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Medicine » Oncology » "Evolution of the Molecular Biology of Brain Tumors and the Therapeutic Implications", book edited by Terry Lichtor, ISBN 978-953-51-0989-1, Published: February 27, 2013 under CC BY 3.0 license. © The Author(s).

Chapter 23

Nestin: Neural Stem/Progenitor Cell Marker in Brain Tumors

By Yoko Matsuda, Hisashi Yoshimura, Taeko Suzuki and Toshiyuki Ishiwata
DOI: 10.5772/52634

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Nestin: Neural Stem/Progenitor Cell Marker in Brain Tumors

Yoko Matsuda1, Hisashi Yoshimura1, Taeko Suzuki1 and Toshiyuki Ishiwata1

1. Introduction

Glioblastomas are the most common primary malignant neoplasms in the adult brain, and have the characteristics of glial cells [1]. The WHO histopathological classification guidelines categorize gliomas according to their histopathological grades; low-grade gliomas are not anaplastic and are associated with a favorable patient prognosis, while high-grade gliomas exhibit increased cellularity, nuclear atypia, mitotic activity, microvascular proliferation, and necrosis. Glioblastomas are the highest grade of the gliomas. Surgical treatment is the main therapy used for glioblastomas, with radiotherapy and chemotherapy performed as adjuvant care. Despite intensive research and recent advances in treatment, the prognosis for patients with glioblastoma remains poor, with a five-year survival rate of approximately 3% [2, 3]. In addition to having rapid growth rates, glioblastomas aggressively invade the adjacent normal brain tissues, they are often surgically unresectable, and recurrent glioblastomas are resistant to conventional radiotherapy and chemotherapy.

Nestin is a class VI intermediate filament protein that was first described as a neural stem/progenitor cell marker [4, 5]. Neuroepithelial stem cells can differentiate into neurons, oligodendrocytes, and astrocytes, and nestin has been shown to be down-regulated or to completely disappear during such differentiation. Nestin-positive neuroepithelial stem cells are detected in the subventricular zone of the human adult brain and they remain mitotically active throughout adulthood [6]. Unlike other intermediate filament proteins, nestin plays important roles in cellular processes, including stemness, migration, and cell cycle regulation.

Nestin expression has been reported in various types of tumor cells originating from the central nervous system, including glioblastomas. Several reports have indicated a close relationship between neuroepithelial stem cells and glioblastoma cells at their origin because both cell types express the same stem cell markers, such as CD133 and nestin. High-grade gliomas express higher nestin levels compared to low-grade gliomas [7, 8]. We have reported that knockdown of nestin using short hairpin RNA (shRNA) suppressed cell growth, migration, and invasion [9]; therefore, nestin may serve as a novel candidate for molecular targeted therapy for glioblastomas. In the present chapter, we summarize the available data regarding the expression and roles of nestin in normal brain tissues and brain tumor tissues, and discuss the possibility of using nestin as a novel therapeutic target in brain tumors, mainly for glioblastomas.

2. Structure and characterization of nestin

Nestin is a large protein (>1600 amino acids) that contains a short N-terminal and an unusually long C-terminal. It interacts with other intermediate filament proteins, including vimentin, desmin, and internexin, to form heterodimers and mixed polymers; however, in contrast to other intermediate filament proteins, nestin cannot form homopolymers [10]. The nestin gene has four exons and three introns; in humans, neural cell-specific expression is reportedly regulated by the second intron, whereas nestin expression in tumor endothelium is enhanced by the first intron [11]. Nestin is known to be phosphorylated on Thr316 by cdc2 kinase [12] and/or cyclin-dependent kinase 5 [13], and to modulate mitosis-associated cytoplasmic reorganization during mitosis. However, the roles of glycosylation of nestin have not been closely examined [14].

During early stages of development, nestin is expressed in dividing cells in the central nervous system (CNS), peripheral nervous system, and in myogenic and other tissues. During differentiation in normal brain tissue, nestin expression is downregulated and replaced by expression of tissue-specific intermediate filament proteins; therefore, nesting is widely used as a neuronal stem cell marker. Nestin is also expressed in immature non-neuronal cells and progenitor cells in normal tissues [15-17]. High levels of nestin expression have been detected in oligodendroglial lineage cells, ependymocytes, Sertoli cells, enteroglia, hair follicle cells, podocytes of renal glomeruli, pancreatic stellate cells, pericytes, islets, optic nerve, and odontoblasts [18-23].

In pathological conditions, nestin is re-expressed during repair processes, as well as in various neoplasms and proliferating endothelial cells. Nestin expression has been observed in repair processes in the CNS, muscle, liver, and infarcted myocardium [24-26]. Furthermore, increased nestin expression has been reported in various tumor cells, including CNS tumors, pancreatic cancer, gastrointestinal stromal tumors (GISTs), prostate cancers, breast cancers, malignant melanomas, dermatofibrosarcoma protuberances, and thyroid tumors [27-31]. In several tumors, expression of nestin has been reported to be closely correlated with poor prognosis. Nestin is specifically expressed in proliferating small-sized vascular endothelial cells in glioblastomas and in colorectal, prostate, and pancreatic cancers [7, 32-34].

3. Nestin in normal fetal and adult brain tissues

Many lines of evidence have shown nestin-positive brain cells to be neural stem/progenitor cells; therefore, a great deal of research has involved the use of nestin to detect neural stem cells [35-37]. Children, but not adult humans, exhibit nestin-positive cells in the subventricular zone of the third ventricle [6], and the human embryonic midbrain stem cell line NGC-407 showed degradation of nestin after induction of differentiation [38]. However, in adult mice, nestin-positive cells were detected in CA2 lesions of the hippocampus after transient ischemia [39]. Another study reported that nestin-positive neuroepithelial stem cells are detected in the subventricular zone of the human adult brain and remain mitotically active throughout adulthood [40]. Nestin has been used for research in the field of neural progenitor cells; for example, neural progenitor cell-specific gene transfection was successfully performed using a nestin-driven gene transfection system [41-46]. A recent study has shown that nestin is also a stem/progenitor cell marker in the pituitary gland [47].

