Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells

Thant S. Zhu, Mark A. Costello, Caroline E. Talsma, Callie G. Flack, Jessica G. Crowley, Lisa L. Hamm, Xiaobing He, Shawn L. Hervey-Jumper, Jason A. Heth, Karin M. Muraszko, Francesco DiMeco, Angelo L. Vescovi, Xing Fan

Research output: Contribution to journalArticle

Abstract

One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment.

Original languageEnglish (US)
Pages (from-to)6061-6072
Number of pages12
JournalCancer Research
Volume71
Issue number18
DOIs
StatePublished - Sep 15 2011

Fingerprint

Stem Cell Niche
Neoplastic Stem Cells
Glioblastoma
Endothelial Cells
Ligands
Neoplasms
Tumor Microenvironment
Growth
RNA Interference
Endothelium
Brain

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. / Zhu, Thant S.; Costello, Mark A.; Talsma, Caroline E.; Flack, Callie G.; Crowley, Jessica G.; Hamm, Lisa L.; He, Xiaobing; Hervey-Jumper, Shawn L.; Heth, Jason A.; Muraszko, Karin M.; DiMeco, Francesco; Vescovi, Angelo L.; Fan, Xing.

In: Cancer Research, Vol. 71, No. 18, 15.09.2011, p. 6061-6072.

Research output: Contribution to journalArticle

Zhu, TS, Costello, MA, Talsma, CE, Flack, CG, Crowley, JG, Hamm, LL, He, X, Hervey-Jumper, SL, Heth, JA, Muraszko, KM, DiMeco, F, Vescovi, AL & Fan, X 2011, 'Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells', Cancer Research, vol. 71, no. 18, pp. 6061-6072. https://doi.org/10.1158/0008-5472.CAN-10-4269
Zhu, Thant S. ; Costello, Mark A. ; Talsma, Caroline E. ; Flack, Callie G. ; Crowley, Jessica G. ; Hamm, Lisa L. ; He, Xiaobing ; Hervey-Jumper, Shawn L. ; Heth, Jason A. ; Muraszko, Karin M. ; DiMeco, Francesco ; Vescovi, Angelo L. ; Fan, Xing. / Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. In: Cancer Research. 2011 ; Vol. 71, No. 18. pp. 6061-6072.
@article{35a85d5298364a9da3e09ea1ee675c5b,
title = "Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells",
abstract = "One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment.",
author = "Zhu, {Thant S.} and Costello, {Mark A.} and Talsma, {Caroline E.} and Flack, {Callie G.} and Crowley, {Jessica G.} and Hamm, {Lisa L.} and Xiaobing He and Hervey-Jumper, {Shawn L.} and Heth, {Jason A.} and Muraszko, {Karin M.} and Francesco DiMeco and Vescovi, {Angelo L.} and Xing Fan",
year = "2011",
month = "9",
day = "15",
doi = "10.1158/0008-5472.CAN-10-4269",
language = "English (US)",
volume = "71",
pages = "6061--6072",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells

AU - Zhu, Thant S.

AU - Costello, Mark A.

AU - Talsma, Caroline E.

AU - Flack, Callie G.

AU - Crowley, Jessica G.

AU - Hamm, Lisa L.

AU - He, Xiaobing

AU - Hervey-Jumper, Shawn L.

AU - Heth, Jason A.

AU - Muraszko, Karin M.

AU - DiMeco, Francesco

AU - Vescovi, Angelo L.

AU - Fan, Xing

PY - 2011/9/15

Y1 - 2011/9/15

N2 - One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment.

AB - One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment.

UR - http://www.scopus.com/inward/record.url?scp=80052795862&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052795862&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-10-4269

DO - 10.1158/0008-5472.CAN-10-4269

M3 - Article

C2 - 21788346

AN - SCOPUS:80052795862

VL - 71

SP - 6061

EP - 6072

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 18

ER -