Association of reactive oxygen species levels and radioresistance in cancer stem cells.
The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.
Diehn
Maximilian
M
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305, USA.
Cho
Robert W
RW
Lobo
Neethan A
NA
Kalisky
Tomer
T
Dorie
Mary Jo
MJ
Kulp
Angela N
AN
Qian
Dalong
D
Lam
Jessica S
JS
Ailles
Laurie E
LE
Wong
Manzhi
M
Joshua
Benzion
B
Kaplan
Michael J
MJ
Wapnir
Irene
I
Dirbas
Frederick M
FM
Somlo
George
G
Garberoglio
Carlos
C
Paz
Benjamin
B
Shen
Jeannie
J
Lau
Sean K
SK
Quake
Stephen R
SR
Brown
J Martin
JM
Weissman
Irving L
IL
Clarke
Michael F
MF
D000818:Animals; D001943:Breast Neoplasms / Q000503:physiopathology; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D005260:Female; D015870:Gene Expression; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000528:radiation effects*; D011836:Radiation Tolerance / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D017382:Reactive Oxygen Species