4. Nestin in various types of brain tumors

Nestin expression in brain tumor cells has been reported in schwannomas [48], ependymomas [49, 50], neurocytomas [51], adamantinomatous craniopharyngiomas [52], pituitary adenomas [53], medulloblastomas [54-59], oligodendrogliomas [60], and glioblastomas [7, 8, 48, 61] (Table 1). Tissue microarrays of 257 brain tumors have revealed frequent nestin expression in gliomas and schwannomas [48]. Another analysis included 379 tumors, and the results further revealed that nestin immunoreactivity is associated with poor outcome in intracranial ependymomas, and that nestin is an independent marker for poor progression-free survival and overall survival [49].

Expression of nestin has also been reported in tanycytic ependymoma, a rare variant of ependymoma [50], and central neurocytoma cases express nestin, as determined by PCR [51]. Co-expression of nestin, microtubule-associated protein 2 (MAP2), and GFAP has been reported in adamantinomatous craniopharyngiomas [52]. In pituitary adenomas, CD133-positive cells ubiquitously co-express CD34, nestin, and VEGFR2, and may play a role in the neovascularization of tumors [53]. Human medulloblastoma cell lines [54] and medulloblastoma stem cells [55-58] express nestin, and secreted protein acidic and rich in cysteine (SPARC) has been shown to induce neuronal differentiation in medulloblastoma cells with elevations of nestin, NeuN, and neurofilament [59]. One study found that oligodendrogliomas express no or weak nestin, but high Olig2 and alpha-internexin [60]. Oligoastrocytomas moderately express nestin, while astrocytoma and glioblastoma strongly express nestin. Nestin is an intermediate filament protein and is localized in the cytoplasm in most brain tumors; however, in human neuroblastoma and medulloblastoma cell lines, nestin has been observed in nuclei [62], suggesting that nestin may directly bind to DNA or intranucleic proteins. Altogether, these findings demonstrate that nestin is expressed in a wide variety of brain tumors and that this expression correlates with their functions or cell behaviors.

Brain tumors Expression pattern and roles
SchwannomasFrequent nestin expression [48]
EpendymomasPoor progression-free survival and overall survival [49]
Neurocytomas [51]N/D
Adamantinomatous craniopharyngiomas Expressed in the invasion niche [52]
Pituitary adenomas Coexpressed with CD133 [53]
MedulloblastomasExpressed in tumor stem cells [55-58]
Oligodendrogliomas [60]N/D
GliomasHigh grade [7,8]
Worse overall survival [48,61]
GlioblastomasInfiltration into surrounding tissue [8]
 Tumor stem cells [72-77]
N/D: Not determined.

Table 1.

Expression and roles of nestin in brain tumors

5. Nestin in glioblastoma

5.1. Nestin in low-grade gliomas and glioblastomas

Immunohistochemical analysis has demonstrated nestin expression in the cytoplasm of glioblastoma cells (Figure 1). Large-scale and multicenter studies have shown high immunoreactivity of nestin in glioma cases to be correlated with high grade [7, 8] and worse overall survival [48, 61] (Table 1). Furthermore, expression of nestin and MIB-1 labeling indices in immunohistochemical analyses may correlate with aggressiveness of pilocytic astrocytoma and pilomyxoid astrocytoma [63]. An analysis of several stem cell markers—including CD133, nestin, B lymphoma Mo-MLV insertion region 1 homolog (BMI-1), Maternal embryonic leucine zipper kinase (MELK), and Notch 1-4—was performed using quantitative RT-PCR in 42 glioblastoma samples; MELK was most upregulated, followed by nestin [64]. In contrast, others have reported that nestin immunoreactivity is mostly due to an acute glial reaction and is not specific to the neoplasm [65], and that nestin expression in gliomas does not correlate with prognosis [66].


Figure 1.

Expression of nestin in glioblastomas. Bar, 100 μm

Immunostaining of nestin in glioblastoma cells has been demonstrated to delineate between invading tumor and the adjacent gray and white matter; therefore, nestin is considered to be a useful marker for examining the infiltration of glioblastomas into surrounding tissues [8]. Furthermore, knockdown of nestin in human glioblastoma cells has been shown to suppress cell migration and invasion, and to increase F-actin expression and cell adhesion to extracellular matrices [9].

Nestin-positive non-tumorous brain cells migrate into the glioblastoma cells and delay astrocytic or elongated bipolar morphology and glomerulus-like microvasculature [67]; therefore, nestin-positive cells have been considered an important component of the tumor microenvironment. CD133-positive and nestin-positive niches are perivascularly localized in all glioma tissues, and the presence of these niches increases significantly with increasing tumor grade [68]. Mice were engineered to co-express platelet-derived growth factor B receptor and Bcl-2 under the control of the glioneuronal-specific nestin promoter, and this resulted in the development of low- and high-grade gliomas [69]. Another study found that human glioblastoma subclones characterized by high nestin levels formed tumors in vivo at a significantly faster rate than subclones with low nestin expression, suggesting that induction of nestin plays an important role in glioblastoma carcinogenesis [70]. However, the opposite result has also been reported [71].

