MAP2

Gene Summary

Gene:MAP2; microtubule associated protein 2
Aliases: MAP-2, MAP2A, MAP2B, MAP2C
Location:2q34
Summary:This gene encodes a protein that belongs to the microtubule-associated protein family. The proteins of this family are thought to be involved in microtubule assembly, which is an essential step in neurogenesis. The products of similar genes in rat and mouse are neuron-specific cytoskeletal proteins that are enriched in dentrites, implicating a role in determining and stabilizing dentritic shape during neuron development. A number of alternatively spliced variants encoding distinct isoforms have been described. [provided by RefSeq, Jan 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:microtubule-associated protein 2
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Brain Tumours
  • Infant
  • ras Proteins
  • Phenotype
  • Neuroblastoma
  • Cell Proliferation
  • Biomarkers
  • Cancer Gene Expression Regulation
  • Immunohistochemistry
  • Messenger RNA
  • RTPCR
  • Gene Expression Profiling
  • Tumor Suppressor Proteins
  • Risk Factors
  • Neoplasm Invasiveness
  • Cell Division
  • Cell Shape
  • Glial Fibrillary Acidic Protein
  • Biomarkers, Tumor
  • Melanoma
  • Chromosome 2
  • Neurons
  • Oligonucleotide Array Sequence Analysis
  • Brain Tumours
  • SOXB1 Transcription Factors
  • Uniparental Disomy
  • Glioblastoma
  • Transcription Factors
  • BRAF
  • Neuroglia
  • Tuberous Sclerosis
  • MicroRNAs
  • Childhood Cancer
  • Cell Movement
  • Loss of Heterozygosity
  • Nestin
  • Microtubule-Associated Proteins
  • Proteomics
  • Cell Differentiation
  • Nerve Tissue Proteins
  • Transcriptional Activation
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MAP2 (cancer-related)

Chen MK, Peng CC, Maner RS, et al.
Geniposide ameliorated fluoxetine-suppressed neurite outgrowth in Neuro2a neuroblastoma cells.
Life Sci. 2019; 226:1-11 [PubMed] Related Publications
AIM: Fluoxetine (FXT), a selective serotonin reuptake inhibitor (SSRI), is one of the most common psychiatric medications clinically prescribed; while over-produced serotonin may suppress neurite development. The role of major iridoids like geniposide (GPS) and genipin (GNP) from Gardenia jasminoides Ellis fruit (family Rubiaceae) in ameliorating the anti-neurite outgrowth effect of FXT is poorly understood. In this study, the effects of these iridoids on FXT-suppressed neurite outgrowth in Neuro2a neuroblastoma cells were investigated.
MAIN METHODS: Neuro2a cells were treated with FXT and GPS. The effect of GPS-FXT co-treatment on neurite outgrowth was observed using inverted phase-contrast microscope imaging system, while neurite outgrowth markers - microtubule-associated protein-2 (MAP2) and growth-associated protein 43 (GAP43) were analyzed using RT-PCR, Western blot and immunofluorescence staining. The transcription factor-cAMP response element binding (CREB), and signaling pathways - mitogen-activated protein kinase (MAPK) and protein kinase B/mammalian target of rapamycin (AKT/mTOR) were also analyzed with the help of Western blot.
KEY FINDINGS: The results showed that FXT decreased the neurite outgrowth in Neuro2a cells and also downregulated gene and protein expression of MAP2 and GAP43. It also downregulated the protein expression of phosphorylated-CREB, MAPK, and AKT/mTOR signaling pathways. In contrast, GPS counteracted the effects of FXT. GPS-FXT co-treatment increased the percentage of neurite-bearing cells by 3.6-fold at 200 μM as compared to FXT treatment only.
SIGNIFICANCE: This study has provided the possible molecular mechanism showing how FXT exerted its detrimental side-effects on the neurite differentiation, and via the same mechanism how GPS attenuated these side effects.

Hsu JB, Chang TH, Lee GA, et al.
Identification of potential biomarkers related to glioma survival by gene expression profile analysis.
BMC Med Genomics. 2019; 11(Suppl 7):34 [PubMed] Related Publications
BACKGROUND: Recent studies have proposed several gene signatures as biomarkers for different grades of gliomas from various perspectives. However, most of these genes can only be used appropriately for patients with specific grades of gliomas.
METHODS: In this study, we aimed to identify survival-relevant genes shared between glioblastoma multiforme (GBM) and lower-grade glioma (LGG), which could be used as potential biomarkers to classify patients into different risk groups. Cox proportional hazard regression model (Cox model) was used to extract relative genes, and effectiveness of genes was estimated against random forest regression. Finally, risk models were constructed with logistic regression.
RESULTS: We identified 104 key genes that were shared between GBM and LGG, which could be significantly correlated with patients' survival based on next-generation sequencing data obtained from The Cancer Genome Atlas for gene expression analysis. The effectiveness of these genes in the survival prediction of GBM and LGG was evaluated, and the average receiver operating characteristic curve (ROC) area under the curve values ranged from 0.7 to 0.8. Gene set enrichment analysis revealed that these genes were involved in eight significant pathways and 23 molecular functions. Moreover, the expressions of ten (CTSZ, EFEMP2, ITGA5, KDELR2, MDK, MICALL2, MAP 2 K3, PLAUR, SERPINE1, and SOCS3) of these genes were significantly higher in GBM than in LGG, and comparing their expression levels to those of the proposed control genes (TBP, IPO8, and SDHA) could have the potential capability to classify patients into high- and low- risk groups, which differ significantly in the overall survival. Signatures of candidate genes were validated, by multiple microarray datasets from Gene Expression Omnibus, to increase the robustness of using these potential prognostic factors. In both the GBM and LGG cohort study, most of the patients in the high-risk group had the IDH1 wild-type gene, and those in the low-risk group had IDH1 mutations. Moreover, most of the high-risk patients with LGG possessed a 1p/19q-noncodeletion.
CONCLUSION: In this study, we identified survival relevant genes which were shared between GBM and LGG, and those enabled to classify patients into high- and low-risk groups based on expression level analysis. Both the risk groups could be correlated with the well-known genetic variants, thus suggesting their potential prognostic value in clinical application.

