EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction

Xun Jin, Jinlong Yin, Sung Hak Kim, Young Woo Sohn, Samuel Beck, Young Chang Lim, Do Hyun Nam, Yun Jaie Choi, Hyunggee Kim

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Aberrant activation of receptor tyrosine kinases (RTK) is causally linked to the pathobiological traits of glioblastoma and genesis of glioma stem-like cells (GSC), but the underlying mechanism is still unknown. Here, we show that epidermal growth factor receptor (EGFR) signaling regulates the proliferation, angiogenesis, and acquisition of GSC characteristics by inducing inhibitor of differentiation 3 (ID3) and ID3-regulated cytokines [GRO1 and interleukins (IL)-6 and 8] induction. We found that EGFR-mediated ID3 expression was regulated by Smad5, which was directly phosphorylated by AKT. Furthermore, ID3 alone imparted GSC features to primary astrocytes derived from Ink4a/Arf-deficient mouse, and EGFR-ID3-IL-6 signaling axis gave rise to tumor cell heterogeneity. Conversely, EGFR inhibitors suppressed EGFR-AKT-Smad5-driven induction of ID3, which led to a decrease in the tumorsphere forming ability of GSCs and U87MG cells that possess an active mutant EGFR, EGFRvIII, without obvious cytotoxic effects. However, these cells seemed to regain colonogenic ability after removal of the EGFR inhibitors. Together, the results delineate a novel integrative molecular mechanism in which the RTK-ID signaling pathway governs genesis and maintenance of GBM histopathologic features, such as GSCs-based tumor initiation, progression, and angiogenesis.

Original languageEnglish
Pages (from-to)7125-7134
Number of pages10
JournalCancer Research
Volume71
Issue number22
DOIs
Publication statusPublished - 2011 Nov 15

Fingerprint

Angiogenesis Inhibitors
Neoplastic Stem Cells
Epidermal Growth Factor Receptor
Glioma
Cytokines
Stem Cells
Receptor Protein-Tyrosine Kinases
Interleukin-6
Glioblastoma
Interleukin-8
Astrocytes
Neoplasms
Maintenance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction. / Jin, Xun; Yin, Jinlong; Kim, Sung Hak; Sohn, Young Woo; Beck, Samuel; Lim, Young Chang; Nam, Do Hyun; Choi, Yun Jaie; Kim, Hyunggee.

In: Cancer Research, Vol. 71, No. 22, 15.11.2011, p. 7125-7134.

Research output: Contribution to journalArticle

Jin, Xun ; Yin, Jinlong ; Kim, Sung Hak ; Sohn, Young Woo ; Beck, Samuel ; Lim, Young Chang ; Nam, Do Hyun ; Choi, Yun Jaie ; Kim, Hyunggee. / EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction. In: Cancer Research. 2011 ; Vol. 71, No. 22. pp. 7125-7134.
@article{6846803435f64647be7c0887a1b338a5,
title = "EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction",
abstract = "Aberrant activation of receptor tyrosine kinases (RTK) is causally linked to the pathobiological traits of glioblastoma and genesis of glioma stem-like cells (GSC), but the underlying mechanism is still unknown. Here, we show that epidermal growth factor receptor (EGFR) signaling regulates the proliferation, angiogenesis, and acquisition of GSC characteristics by inducing inhibitor of differentiation 3 (ID3) and ID3-regulated cytokines [GRO1 and interleukins (IL)-6 and 8] induction. We found that EGFR-mediated ID3 expression was regulated by Smad5, which was directly phosphorylated by AKT. Furthermore, ID3 alone imparted GSC features to primary astrocytes derived from Ink4a/Arf-deficient mouse, and EGFR-ID3-IL-6 signaling axis gave rise to tumor cell heterogeneity. Conversely, EGFR inhibitors suppressed EGFR-AKT-Smad5-driven induction of ID3, which led to a decrease in the tumorsphere forming ability of GSCs and U87MG cells that possess an active mutant EGFR, EGFRvIII, without obvious cytotoxic effects. However, these cells seemed to regain colonogenic ability after removal of the EGFR inhibitors. Together, the results delineate a novel integrative molecular mechanism in which the RTK-ID signaling pathway governs genesis and maintenance of GBM histopathologic features, such as GSCs-based tumor initiation, progression, and angiogenesis.",
author = "Xun Jin and Jinlong Yin and Kim, {Sung Hak} and Sohn, {Young Woo} and Samuel Beck and Lim, {Young Chang} and Nam, {Do Hyun} and Choi, {Yun Jaie} and Hyunggee Kim",
year = "2011",
month = "11",
day = "15",
doi = "10.1158/0008-5472.CAN-11-1330",
language = "English",
volume = "71",
pages = "7125--7134",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "22",

