Printed in the USA. All rights reserved. DOI: 10.3727/096368910X532774
Copyright 2011 Cognizant Comm. Corp. E-ISSN 1555-3892
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The Role of Cancer Stem Cells (CD133
+) in Malignant Gliomas
Der-Yang Cho,*† Shinn-Zong Lin,*† Wen-Kuang Yang,* Den-Mei Hsu,*
Hung-Lin Lin,* Han-Chung Lee,* Wen-Yeun Lee,* and Shao-Chih Chiu†
*Department of Neurosurgery, Neuropsychiatric Center, Cell/Gene Therapy Research Laboratory, China Medical University Hospital, Taichung, Taiwan
†Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
Malignant gliomas, particularly glioblastoma multiforme (GBM) tumors, are very difficult to treat by con-ventional approaches. Although most of the tumor mass can be removed by surgical resection, radiotherapy, and chemotherapy, it eventually recurs. There is growing evidence that cancer stem cells (CSCs) play an important role in tumor recurrence. These stem cells are radioresistant and chemoresistant. The most com-monly used tumor marker for CSCs is CD133. The amount of CSC component is closely correlated with tumor malignancy grading. Isolating, identifying, and treating CSCs as the target is crucial for treating malignant gliomas. CSC-associated vascular endothelial growth factor (VEGF) promotes tumor angiogen-esis, tumor hemorrhage, and tumor infiltration. Micro-RNA (miRNA) plays a role in CSC gene expression, which may regulate oncogenesis or suppression to influence tumor development or progression. The antigen-esis of CSCs and normal stem cells may be different. The CSCs may escape the T-cell immune response. Identifying a new specific antigen from CSCs for vaccine treatment is a key point for immunotherapy. On the other hand, augmented treatment with radiosensitizer or chemosensitizer may lead to reduction of CSCs and lead to CSCs being vulnerable to radiotherapy and chemotherapy. The control of signaling pathway and cell differentiation to CSC growth is another new hope for treatment of malignant gliomas. Although the many physiological behavioral differences between CSCs and normal stem cells are unclear, the more we know about these differences the better we will be able to treat CSCs effectively.
Key words: Cancer stem cells (CSCs); CD133+; Glioblastoma multiforme (GBM); Malignant gliomas;
Micro-RNA (miRNA); Signaling pathway
INTRODUCTION neural progenitor proteins such as nestin (8), Sox2, Oct 4, and Musashi (4).
Various stem cell markers are found in different ma-Malignant gliomas are the most common malignant
primary intracranial tumors. Their incidence is 5.4/ lignant tumors. The CD133 tumor marker is specific and commonly used for CSCs of malignant gliomas (30). 100,000 (11). Glioblastoma multiforme (GBM) (WHO
IV) tumors are the most common highly invasive malig- Recent studies showed that biological behaviors of
CD133+ were like the CSC subpopulation that confers nant gliomas. Their prognosis is still dismal even though
aggressive surgery, radiotherapy, and chemotherapy are glioma radio- and chemoresistance (21,34). These stem cells may be the source of tumor recurrence after radia-used for treatment (40). The median survival is only
12–15 months for GBM (22,37). It seems to be an incur- tion (25). Oka et al. (29) reported that CD133+ CSCs were identified in the peripheral brain regions adjacent able disease due to its highly infiltrative phenotype.
There is growing evidence that GBM harbors small cell to the tumor. They were frequently localized around vas-cular structures (the vasvas-cular niche). Singh et al. (36) populations that may sustain tumor formation and
growth. These cells are called cancer stem cells (CSCs) reported that CD133+ CSCs in GBM might be
trans-plantable to xenograft tumors in SCID (severe combined (31,32). Cancer stem cells are not only found in
leuke-mia, multiple myeloma, and breast cancer but also in immunodeficiency disease) mice brain, which
recap-tured the features of the original tumor regarding mor-GBM. The CSCs share many properties with normal
stem cells including self-renewal and multipotency (14). phology lineage and marker expression, and generated both CD133+and CD133− cells. However, in the same They have also been shown to express various specific
Online prepub date: September 30, 2010.