5.2. Nestin in glioma stem cells

Cancer stem cells appear to be responsible for tumor metastasis, resistance to radiotherapy and chemotherapy, and disease relapse; thus, their analysis and therapeutic targeting are believed to be crucial. Many studies have shown that there is a small population of cancer stem cells in glioblastomas, and that nestin is one of the stem/progenitor cell markers of glioblastomas [72-77]. CD133, Oct4, Sox2, and Nanog have also been considered to be stem cell markers in glioblastomas [78, 79]. However, CD133-negative and nestin-negative glioblastoma cells show tumorigenic potential in vivo [71]; thus, there remains some controversy over which specific markers should be used to detect glioblastoma stem cells. An in vitro study has shown that neurospheres of glioblastoma cells exhibit high expressions of nestin, CD133, and Oct4 compared to the expressions in monolayer cells [80]. One study reported that radiation induces increased expressions of stem cell markers, including nestin, CD133, and Musashi [81]; in contrast, another study has shown that radiation induced accumulation of CD133-positive glioblastoma cells, but not nestin [82]. Glioblastoma stem cells are maintained in vivo in a niche characterized by hypoxia, and hypoxia reportedly increases the expressions of nestin, CD133, podoplanin, and Bmi-1 [83]. Together, these available data suggest that there is close relationship between nestin and stemness in glioblastoma.

Expression of nestin in cancer stem cells of glioblastoma may indicate the origin and function of these cells. Potential cancer stem cell origins include migration of neural stem cells toward the tumor, migration of mesenchymal stem cells from bone marrow, or dedifferentiation of tumor cells [84]; each of these hypotheses have been proven experimentally. In brain tumors, long-term cultured human neural stem cells undergo spontaneous transformation to tumor-initiating cells [37]. In contrast, Nanog promotes dedifferentiation of p53-deficient mouse astrocytes into glioblastoma stem cells [85]. These results indicate that glioblastoma stem cells may arise from both the transformation of nestin-positive neural stem cells and differentiated astrocytes. Retinoic acid treatment for glioblastoma stem cells was demonstrated to reduce the expression of neural stem cell markers, such as nestin, CD133, Msi-1, and Sox-2 [86].

Xenografts developed from human anaplastic astrocytoma and glioblastoma tumor-derived spheres in the brain of a nude mouse revealed co-expression of PCNA, VCAM-1, caspase-3, and nestin [87]. Cells positive for both caspase-3 and nestin were located adjacent to or around the blood vessels. Glioblastoma stem cells expressed nestin/CD31 or CD133/CD31, and these cells were capable of differentiating into endothelial cells [88]. Dong et al. have shown that human glioma stem/progenitor cells transdifferentiate into vascular endothelial cells in vitro and in vivo [89]. Glioblastoma stem cells have close relationships with the angiogenic switch, intratumor hypoxia, and the neoplastic microvascular network. These findings provide new insights for targeted therapy against glioblastomas.

5.3. Regulation of nestin in glioblastoma cells

Glioblastomas usually show hyperactivation of the PI3K-Akt pathway. Exogeneous expression of the Akt-binding domain of Girdin inhibits its Akt-mediated phosphorylation, and reportedly diminishes migration and the expression of the stem cell markers nestin and SOX2 [90]. Nestin expression in glioblastomas is correlated with proangiogenic chemokines (CXCL12 and its receptor CXCR4) and growth factors (VEGF and PDGF-B and its receptor PDGFRbeta) [91]. Hypoxia and radiation are both inducers of stem cells, and were associated with increased expression of nestin [81, 83]. In glioblastoma cases, a 9-gene profile that included podoplanin and insulin-like growth factor binding protein 2 was found to predict the prognosis, and was also positively associated with expressions of nestin and CD133 [92]. Additionally, the enhancer lesion of nestin is known to be located in the second intron in neural cells, and this lesion is highly conserved in mouse, rat, and human [93].

5.4. Nestin in interstitial tissues and angiogenesis of glioblastoma

Glioblastoma-conditioned medium has been shown to induce human mesenchymal stem cells (hMSCs) to increase expressions of nestin, CD151, VE-cadherin, desmin, α-smooth muscle actin, and nerval/glial antigen 2—indicating pericyte-like differentiation, rather than differentiation to endothelial cells or smooth muscle cells [94]. hMSCs migrate towards glioblastoma and are incorporated into tumor microvessels.

Much evidence has shown that expression of nestin in vascular endothelial cells is associated with proliferation and angiogenesis [32, 95-98]. In glioblastomas, expression of nestin in both tumor cells and endothelial cells was increased according to increasing tumor grade [7]. A recent study has indicated that the capillaries in gliomas may come from the differentiation of glioblastoma stem cells, and that the glioblastoma stem cells are accumulated around the capillaries [99]. In contrast, CD105 has been proposed to be a more useful marker of tumor angiogenesis in glioblastomas than nestin [100]. The morphology of nestin-positive cells in brain tumors is reportedly more typical of neural stem cells, and less than 0.1% of these cells co-express the endothelial marker CD34 [101].

5.5. Nestin as a therapeutic target for glioblastoma

We have reported that knockdown of nestin using shRNA suppresses cell migration and invasion [9]. Lu et al. demonstrated that blocking the expression of nestin in glioblastomas via intratumor injection of shRNA significantly slowed tumor growth and volume [70]; therefore, nestin may serve as a novel candidate for molecular targeted therapy for glioblastomas [9]. The phytoalexin resveratrol suppresses cell growth, migration, invasion, and expression of nestin in glioblastoma cells [102]. It has been shown that peptides can bind to a nestin isotype that is specifically expressed in glioma stem cells, which enables them to target nestin-positive cells in human glioma tissue [103]. Future studies should focus on developing delivery systems to target these anti-nestin reagents to brain tumors, and on the estimation of the side-effects for normal brain stem cells that express nestin.

