NOTCH Pathway Blockade Depletes CD133‐Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts
Xing Fan,Leila Khaki,Thant S. Zhu,Mary E. Soules,Caroline E. Talsma,Naheed Gul,Cheryl M. Koh,Jiangyang Zhang,Yue Ming Li,Jarek Maciaczyk,Guido Nikkhah,Francesco DiMeco,Sara Grazia Maria Piccirillo,Angelo L. Vescovi,Charles G. Eberhart +14 more
TLDR
It is demonstrated that NOTCH pathway blockade depletes stem‐like cells in GBMs, suggesting that GSIs may be useful as chemotherapeutic reagents to target CSCs in malignant gliomas.Abstract:
Cancer stem cells (CSCs) are thought to be critical for the engraftment and long-term growth of many tumors, including glioblastoma (GBM). The cells are at least partially spared by traditional chemotherapies and radiation therapies, and finding new treatments that can target CSCs may be critical for improving patient survival. It has been shown that the NOTCH signaling pathway regulates normal stem cells in the brain, and that GBMs contain stem-like cells with higher NOTCH activity. We therefore used low-passage and established GBM-derived neurosphere cultures to examine the overall requirement for NOTCH activity, and also examined the effects on tumor cells expressing stem cell markers. NOTCH blockade by γ-secretase inhibitors (GSIs) reduced neurosphere growth and clonogenicity in vitro, whereas expression of an active form of NOTCH2 increased tumor growth. The putative CSC markers CD133, NESTIN, BMI1, and OLIG2 were reduced following NOTCH blockade. When equal numbers of viable cells pretreated with either vehicle (dimethyl sulfoxide) or GSI were injected subcutaneously into nude mice, the former always formed tumors, whereas the latter did not. In vivo delivery of GSI by implantation of drug-impregnated polymer beads also effectively blocked tumor growth, and significantly prolonged survival, albeit in a relatively small cohort of animals. We found that NOTCH pathway inhibition appears to deplete stem-like cancer cells through reduced proliferation and increased apoptosis associated with decreased AKT and STAT3 phosphorylation. In summary, we demonstrate that NOTCH pathway blockade depletes stem-like cells in GBMs, suggesting that GSIs may be useful as chemotherapeutic reagents to target CSCs in malignant gliomas.read more
Citations
More filters
Journal ArticleDOI
Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche
TL;DR: This work has identified a broader spectrum of stem cells influenced by hypoxia that includes cancer stem cells and induced pluripotent stem cells, and elucidate an added dimension of stem cell control within the niche.
Journal ArticleDOI
Cancer stem cells in glioblastoma
Justin D. Lathia,Justin D. Lathia,Stephen C. Mack,Erin E. Mulkearns-Hubert,Claudia L.L. Valentim,Jeremy N. Rich,Jeremy N. Rich +6 more
TL;DR: To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial.
Journal ArticleDOI
Notch signalling in solid tumours: a little bit of everything but not all the time
TL;DR: The discovery of Notch in Drosophila melanogaster opened the door to an ever-widening understanding of cellular processes that are controlled or influenced by Notch signalling, and a role for Notch is well established in haematological malignancies.
Journal ArticleDOI
Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells
Eunhee Kim,Mi-Suk Kim,Dong Hun Woo,Yongjae Shin,Jihye Shin,Nakho Chang,Young-Taek Oh,Hong Sug Kim,Jingeun Rheey,Ichiro Nakano,Cheolju Lee,Kyeung Min Joo,Jeremy N. Rich,Do-Hyun Nam,Jeongwu Lee +14 more
TL;DR: It is shown that EZH2 binds to and methylates STAT3, leading to enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3.
Journal ArticleDOI
The Varied Roles of Notch in Cancer
TL;DR: The varied roles of Notch in cancer are discussed, focusing on cell autonomous activities that may be either oncogenic or tumor suppressive.
References
More filters
Journal ArticleDOI
Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma
Roger Stupp,Warren P. Mason,Martin J. van den Bent,Michael Weller,Barbara Fisher,Martin J.B. Taphoorn,Karl Belanger,Alba A. Brandes,Christine Marosi,Ulrich Bogdahn,Jürgen Curschmann,Robert C. Janzer,Samuel K. Ludwin,Thierry Gorlia,Anouk Allgeier,Denis Lacombe,J. Gregory Cairncross,Elizabeth Eisenhauer,René O. Mirimanoff +18 more
TL;DR: The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.
Journal ArticleDOI
The 2007 WHO Classification of Tumours of the Central Nervous System
David N. Louis,Hiroko Ohgaki,Otmar D. Wiestler,Webster K. Cavenee,Peter C. Burger,Anne Jouvet,Bernd W. Scheithauer,Paul Kleihues +7 more
TL;DR: The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneurs tumour of the fourth ventricle, Papillary tumourof the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis.
Journal ArticleDOI
Prospective identification of tumorigenic breast cancer cells
Muhammad Al-Hajj,Max S. Wicha,Adalberto Benito-Hernandez,Sean J. Morrison,Sean J. Morrison,Michael F. Clarke +5 more
TL;DR: The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival and strategies designed to target this population may lead to more effective therapies.
Journal ArticleDOI
Stem cells, cancer, and cancer stem cells
TL;DR: Stem cell biology has come of age: Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine.
Journal ArticleDOI
Identification of human brain tumour initiating cells
Sheila K. Singh,Cynthia Hawkins,Ian D. Clarke,Jeremy A. Squire,Jane Bayani,Takuichiro Hide,R. Mark Henkelman,Michael D. Cusimano,Peter B. Dirks +8 more
TL;DR: The development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo gives strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.
Related Papers (5)
Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma
Roger Stupp,Warren P. Mason,Martin J. van den Bent,Michael Weller,Barbara Fisher,Martin J.B. Taphoorn,Karl Belanger,Alba A. Brandes,Christine Marosi,Ulrich Bogdahn,Jürgen Curschmann,Robert C. Janzer,Samuel K. Ludwin,Thierry Gorlia,Anouk Allgeier,Denis Lacombe,J. Gregory Cairncross,Elizabeth Eisenhauer,René O. Mirimanoff +18 more