}

TY - JOUR

T1 - EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction

AU - Jin, Xun

AU - Yin, Jinlong

AU - Kim, Sung Hak

AU - Sohn, Young Woo

AU - Beck, Samuel

AU - Lim, Young Chang

AU - Nam, Do Hyun

AU - Choi, Yun Jaie

AU - Kim, Hyunggee

PY - 2011/11/15

Y1 - 2011/11/15

N2 - Aberrant activation of receptor tyrosine kinases (RTK) is causally linked to the pathobiological traits of glioblastoma and genesis of glioma stem-like cells (GSC), but the underlying mechanism is still unknown. Here, we show that epidermal growth factor receptor (EGFR) signaling regulates the proliferation, angiogenesis, and acquisition of GSC characteristics by inducing inhibitor of differentiation 3 (ID3) and ID3-regulated cytokines [GRO1 and interleukins (IL)-6 and 8] induction. We found that EGFR-mediated ID3 expression was regulated by Smad5, which was directly phosphorylated by AKT. Furthermore, ID3 alone imparted GSC features to primary astrocytes derived from Ink4a/Arf-deficient mouse, and EGFR-ID3-IL-6 signaling axis gave rise to tumor cell heterogeneity. Conversely, EGFR inhibitors suppressed EGFR-AKT-Smad5-driven induction of ID3, which led to a decrease in the tumorsphere forming ability of GSCs and U87MG cells that possess an active mutant EGFR, EGFRvIII, without obvious cytotoxic effects. However, these cells seemed to regain colonogenic ability after removal of the EGFR inhibitors. Together, the results delineate a novel integrative molecular mechanism in which the RTK-ID signaling pathway governs genesis and maintenance of GBM histopathologic features, such as GSCs-based tumor initiation, progression, and angiogenesis.

AB - Aberrant activation of receptor tyrosine kinases (RTK) is causally linked to the pathobiological traits of glioblastoma and genesis of glioma stem-like cells (GSC), but the underlying mechanism is still unknown. Here, we show that epidermal growth factor receptor (EGFR) signaling regulates the proliferation, angiogenesis, and acquisition of GSC characteristics by inducing inhibitor of differentiation 3 (ID3) and ID3-regulated cytokines [GRO1 and interleukins (IL)-6 and 8] induction. We found that EGFR-mediated ID3 expression was regulated by Smad5, which was directly phosphorylated by AKT. Furthermore, ID3 alone imparted GSC features to primary astrocytes derived from Ink4a/Arf-deficient mouse, and EGFR-ID3-IL-6 signaling axis gave rise to tumor cell heterogeneity. Conversely, EGFR inhibitors suppressed EGFR-AKT-Smad5-driven induction of ID3, which led to a decrease in the tumorsphere forming ability of GSCs and U87MG cells that possess an active mutant EGFR, EGFRvIII, without obvious cytotoxic effects. However, these cells seemed to regain colonogenic ability after removal of the EGFR inhibitors. Together, the results delineate a novel integrative molecular mechanism in which the RTK-ID signaling pathway governs genesis and maintenance of GBM histopathologic features, such as GSCs-based tumor initiation, progression, and angiogenesis.

UR - http://www.scopus.com/inward/record.url?scp=81155154258&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81155154258&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-11-1330

DO - 10.1158/0008-5472.CAN-11-1330

M3 - Article

VL - 71

SP - 7125

EP - 7134

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 22

ER -