6. Conclusion

The neuronal stem cell marker nestin regulates cell growth, migration, invasion, and stemness, and has been found to be expressed in a wide variety of brain tumors. Nestin may be a candidate for the development of promising therapeutic and diagnostic modalities for glioblastoma.


The authors thank Dr. Zenya Naito, Mr. Yuji Yanagisawa, Ms. Yoko Kawamoto, Ms. Kiyoko Kawahara, and Ms. Megumi Murase (Departments of Pathology and Integrative Oncological Pathology) for helpful discussions, and Ms. Yuko Ono (Departments of Pathology and Integrative Oncological Pathology) for preparing the manuscript.


1 - Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114(2):97-109.
2 - Bondy ML, Scheurer ME, Malmer B, Barnholtz-Sloan JS, Davis FG, Il'yasova D, Kruchko C, McCarthy BJ, Rajaraman P, Schwartzbaum JA, Sadetzki S, Schlehofer B, Tihan T, Wiemels JL, Wrensch M, Buffler PA. Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer 2008;113(7 Suppl):1953-68.
3 - Brem SS, Bierman PJ, Black P, Blumenthal DT, Brem H, Chamberlain MC, Chiocca EA, DeAngelis LM, Fenstermaker RA, Fine HA, Friedman A, Glass J, Grossman SA, Heimberger AB, Junck L, Levin V, Loeffler JJ, Maor MH, Narayana A, Newton HB, Olivi A, Portnow J, Prados M, Raizer JJ, Rosenfeld SS, Shrieve DC, Sills AK, Jr., Spence AM, Vrionis FD. Central nervous system cancers: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2005;3(5):644-90.
4 - Lendahl U, Zimmerman LB, McKay RD. CNS stem cells express a new class of intermediate filament protein. Cell 1990;60(4):585-95.
5 - Ishiwata T, Matsuda Y, Naito Z. Nestin in gastrointestinal and other cancers: effects on cells and tumor angiogenesis. World J Gastroenterol 2011;17(4):409-18.
6 - Dahiya S, Lee da Y, Gutmann DH. Comparative characterization of the human and mouse third ventricle germinal zones. J Neuropathol Exp Neurol 2011;70(7):622-33.
7 - Hlobilkova A, Ehrmann J, Knizetova P, Krejci V, Kalita O, Kolar Z. Analysis of VEGF, Flt-1, Flk-1, nestin and MMP-9 in relation to astrocytoma pathogenesis and progression. Neoplasma 2009;56(4):284-90.
8 - Kitai R, Horita R, Sato K, Yoshida K, Arishima H, Higashino Y, Hashimoto N, Takeuchi H, Kubota T, Kikuta K. Nestin expression in astrocytic tumors delineates tumor infiltration. Brain Tumor Pathol 2010;27(1):17-21.
9 - Ishiwata T, Teduka K, Yamamoto T, Kawahara K, Matsuda Y, Naito Z. Neuroepithelial stem cell marker nestin regulates the migration, invasion and growth of human gliomas. Oncol Rep 2011;26(1):91-9.
10 - Steinert PM, Chou YH, Prahlad V, Parry DA, Marekov LN, Wu KC, Jang SI, Goldman RD. A high molecular weight intermediate filament-associated protein in BHK-21 cells is nestin, a type VI intermediate filament protein. Limited co-assembly in vitro to form heteropolymers with type III vimentin and type IV alpha-internexin. J Biol Chem 1999;274(14):9881-90.
11 - Aihara M, Sugawara K, Torii S, Hosaka M, Kurihara H, Saito N, Takeuchi T. Angiogenic endothelium-specific nestin expression is enhanced by the first intron of the nestin gene. Lab Invest 2004;84(12):1581-92.
12 - Sahlgren CM, Mikhailov A, Hellman J, Chou YH, Lendahl U, Goldman RD, Eriksson JE. Mitotic reorganization of the intermediate filament protein nestin involves phosphorylation by cdc2 kinase. J Biol Chem 2001;276(19):16456-63.
13 - Sahlgren CM, Mikhailov A, Vaittinen S, Pallari HM, Kalimo H, Pant HC, Eriksson JE. Cdk5 regulates the organization of Nestin and its association with p35. Mol Cell Biol 2003;23(14):5090-106.
14 - Grigelioniene G, Blennow M, Torok C, Fried G, Dahlin I, Lendahl U, Lagercrantz H. Cerebrospinal fluid of newborn infants contains a deglycosylated form of the intermediate filament nestin. Pediatr Res 1996;40(6):809-14.
15 - Sejersen T, Lendahl U. Transient expression of the intermediate filament nestin during skeletal muscle development. J Cell Sci 1993;106 ( Pt 4):1291-300.
16 - Frojdman K, Pelliniemi LJ, Lendahl U, Virtanen I, Eriksson JE. The intermediate filament protein nestin occurs transiently in differentiating testis of rat and mouse. Differentiation 1997;61(4):243-9.
17 - Terling C, Rass A, Mitsiadis TA, Fried K, Lendahl U, Wroblewski J. Expression of the intermediate filament nestin during rodent tooth development. Int J Dev Biol 1995;39(6):947-56.
18 - Yang J, Bian W, Gao X, Chen L, Jing N. Nestin expression during mouse eye and lens development. Mech Dev 2000;94(1-2):287-91.
19 - Almazan G, Vela JM, Molina-Holgado E, Guaza C. Re-evaluation of nestin as a marker of oligodendrocyte lineage cells. Microsc Res Tech 2001;52(6):753-65.
