Metabolic activation of mitochondria in glioma stem cells promotes cancer development through a reactive oxygen species-mediated mechanism
Yuan et al. Stem Cell Research & Therapy
Metabolic activation of mitochondria in glioma stem cells promotes cancer development through a reactive oxygen species-mediated mechanism
Shuqiang Yuan 0 1
Yunxin Lu 0 1
Jing Yang 0 1
Gang Chen 1 3
Sangbae Kim 1 2
Li Feng 1 3
Marcia Ogasawara 1 3
Naima Hammoudi 1 3
Weiqin Lu 1 3
Hui Zhang 1 3
Jinyun Liu 1 3
Howard Colman 1 5
Ju-Seog Lee 1 2
Xiao-Nan Li 1 4
Rui-hua Xu 0 1
Peng Huang 0 1 3
Feng Wang 0 1
0 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine , 651 E Dongfeng Road, Guangzhou, Guangdong 510060 , China
1 SY and YL are co-first authors
2 Department of Systems Biology, The University of Texas MD Anderson Cancer Center , Houston, TX 77054 , USA
3 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center , Houston, TX 77054 , USA
4 Laboratory of Molecular Neuro-oncology, Texas Children's Cancer Center, Baylor College of Medicine , Houston, TX 77030 , USA
5 Department of Neuro-Oncology, University of Utah , Salt Lake City, UT , USA
Introduction: Cancer stem cells (CSCs) possess characteristics associated with normal stem cells, specifically the abilities to renew themselves and to give rise to all cell types (differentiation). It is assumed that induction of differentiation in CSCs would reduce their ability to form tumors. What triggers CSC differentiation and the role of “differentiation” in tumorigenesis remain elusive. Methods: Glioma stem cell (GSC) lines and subcutaneous as well as orthotopic xenografts established from fresh surgical specimens of glioblastoma multiforme were used. Results: Exposure of GSCs to serum activates mitochondrial respiration and causes an increase in mitochondrial reactive oxygen species (ROS) as well as oxidative stress responses, leading to the appearance of differentiation morphology and a deceased expression of CSC markers. Chemical perturbation of the mitochondrial electron transport chain causes ROS increase and further downregulation of stem cell markers, while antioxidant N-acetylcysteine reduces ROS and suppresses the differentiation of GSCs. Surprisingly, the serum-induced differentiated GSCs exhibit greater ability to form tumor in both orthotopic and subcutaneous xenograft models, which can be suppressed by N-acetyl-cysteine. Mitochondrial ROS from the serum-stimulated cells triggered the activation of nuclear factor-kappa-B (NFκB) pathway, which is a potential mechanism for the promotion of tumorigenesis. Conclusion: This study suggests that ROS generated from active mitochondrial respiration in the presence of serum is critical in CSCs activation, which promotes tumor development in vivo.
Introduction
Recent studies indicate the existence of cancer stem cells
(CSCs) in various types of cancers, including leukemia
and solid tumors [
1, 2
]. Similar to normal stem cells,
CSCs are able to self-renew and to generate the
downstream progeny. Although CSCs constitute a very small
fraction of the total cancer cells in the tumor bulk, this
special subpopulation of malignant cells is thought to
play a major role in cancer initiation and development
and may be a key cause of resistance to chemotherapy
and radiotherapy, leading to persistence of residual
disease and cancer recurrence [3]. This phenomenon is due
in part to the unique biological properties of CSCs,
including high capacity of DNA repair, high expression of
certain ATP-dependent drug exporting pumps, high
levels of glutathione synthesis, and high expression of
cell survival factors [
4–6
]. A detailed understanding of
factors that affect the ability of CSCs to maintain their
self-renewal and promote disease progression is
important for developing new strategies to effectively kill CSCs.
Mounting evidence suggests that the tissue
microenvironment may profoundly affect the biological properties and
the fates of stem cells and CSCs [
7
]. In vivo, normal stem
cells or CSCs reside in special tissue locations known as
stem cell niches, which are thought to provide the
microenvironment important for the maintenance of their
stemness [
8
]. Although the exact nature of the stem cell niches
remains to be defined, it is known that low oxygen and
proper levels of certain growth factors such as epidermal
growth factor (EGF) and basic fibroblast growth factor
(bFGF) are important to maintain the stemness of the cells
[
9
]. Brain CSCs have been found in perivascular niches
[
8, 10
]. Increasing the endothelial cells or blood vessels in
orthotopic brain tumor xenografts enhances self-renewal of
CSCs and accelerates the initiation and growth of tumors
[10]. However, exposure of CSCs to serum in vitro usually
induces differentiation and presumably may compromise
their self-renewal ability [
11, 12
]. CSCs cultured in
serumfree media seem to closely mimic the genotype and gene
expression profiles of their primary tumors in vivo than d (...truncated)