cells and vessel formation. In particular, Ly6G + cells promote conversion of glioblastoma cells to glioblastoma stem cells (GSCs) through the NOS2-NO-ID4 regulatory axis. Specific inhibition of NFκB signaling in irradiated glioma cells using the IκBα super repressor prevents changes in the tumor microenvironment and dedifferentiation of glioblastoma cells. Treatment with Ly6G-neutralizing antibodies also reduces the number of GSCs and prolongs survival in tumor-bearing mice after radiotherapy. Clinically, a positive correlation exists between Ly6G + cells and the NOS2-NO-ID4 regulatory axis in patients diagnosed with recurrent glioblastoma. Together, our results illustrate important roles for Ly6G + inflammatory cells recruited by radiation-induced SASP in cancer cell dedifferentiation and tumor recurrence.

Original languageEnglish
JournalCell Death and Differentiation
DOIs
Publication statusPublished - 2019 Jan 1

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Neoplastic Stem Cells
Glioblastoma
Tumor Microenvironment
Neoplasms
Cell Dedifferentiation
Radiotherapy
Stem Cells
Radiation
Recurrence
Neutralizing Antibodies
Glioma
Cell Survival
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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Ly6G + inflammatory cells enable the conversion of cancer cells to cancer stem cells in an irradiated glioblastoma model . / Jeon, Hee Young; Ham, Seok Won; Kim, Jun Kyum; Jin, Xiong; Lee, Seon Yong; Shin, Yong Jae; Choi, Chang Yong; Sa, Jason K.; Kim, Se Hoon; Chun, Taehoon; Jin, Xun; Nam, Do Hyun; Kim, Hyunggee.

In: Cell Death and Differentiation, 01.01.2019.

Research output: Contribution to journalArticle

Jeon, Hee Young ; Ham, Seok Won ; Kim, Jun Kyum ; Jin, Xiong ; Lee, Seon Yong ; Shin, Yong Jae ; Choi, Chang Yong ; Sa, Jason K. ; Kim, Se Hoon ; Chun, Taehoon ; Jin, Xun ; Nam, Do Hyun ; Kim, Hyunggee. / Ly6G + inflammatory cells enable the conversion of cancer cells to cancer stem cells in an irradiated glioblastoma model In: Cell Death and Differentiation. 2019.
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abstract = "Most glioblastomas frequently recur at sites of radiotherapy, but it is unclear if changes in the tumor microenvironment due to radiotherapy influence glioblastoma recurrence. Here, we demonstrate that radiation-induced senescent glioblastoma cells exhibit a senescence-associated secretory phenotype that functions through NFκB signaling to influence changes in the tumor microenvironment, such as recruitment of Ly6G + inflammatory cells and vessel formation. In particular, Ly6G + cells promote conversion of glioblastoma cells to glioblastoma stem cells (GSCs) through the NOS2-NO-ID4 regulatory axis. Specific inhibition of NFκB signaling in irradiated glioma cells using the IκBα super repressor prevents changes in the tumor microenvironment and dedifferentiation of glioblastoma cells. Treatment with Ly6G-neutralizing antibodies also reduces the number of GSCs and prolongs survival in tumor-bearing mice after radiotherapy. Clinically, a positive correlation exists between Ly6G + cells and the NOS2-NO-ID4 regulatory axis in patients diagnosed with recurrent glioblastoma. Together, our results illustrate important roles for Ly6G + inflammatory cells recruited by radiation-induced SASP in cancer cell dedifferentiation and tumor recurrence.",
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AU - Lee, Seon Yong

AU - Shin, Yong Jae

AU - Choi, Chang Yong

AU - Sa, Jason K.

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AU - Jin, Xun

AU - Nam, Do Hyun

AU - Kim, Hyunggee

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