20 - Amoh Y, Li L, Yang M, Moossa AR, Katsuoka K, Penman S, Hoffman RM. Nascent blood vessels in the skin arise from nestin-expressing hair-follicle cells. Proc Natl Acad Sci U S A 2004;101(36):13291-5.
21 - Lardon J, Rooman I, Bouwens L. Nestin expression in pancreatic stellate cells and angiogenic endothelial cells. Histochem Cell Biol 2002;117(6):535-40.
22 - Takano T, Rutka JT, Becker LE. Overexpression of nestin and vimentin in ependymal cells in hydrocephalus. Acta Neuropathol 1996;92(1):90-7.
23 - Ishizaki M, Ishiwata T, Adachi A, Tamura N, Ghazizadeh M, Kitamura H, Sugisaki Y, Yamanaka N, Naito Z, Fukuda Y. Expression of nestin in rat and human glomerular podocytes. J Submicrosc Cytol Pathol 2006;38(2-3):193-200.
24 - Niki T, Pekny M, Hellemans K, Bleser PD, Berg KV, Vaeyens F, Quartier E, Schuit F, Geerts A. Class VI intermediate filament protein nestin is induced during activation of rat hepatic stellate cells. Hepatology 1999;29(2):520-7.
25 - Lin RC, Matesic DF, Marvin M, McKay RD, Brustle O. Re-expression of the intermediate filament nestin in reactive astrocytes. Neurobiol Dis 1995;2(2):79-85.
26 - El-Helou V, Dupuis J, Proulx C, Drapeau J, Clement R, Gosselin H, Villeneuve L, Manganas L, Calderone A. Resident nestin+ neural-like cells and fibers are detected in normal and damaged rat myocardium. Hypertension 2005;46(5):1219-25.
27 - Yamada H, Takano T, Ito Y, Matsuzuka F, Miya A, Kobayashi K, Yoshida H, Watanabe M, Iwatani Y, Miyauchi A. Expression of nestin mRNA is a differentiation marker in thyroid tumors. Cancer Lett 2009;280(1):61-4.
28 - Strojnik T, Rosland GV, Sakariassen PO, Kavalar R, Lah T. Neural stem cell markers, nestin and musashi proteins, in the progression of human glioma: correlation of nestin with prognosis of patient survival. Surg Neurol 2007;68(2):133-43; discussion 43-4.
29 - Brychtova S, Fiuraskova M, Hlobilkova A, Brychta T, Hirnak J. Nestin expression in cutaneous melanomas and melanocytic nevi. J Cutan Pathol 2007;34(5):370-5.
30 - Tsujimura T, Makiishi-Shimobayashi C, Lundkvist J, Lendahl U, Nakasho K, Sugihara A, Iwasaki T, Mano M, Yamada N, Yamashita K, Toyosaka A, Terada N. Expression of the intermediate filament nestin in gastrointestinal stromal tumors and interstitial cells of Cajal. Am J Pathol 2001;158(3):817-23.
31 - Li H, Cherukuri P, Li N, Cowling V, Spinella M, Cole M, Godwin AK, Wells W, DiRenzo J. Nestin is expressed in the basal/myoepithelial layer of the mammary gland and is a selective marker of basal epithelial breast tumors. Cancer Res 2007;67(2):501-10.
32 - Gravdal K, Halvorsen OJ, Haukaas SA, Akslen LA. Proliferation of immature tumor vessels is a novel marker of clinical progression in prostate cancer. Cancer Res 2009;69(11):4708-15.
33 - Teranishi N, Naito Z, Ishiwata T, Tanaka N, Furukawa K, Seya T, Shinji S, Tajiri T. Identification of neovasculature using nestin in colorectal cancer. Int J Oncol 2007;30(3):593-603.
34 - Yamahatsu K, Matsuda Y, Ishiwata T, Uchida E, Naito Z. Nestin as a novel therapeutic target for pancreatic cancer via tumor angiogenesis. Int J Oncol 2012;40(5):1345-57.
35 - Liu L, Shi M, Wang L, Hou S, Wu Z, Zhao G, Deng Y. Ndrg2 expression in neurogenic germinal zones of embryonic and postnatal mouse brain. J Mol Histol 2012; 43 (1): 27-35.
36 - Romero-Grimaldi C, Murillo-Carretero M, Lopez-Toledano MA, Carrasco M, Castro C, Estrada C. ADAM-17/tumor necrosis factor-alpha-converting enzyme inhibits neurogenesis and promotes gliogenesis from neural stem cells. Stem Cells 2011;29(10):1628-39.
37 - Wu W, He Q, Li X, Zhang X, Lu A, Ge R, Zhen H, Chang AE, Li Q, Shen L. Long-term cultured human neural stem cells undergo spontaneous transformation to tumor-initiating cells. Int J Biol Sci 2011;7(6):892-901.
38 - Khan Z, Akhtar M, Ekstrom TJ. HDAC inhibitor 4-phenylbutyrate preserves immature phenotype of human embryonic midbrain stem cells: implications for the involvement of DNA methyltransferase. Int J Mol Med 2011;28(6):977-83.
39 - Wang H, Imamura Y, Ishibashi R, Chandana EP, Yamamoto M, Noda M. The Reck tumor suppressor protein alleviates tissue damage and promotes functional recovery after transient cerebral ischemia in mice. J Neurochem 2010;115(2):385-98.
40 - Kaneko Y, Sakakibara S, Imai T, Suzuki A, Nakamura Y, Sawamoto K, Ogawa Y, Toyama Y, Miyata T, Okano H. Musashi1: an evolutionally conserved marker for CNS progenitor cells including neural stem cells. Dev Neurosci 2000;22(1-2):139-53.
