Background
Gliomas, the most frequent primary tumors in the human central nervous system (CNS), are classified into low- and high-grade glioma according to their morphological features [
1]. Cells of low-grade (WHO grade I and II) gliomas are well differentiated with clear histological similarity to astrocyte or oligodendrocyte lineage. High-grade (WHO grade III and IV) gliomas are more anaplastic, with features resembling immature astrocytes, oligodendrocytes or a mixture of both types [
2]. A considerable number of advances on therapeutics of malignant gliomas have been got in the last decade [
3,
4]. But unfortunately, surgical cure, as the basic treatment of malignant gliomas, is practically impossible to resect effectively because of their infiltrating nature and high recurrence, as this result, gliomas portend a poor prognosis [
5,
6]. To address this problem, many investigations have been performed and recent discoveries have shed light on the genetic events which lead to human gliomas.
Currently, a growing body of evidence suggests that gliomas may be generated from tumor stem cells (TSC) sharing many properties with those of neural stem cells (NSC) [
7,
8]. Nestin is an intermediate filament (IF) protein expressed in proliferating cells during the developmental stages in a variety of embryonic and fetal tissues [
9]. It may be involved in the organization of the cytoskeleton, cell signaling, organogenesis, cell metabolism, and represent the proliferation, migration and multi-differentiated characteristics of multi-lineage progenitor cells [
10]. CD133 (also named as Prominin) is a cell surface marker expressed on normal human NSC and acutely dissociated brain tumor cells [
11]. Five alternative promoters, three of which are partially regulated by methylation, drive the transcription of several mRNA isoforms of CD133. Its localization is in membrane protrusions, which suggests an involvement in the dynamic organization of membrane protrusions and therefore in the mechanisms influencing cell polarity, migration and interaction of stem cells with neighbouring cells and/or extracellular matrix [
12].
It has been reported that TSC expressing the markers Nestin and CD133 in a variety of brain tumors [
13]. Analyses on their expression may be useful in predicting behavior of tumors in order to identify which tumors are most amenable to therapy. Therefore, the purpose of this study is to determine the correlation of Nestin and CD133 expression with the grading of gliomas and their predictive efficiency in clinical outcome of patients.
Discussion
To our knowledge, malignant gliomas are highly recurrent tumors even after surgery, chemotherapy, radiation and immunotherapy. Ionizing radiation represents the most effective therapy for gliomas but radiotherapy remains only palliative because of radioresistance. In the last decades, the treatment strategies for gliomas have not changed appreciably because of the limited understanding of the biology of the disease. Several recent reports suggest that normal and TSCs share the expression of several markers, the ability for self-renewal and differentiation, and signalling pathways involved in the regulation of cellular survival, proliferation [
17,
18]. It also has been demonstrated that TSCs exist in high-grade brain tumors and could be isolated from them. Nevertheless, little is known about the expression of these markers in solid brain tumors, especially in relation with the malignant grades of these tumors. To address this problem, we investigate, in this study, the expression of two TSC markers – Nestin and CD133, which are the most accredited markers for the identification of NSCs and have been used to fundamentally reveal the biological properties of TSCs, on protein level. In our small series of cases, Nestin and CD133 expression was associated with a poor prognosis and correlated better with clinical course than the histological grading. While the prognostic significance of the histological diagnosis strongly depends on the experience of the respective neuropathologist, analysis of both available data sets revealed that Nestin and CD133 expression was superior in predicting the patient's survival.
Nestin belongs to class VI of IFs, produced in stem cells in the mammalian CNS during development. It is a marker of proliferating and migrating cells [
19]. IFs as the cytoskeleton constituents are involved in the control of cell morphology, adhesion and proliferation. When differentiation starts, cells that exit the cell cycle down-regulate Nestin and subsequently up-regulate alternative IFs such as neurofilaments in committed neurons, and GFAP in glial precursors [
20]. Down-regulated Nestin may be re-expressed in the adult organism under certain pathological conditions such as brain injury, ischemia, inflammation and neoplastic transformation [
21]. Nestin has been detected in brain tumors such as pilocytic astrocytomas and malignant gliomas including GBM [
22‐
25]. IF is linked to enhanced motility and invasion in a number of different cancer subtypes. The expression of Nestin in different astrocytoma cell lines has been related to a migratory cell phenotype with increased motility and invasiveness of different astrocytoma cell lines [
23]. Moreover, Dahlstrand, et al. showed high Nestin expression in high malignant tumors such as GBM when compared to less anaplastic glial tumours, which assigns to Nestin a role as new potential prognostic marker for glioblastomas [
26]. In addition, Nestin has been also identified in the cell nucleus of tumor cell lines obtained from glioblastoma patients [
27]. In our work, in agreement with literature data, Nestin was expressed more frequently in higher malignant grade gliomas by tumor cells, being predictive of a significantly lower 5-year survival rate.
CD133/prominin is originally found on neuroepithelial stem cells in mice. It has been isolated from hematopoietic stem cells by an antibody recognizing AC133 [
28]. In general, CD133 is present in different types of stem cells and several cancers, and is down-regulated in differentiated cells [
29]. CD133 localization in membrane protrusions suggests an involvement in the dynamic organization of membrane protrusions and therefore in the mechanisms influencing cell polarity, migration and interaction of stem cells with neighbour cells and/or extracellular matrix, but experimental data are currently lacking [
30]. In addition, it is not known whether CD133 has a role in self-renewal and differentiation of stem cells, which has important implication in cancerogenesis. Our study investigated CD133 expression, yielding results similar to those reported by Dagmar [
11] for CD133 (namely, a predictive value for a worse outcome in high-grade oligodendroglial tumor patients displaying positivity for CD133 expression).
In conclusion, Nestin and CD133 expression may be a potential indicator of the biological aggressiveness of gliomas. With its disease specificity and response to treatment demonstrated in further analysis, Nestin and CD133 can be considered as markers of tumor burden and recurrence in human gliomas.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
MZ and TS carried out the experiment of this manuscript and drafted the manuscript; LY, RC, and LW participated the experiment and revised the manuscript, ZY and JF participated in the design of the study and and approved the final manuscript.