Address correspondence to Wen-Kuang Yang, M.D., Ph.D., Professor, Cell/Gene Therapy Research Laboratory, China Medical University Hospital, No. 2 Yu-Der Road, Taichung, Taiwan, R.O.C. Tel: 886-42-2052121, ext. 2779; Fax: 886-42-2079649, ext. 5035; E-mail: wkyang@mail.cmu.edu.tw
patient from whom the CD133 cells were obtained, the of tumor CSCs varied from 1.02% to 2.32% based on flow cytometric analysis. Singh et al. (36) reported less cells could not form neurospheres in culture medium
and could not form tumor growth in SCID mice (18). than 20% of CD133+in total tumor mass, but wide rang-ing variations in the CD133+ cell ratio (0.1–50% in The CD133 CSC marker is analyzed by
immunohis-tochemistry staining and Western blotting. The compo- GBM) were reported. Low-grade gliomas also contain
glioma stem cells, but in relatively low numbers. Thon nent amount of CD133+cells closely correlates with
gli-oma malignancy. The quantities of CD133+CSCs within et al. (38) also reported that the number of CD133+cells quantitatively correlated with tumor grade.
the tumor mass might show a clear quantitative correla-tion with glioma grading (WHO II, III, and IV). These
NEOANGIOGENESIS IN CSCs
findings support the concept of CD133+CSC-dependent
gliomagenesis (38). The CD133+ cells from gliomas of different grades
might contribute to intratumoral neoangiogenesis. CD133+
ISOLATION AND IDENTIFICATION
cells frequently accumulate within highly vascularized
OF CSCs IN GLIOMAS
regions, particularly in the case of GBM. Bao et al. (2) The definition of CSCs must meet the following four
reported evidence that the mutual influence of stem cells criteria: 1) generate clonally derived cells that form
neu-and endothelium account for neoangiogenesis. Thon et rospheres; 2) possess properties of cell renewal and
pro-al. (38) also reported that CD133+cells exhibit expres-liferation; 3) differentiate and express typical CSC
sion of endothelial progenitor and display a typical en-markers of tumor cells; 4) generate tumors after in vivo
dothelial “cobblestone” growing pattern. Vascular endo-transplantation in animal models that resemble the
origi-thelial growth factor (VEGF) promotes tumorigenesis nal donor tumors (39).
via angiogenesis (28). VEGF-repressing CSCs lead to CSCs of brain tumors were first identified in primary
the massive expansion of vascular-rich GBM and tumor-brain tumors (e.g., GBM, medulloblastoma, pilocytic
associated hemorrhage, thereby causing high morbidity. astrocytoma, and ganglioglioma). They formed
clono-VEGF provides a vascular-rich tumor environment stem genic spheres (neurospheres) in serum-free culture
me-cell niche. dia containing epidermal growth factor (EGF) and basic
fibroblast growth factor (bFGF). The CD133 marker is MICRO-RNA REGULATION OF CSCs
a 120-kDa transmembrane cell-surface protein. In the
Micro-RNAs (miRNAs) are a novel group of short course of enzymatic digestion of tumor tissue, an
exces-RNAs, about 22 nucleotides in length, that regulate gene sively long incubation period easily damages CSCs and
expression in a posttranscriptional manner by paring breaks the structure of cell-surface antigens. The CD133 with complementary nucleotide sequences in the 3′-tumor marker can be also present in other 3′-tumors
includ-untranslatable region of target mRNA. The miRNAs ing prostate tumors and colon cancers. We may identify
regulate cell functions, either oncogenesis or tumor sup-CSCs in cell culture by neurosphere formation with
pos-pression, which influence cancer development and pro-itive CD133+ and nestin neural stem cell markers (42).
gression. Recently, 7, 21, and miRNA-When the CSCs of brain tumor cells are transferred into
451 were found to be involved in regulation of brain the nude or SCID mice brain they may induce tumor
differentiation (16). MiRNA-451 may disperse neu-formation (26). Singh et al. (36) demonstrated that as
rospheres and inhibit the growth of GBM cells. MiRNAs
few as 100 CD133+ cells derived from human GBM
may drive CD133+ cells to differentiate and lose their could form GBM in SCID mice; however, the injection
stem cell character. When the miRNA levels in CD133+ of 5× 104 to 1× 105 CD133− cells did not. The CSCs
cells are raised by transfection, there may be inhibition from gliomas are concentrated by cell sorting or
mag-of cell growth and proliferation from loss mag-of cell renewal netic columns using specific immunoreactivities. The
potential. MiRNA-124 and miRNA-137 may also inhibit CSCs are thought to maintain their drug (Hoechst 33342
proliferation of GBM cells and induce differentiation of dye) efflux ability, which makes it possible to separate
brain tumor stem cells (35). CSCs in unstained cell fractions (17). Kang et al. (19)
reported radiation might increase CSCs from 2–3% ini- IMMUNE RESPONSE TO CSCs
tially to 5–7% in recurrent tumor. Low-dose radiation
The brain is not an immunologically exempt organ or hypoxic challenge might be used in the future for
without elicitation of inflammation and immune re-experimental study to increase the concentration of
sponse (1). According to tumor immunosurveillance the-CSCs in cell culture (20).