41 - Seok SH, Na YR, Han JH, Kim TH, Jung H, Lee BH, Emelyanov A, Parinov S, Park JH. Cre/loxP-regulated transgenic zebrafish model for neural progenitor-specific oncogenic Kras expression. Cancer Sci 2010;101(1):149-54.
42 - Goto J, Talos DM, Klein P, Qin W, Chekaluk YI, Anderl S, Malinowska IA, Di Nardo A, Bronson RT, Chan JA, Vinters HV, Kernie SG, Jensen FE, Sahin M, Kwiatkowski DJ. Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proc Natl Acad Sci U S A 2011;108(45):E1070-9.
43 - Nagy JI, Lynn BD, Tress O, Willecke K, Rash JE. Connexin26 expression in brain parenchymal cells demonstrated by targeted connexin ablation in transgenic mice. Eur J Neurosci 2011;34(2):263-71.
44 - Wey A, Knoepfler PS. c-myc and N-myc promote active stem cell metabolism and cycling as architects of the developing brain. Oncotarget 2010;1(2):120-30.
45 - Tanori M, Santone M, Mancuso M, Pasquali E, Leonardi S, Di Majo V, Rebessi S, Saran A, Pazzaglia S. Developmental and oncogenic effects of insulin-like growth factor-I in Ptc1+/- mouse cerebellum. Mol Cancer 2010;9:53.
46 - See WL, Miller JP, Squatrito M, Holland E, Resh MD, Koff A. Defective DNA double-strand break repair underlies enhanced tumorigenesis and chromosomal instability in p27-deficient mice with growth factor-induced oligodendrogliomas. Oncogene 2010;29(12):1720-31.
47 - Florio T. Adult pituitary stem cells: from pituitary plasticity to adenoma development. Neuroendocrinology 2011;94(4):265-77.
48 - Arai H, Ikota H, Sugawara KI, Nobusawa S, Hirato J, Nakazato Y. Nestin expression in brain tumors: its utility for pathological diagnosis and correlation with the prognosis of high-grade gliomas. Brain Tumor Pathol 2012; 29 (3): 160-7.
49 - Milde T, Hielscher T, Witt H, Kool M, Mack SC, Deubzer HE, Oehme I, Lodrini M, Benner A, Taylor MD, von Deimling A, Kulozik AE, Pfister SM, Witt O, Korshunov A. Nestin Expression Identifies Ependymoma Patients with Poor Outcome. Brain Pathol 2012.
50 - Zhang S, Wang X, Zhang Z, Chen Y. Tanycytic ependymoma arising from the right lateral ventricle: a case report and review of the literature. Neuropathology 2008;28(4):427-32.
51 - Paek SH, Shin HY, Kim JW, Park SH, Son JH, Kim DG. Primary culture of central neurocytoma: a case report. J Korean Med Sci 2010;25(5):798-803.
52 - Burghaus S, Holsken A, Buchfelder M, Fahlbusch R, Riederer BM, Hans V, Blumcke I, Buslei R. A tumor-specific cellular environment at the brain invasion border of adamantinomatous craniopharyngiomas. Virchows Arch 2010;456(3):287-300.
53 - Yunoue S, Arita K, Kawano H, Uchida H, Tokimura H, Hirano H. Identification of CD133+ cells in pituitary adenomas. Neuroendocrinology 2011;94(4):302-12.
54 - Kim YH, Cho SH, Lee SJ, Choi SA, Phi JH, Kim SK, Wang KC, Cho BK, Kim CY. Growth-inhibitory effect of neurotrophin-3-secreting adipose tissue-derived mesenchymal stem cells on the D283-MED human medulloblastoma cell line. J Neurooncol 2012;106(1):89-98.
55 - Huang X, Ketova T, Litingtung Y, Chiang C. Isolation, enrichment, and maintenance of medulloblastoma stem cells. J Vis Exp 2010(43).
56 - Pistollato F, Rampazzo E, Persano L, Abbadi S, Frasson C, Denaro L, D'Avella D, Panchision DM, Della Puppa A, Scienza R, Basso G. Interaction of hypoxia-inducible factor-1alpha and Notch signaling regulates medulloblastoma precursor proliferation and fate. Stem Cells 2010;28(11):1918-29.
57 - Yu CC, Chiou GY, Lee YY, Chang YL, Huang PI, Cheng YW, Tai LK, Ku HH, Chiou SH, Wong TT. Medulloblastoma-derived tumor stem-like cells acquired resistance to TRAIL-induced apoptosis and radiosensitivity. Childs Nerv Syst 2010;26(7):897-904.
58 - Sutter R, Shakhova O, Bhagat H, Behesti H, Sutter C, Penkar S, Santuccione A, Bernays R, Heppner FL, Schuller U, Grotzer M, Moch H, Schraml P, Marino S. Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas. Oncogene 2010;29(12):1845-56.
59 - Bhoopathi P, Chetty C, Dontula R, Gujrati M, Dinh DH, Rao JS, Lakka SS. SPARC stimulates neuronal differentiation of medulloblastoma cells via the Notch1/STAT3 pathway. Cancer Res 2011;71(14):4908-19.
60 - Durand K, Guillaudeau A, Pommepuy I, Mesturoux L, Chaunavel A, Gadeaud E, Porcheron M, Moreau JJ, Labrousse F. Alpha-internexin expression in gliomas: relationship with histological type and 1p, 19q, 10p and 10q status. J Clin Pathol 2011;64(9):793-801.
61 - Wan F, Herold-Mende C, Campos B, Centner FS, Dictus C, Becker N, Devens F, Mogler C, Felsberg J, Grabe N, Reifenberger G, Lichter P, Unterberg A, Bermejo JL, Ahmadi R. Association of stem cell-related markers and survival in astrocytic gliomas. Biomarkers 2011;16(2):136-43.
62 - Krupkova O, Jr., Loja T, Redova M, Neradil J, Zitterbart K, Sterba J, Veselska R. Analysis of nuclear nestin localization in cell lines derived from neurogenic tumors. Tumour Biol 2011;32(4):631-9.
63 - Nagaishi M, Yokoo H, Hirato J, Yoshimoto Y, Nakazato Y. Clinico-pathological feature of pilomyxoid astrocytomas: three case reports. Neuropathology 2011;31(2):152-7.
64 - Yoshimoto K, Ma X, Guan Y, Mizoguchi M, Nakamizo A, Amano T, Hata N, Kuga D, Sasaki T. Expression of stem cell marker and receptor kinase genes in glioblastoma tissue quantified by real-time RT-PCR. Brain Tumor Pathol 2011;28(4):291-6.
65 - Idoate MA, Diez Valle R, Echeveste J, Tejada S. Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence. Neuropathology 2011;31(6):575-82.
66 - Kim KJ, Lee KH, Kim HS, Moon KS, Jung TY, Jung S, Lee MC. The presence of stem cell marker-expressing cells is not prognostically significant in glioblastomas. Neuropathology 2011;31(5):494-502.
67 - Najbauer J, Huszthy PC, Barish ME, Garcia E, Metz MZ, Myers SM, Gutova M, Frank RT, Miletic H, Kendall SE, Glackin CA, Bjerkvig R, Aboody KS. Cellular host responses to gliomas. PLoS One 2012;7(4):e35150.
68 - He H, Li MW, Niu CS. The pathological characteristics of glioma stem cell niches. J Clin Neurosci 2012;19(1):121-7.
69 - Kong LY, Wu AS, Doucette T, Wei J, Priebe W, Fuller GN, Qiao W, Sawaya R, Rao G, Heimberger AB. Intratumoral mediated immunosuppression is prognostic in genetically engineered murine models of glioma and correlates to immunotherapeutic responses. Clin Cancer Res 2010;16(23):5722-33.
70 - Lu WJ, Lan F, He Q, Lee A, Tang CZ, Dong L, Lan B, Ma X, Wu JC, Shen L. Inducible expression of stem cell associated intermediate filament nestin reveals an important role in glioblastoma carcinogenesis. Int J Cancer 2011;128(2):343-51.
71 - Prestegarden L, Svendsen A, Wang J, Sleire L, Skaftnesmo KO, Bjerkvig R, Yan T, Askland L, Persson A, Sakariassen PO, Enger PO. Glioma cell populations grouped by different cell type markers drive brain tumor growth. Cancer Res 2010;70(11):4274-9.
72 - Zhu G, Su W, Jin G, Xu F, Hao S, Guan F, Jia W, Liu F. Glioma stem cells targeted by oncolytic virus carrying endostatin-angiostatin fusion gene and the expression of its exogenous gene in vitro. Brain Res 2011;1390:59-69.
73 - Bulnes S, Garcia-Blanco A, Bengoetxea H, Ortuzar N, Argandona EG, Lafuente JV. Glial stem cells and their relationship with tumour angiogenesis process. Rev Neurol 2011;52(12):743-50.
74 - Xiao ZY, Tang H, Xu ZM, Yan ZJ, Li P, Cai YQ, Jiang XD, Xu RX. An experimental study of dendritic cells transfected with cancer stem-like cells RNA against 9L brain tumors. Cancer Biol Ther 2011;11(11):974-80.
75 - Tomuleasa C, Soritau O, Rus-Ciuca D, Ioani H, Susman S, Petrescu M, Timis T, Cernea D, Kacso G, Irimie A, Florian IS. Functional and molecular characterization of glioblastoma multiforme-derived cancer stem cells. J BUON 2010;15(3):583-91.
76 - Qin K, Jiang X, Zou Y, Wang J, Qin L, Zeng Y. Study on the proliferation and drug-resistance of human brain tumor stem-like cells. Cell Mol Neurobiol 2010;30(6):955-60.
77 - Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2010;2(31):31ra4.
78 - Guo Y, Liu S, Wang P, Zhao S, Wang F, Bing L, Zhang Y, Ling EA, Gao J, Hao A. Expression profile of embryonic stem cell-associated genes Oct4, Sox2 and Nanog in human gliomas. Histopathology 2011;59(4):763-75.
79 - Wookey PJ, McLean CA, Hwang P, Furness SG, Nguyen S, Kourakis A, Hare DL, Rosenfeld JV. The expression of calcitonin receptor detected in malignant cells of the brain tumour glioblastoma multiforme and functional properties in the cell line A172. Histopathology 2012;60(6):895-910.
80 - Binello E, Qadeer ZA, Kothari HP, Emdad L, Germano IM. Stemness of the CT-2A Immunocompetent Mouse Brain Tumor Model: Characterization In Vitro. J Cancer 2012;3:166-74.
81 - Kim RK, Yoon CH, Hyun KH, Lee H, An S, Park MJ, Kim MJ, Lee SJ. Role of lymphocyte-specific protein tyrosine kinase (LCK) in the expansion of glioma-initiating cells by fractionated radiation. Biochem Biophys Res Commun 2010;402(4):631-6.
82 - Tamura K, Aoyagi M, Wakimoto H, Ando N, Nariai T, Yamamoto M, Ohno K. Accumulation of CD133-positive glioma cells after high-dose irradiation by Gamma Knife surgery plus external beam radiation. J Neurosurg 2010;113(2):310-8.