ory, tumor can be recognized and eliminated as a result
THE COMPONENT AMOUNT of the natural antitumor immune response (9). But in
OF CSCs IN GLIOMAS tumor development, tumor cells may influence immu-nity either from the tumor environment, rendering a tu-CD133+cell markers are positive in 60–70% of
the antitumor response. Most cancers are composed of a cells also involve tumor stem cell proliferation. Know-ing how to identify such tumor-specific signalKnow-ing path-mixture of normal stem cell and CSCs. The antigenesis
of normal stem cells and CSCs may be different. The ways and their inactivation mechanism will provide in-formation on key targets for glioma treatment. In CSCs frequently escape the T-cell immune response. It
is critical to fully characterize the immunological fea- comparison to CD133−tumor cells, CD133+CSCs have
higher DNA repair capacity, which results in a selective tures of CSCs and to develop immunotherapeutic
ap-proaches to eliminate CSCs without excessive toxicity postirradiation increase in the CD133+population (15). CSCs express multidrug resistance genes (e.g., ABCG2 to normal stem cells (41).
and BCRPI) that aide in the efflux of drugs and in the
CHEMOSENSITIZER AND selective promotion of CSC survival (15). The sonic RADIOSENSITIZER FOR CSCs hedgehog (shh) (10) and the Notch pathway are very
important for brain development and for maintaining Liu et al. (24) reported that CD133+CSCs play an
important role in tumor resistance to chemotherapy. This cell “stemness.” An shh pathway inhibitor, cyclopamine, depletes CSCs (3). In the Notch pathway, γ-secretase resistance is probably contributed to by CD133+ cells
with greater expression of breast cancer resistance pro- inhibitors also decrease the CD133+ fraction (13). Pro-moting the differentiation of stem cells to normal cells tein (BCRP1) and methyl-guanine methyltransferase
(MGMT) as well as the antiapoptosis proteins and inhib- is another possible approach for CSC treatment. Picciri-llo et al. (33) reported that bone morphogenetic protein itors of apoptosis protein families. Miqueli et al. (27)
reported that the monoclonal antibodies for anti-epider- (BMP4) might reduce the CSCs in GBM by differentiat-ing the CSCs to astrocytes.
mal growth factor receptors can increase radiosensitiza-tion to GMB CSCs. Chang et al. (6) reported that the
CONCLUSIONS
mean survival rate of GBM with CD133+ mice treated
with radiation was significantly improved by knock- Cancer stem cell investigation is a good starting point down of silencing information regulator (SirT1), a mem- for controlling tumor growth and recurrence (23). Al-ber of the sirtuin family, which is an NAD-dependent though many differences in physiological behavior be-histone deacetylase and essential mediator of longevity tween CSCs and normal stem cells are unclear, the more in normal cells. Ehtesham et al. (12) showed that cell we know about CSCs the more we can treat them effec-surface chemokine receptor (CCR4), a mediator of can- tively.
cer proliferation and invasion, was overexpressed in
ACKNOWLEDGMENTS: This study is supported in part by GBM CSCs. Administration of CXCL12, the only known Taiwan Department of Health Cancer Research Center of Ex-ligand for CXCR4, stimulates a specific and significant cellence (DOH-TD-C-111-005), and in part by Taiwan De-partment of Health Clinical Trial and Research Center of Ex-proliferative response in progenitors but not in
differen-cellence (DOH-TD-B-111-004). It also is partially granted tiated tumor cells.
from National Science Council (NSC-2314-B-039-012-MY2). Kang and Kang (20) reported pharmacological
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