83 - Kolenda J, Jensen SS, Aaberg-Jessen C, Christensen K, Andersen C, Brunner N, Kristensen BW. Effects of hypoxia on expression of a panel of stem cell and chemoresistance markers in glioblastoma-derived spheroids. J Neurooncol 2011;103(1):43-58.
84 - Schiffer D, Annovazzi L, Caldera V, Mellai M. On the origin and growth of gliomas. Anticancer Res 2010;30(6):1977-98.
85 - Moon JH, Kwon S, Jun EK, Kim A, Whang KY, Kim H, Oh S, Yoon BS, You S. Nanog-induced dedifferentiation of p53-deficient mouse astrocytes into brain cancer stem-like cells. Biochem Biophys Res Commun 2011;412(1):175-81.
86 - Ying M, Wang S, Sang Y, Sun P, Lal B, Goodwin CR, Guerrero-Cazares H, Quinones-Hinojosa A, Laterra J, Xia S. Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition. Oncogene 2011;30(31):3454-67.
87 - Zarnescu O, Brehar FM, Bleotu C, Gorgan RM. Co-localization of PCNA, VCAM-1 and caspase-3 with nestin in xenografts derived from human anaplastic astrocytoma and glioblastoma multiforme tumor spheres. Micron 2011;42(8):793-800.
88 - He H, Niu CS, Li MW. Correlation between glioblastoma stem-like cells and tumor vascularization. Oncol Rep 2012;27(1):45-50.
89 - Dong J, Zhao Y, Huang Q, Fei X, Diao Y, Shen Y, Xiao H, Zhang T, Lan Q, Gu X. Glioma stem/progenitor cells contribute to neovascularization via transdifferentiation. Stem Cell Rev 2010;7(1):141-52.
90 - Natsume A, Kato T, Kinjo S, Enomoto A, Toda H, Shimato S, Ohka F, Motomura K, Kondo Y, Miyata T, Takahashi M, Wakabayashi T. Girdin maintains the stemness of glioblastoma stem cells. Oncogene 2012;31(22):2715-24.
91 - Maderna E, Salmaggi A, Calatozzolo C, Limido L, Pollo B. Nestin, PDGFRbeta, CXCL12 and VEGF in glioma patients: different profiles of (pro-angiogenic) molecule expression are related with tumor grade and may provide prognostic information. Cancer Biol Ther 2007;6(7):1018-24.
92 - Colman H, Zhang L, Sulman EP, McDonald JM, Shooshtari NL, Rivera A, Popoff S, Nutt CL, Louis DN, Cairncross JG, Gilbert MR, Phillips HS, Mehta MP, Chakravarti A, Pelloski CE, Bhat K, Feuerstein BG, Jenkins RB, Aldape K. A multigene predictor of outcome in glioblastoma. Neuro Oncol 2010;12(1):49-57.
93 - Lothian C, Lendahl U. An evolutionarily conserved region in the second intron of the human nestin gene directs gene expression to CNS progenitor cells and to early neural crest cells. Eur J Neurosci 1997;9(3):452-62.
94 - Birnbaum T, Hildebrandt J, Nuebling G, Sostak P, Straube A. Glioblastoma-dependent differentiation and angiogenic potential of human mesenchymal stem cells in vitro. J Neurooncol 2011;105(1):57-65.
95 - Matsuda Y, Fujii T, Suzuki T, Yamahatsu K, Kawahara K, Teduka K, Kawamoto Y, Yamamoto T, Ishiwata T, Naito Z. Comparison of Fixation Methods for Preservation of Morphology, RNAs, and Proteins From Paraffin-embedded Human Cancer Cell-implanted Mouse Models. J Histochem Cytochem 2010; 59 (1): 68-75.
96 - Yamahatsu K, Matsuda Y, Ishiwata T, Uchida E, Naito Z. Nestin as a novel therapeutic target for pancreatic cancer via tumor angiogenesis. Int J Oncol 2012; 40 (5): 1345-57.
97 - Mokry J, Nemecek S. Angiogenesis of extra- and intraembryonic blood vessels is associated with expression of nestin in endothelial cells. Folia Biol (Praha) 1998;44(5):155-61.
98 - Mokry J, Nemecek S. Cerebral angiogenesis shows nestin expression in endothelial cells. Gen Physiol Biophys 1999;18 Suppl 1:25-9.
99 - Li MW, Niu CS. [Correlative study of distribution of brain tumor stem cell with micro-vascular system]. Zhonghua Yi Xue Za Zhi 2010;90(5):305-9.
100 - Sica G, Lama G, Anile C, Geloso MC, La Torre G, De Bonis P, Maira G, Lauriola L, Jhanwar-Uniyal M, Mangiola A. Assessment of angiogenesis by CD105 and nestin expression in peritumor tissue of glioblastoma. Int J Oncol 2011;38(1):41-9.
101 - Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M, Frank A, Bayazitov IT, Zakharenko SS, Gajjar A, Davidoff A, Gilbertson RJ. A perivascular niche for brain tumor stem cells. Cancer Cell 2007;11(1):69-82.
102 - Castino R, Pucer A, Veneroni R, Morani F, Peracchio C, Lah TT, Isidoro C. Resveratrol reduces the invasive growth and promotes the acquisition of a long-lasting differentiated phenotype in human glioblastoma cells. J Agric Food Chem 2011;59(8):4264-72.
103 - Beck S, Jin X, Yin J, Kim SH, Lee NK, Oh SY, Kim MK, Kim EB, Son JS, Kim SC, Nam DH, Kang SK, Kim H, Choi YJ. Identification of a peptide that interacts with Nestin protein expressed in brain cancer stem cells. Biomaterials 2011;32(33):8518-28.