Córdova-Rivas S, Fraire-Soto I, Mercado-Casas Torres A, et al.
5p and 3p Strands of miR-34 Family Members Have Differential Effects in Cell Proliferation, Migration, and Invasion in Cervical Cancer Cells.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
The micro RNA (miR)-34 family is composed of 5p and 3p strands of miR-34a, miR-34b, and miR-34c. The 5p strand's expression and function is studied in cervical cancer. The 3p strand's function and regulation remain to be elucidated. To study the function of the passenger strands of miR-34 family members, we overexpressed 5p and 3p strands using a synthetic miRNA in cervical cell lines. Cell proliferation was evaluated using crystal violet. Migration and invasion were tested using transwell assays, Western blot, and zymography. Possible specific targets and cell signaling were investigated for each strand. We found that miR-34a-5p inhibited proliferation, migration, and cell invasion accompanied by matrix metalloproteinase 9 (MMP9) activity and microtubule-associated protein 2 (MAP2) protein reduction. We also found that miR-34b-5p and miR-34c-5p inhibit proliferation and migration, but not invasion. In contrast, miR-34c-5p inhibits MMP9 activity and MAP2 protein, while miR-34b-5p has no effect on these genes. Furthermore, miR-34a-3p and miR-34b-3p inhibit proliferation and migration, but not invasion, despite the later reducing MMP2 activity, while miR-34c-3p inhibit proliferation, migration, and cell invasion accompanied by MMP9 activity and MAP2 protein inhibition. The difference in cellular processes, MMP2 and MMP9 activity, and MAP2 protein inhibition by miR-34 family members suggests the participation of other regulated genes. This study provides insights into the roles of passenger strands (strand*) of the miR-34 family in cervical cancer.

Lin C, Chen PY, Chan HC, et al.
Peroxisome proliferator-activated receptor alpha accelerates neuronal differentiation and this might involve the mitogen-activated protein kinase pathway.
Int J Dev Neurosci. 2018; 71:46-51 [PubMed] Related Publications
Activation of peroxisome proliferator-activated receptor alpha (PPARα) has been reported to modulate cell proliferation, migration, and differentiation in astrocytes. In this study, we used a retinoic acid (RA)-induced differentiation model of NTERA-2/clone D1 (NT2) cells to explore the functional significance of PPARα in neuronal differentiation. We found that activating PPARα by Wy14643 accelerated neuronal differentiation via regulating the expression of neuronal markers. RT-PCR assays showed a significant increase in NeuroD expression and a decrease in nestin expression in cells treated concomitantly with RA and Wy14643 for 2 days compared to the levels in cells treated with RA alone. Expression of MAP2 protein, a mature neuronal marker, was markedly upregulated at day 10 of Wy14643 treatment, which was maintained after 21 days of neuronal formation. Corresponding to the changes in MAP2 expression, the expression of Cdk5 was upregulated with Wy14643 exposure from day 10 to day 21. Moreover, cells treated with Wy14643 displayed higher expression levels of phospho-ERK and phospho-p38 in the differentiation process than cell treated with RA alone. These results indicated that activation of PPARα accelerated neuronal differentiation through upregulating the expression of NeuroD, MAP2, and Cdk5 and downregulating the expression of nestin. MAPK signals, ERK and p38, might contribute to the accelerated differentiation process. These findings suggest that PPARα plays a role in regulating neuronal differentiation and may be beneficial for functional recovery from neurological disorders.

Kandhavelu J, Subramanian K, Khan A, et al.
Computational Analysis of miRNA and their Gene Targets Significantly Involved in Colorectal Cancer Progression.
Microrna. 2019; 8(1):68-75 [PubMed] Related Publications
BACKGROUND: Globally, colorectal cancer (CRC) is the third most common cancer in women and the fourth most common cancer in men. Dysregulation of small non-coding miRNAs have been correlated with colon cancer progression. Since there are increasing reports of candidate miRNAs as potential biomarkers for CRC, this makes it important to explore common miRNA biomarkers for colon cancer. As computational prediction of miRNA targets is a critical initial step in identifying miRNA: mRNA target interactions for validation, we aim here to construct a potential miRNA network and its gene targets for colon cancer from previously reported candidate miRNAs, inclusive of 10 up- and 9 down-regulated miRNAs from tissues; and 10 circulatory miRNAs.
METHODS: The gene targets were predicted using DIANA-microT-CDS and TarBaseV7.0 databases. Each miRNA and its targets were analyzed further for colon cancer hotspot genes, whereupon DAVID analysis and mirPath were used for KEGG pathway analysis.
RESULTS: We have predicted 874 and 157 gene targets for tissue and serum specific miRNA candidates, respectively. The enrichment of miRNA revealed that particularly hsa-miR-424-5p, hsa-miR-96-5p, hsa-miR-1290, hsa-miR-224, hsa-miR-133a and has-miR-363-3p present possible targets for colon cancer hallmark genes, including BRAF, KRAS, EGFR, APC, amongst others. DAVID analysis of miRNA and associated gene targets revealed the KEGG pathways most related to cancer and colon cancer. Similar results were observed in mirPath analysis. A new insight gained in the colon cancer network pathway was the association of hsa-mir-133a and hsa-mir-96-5p with the PI3K-AKT signaling pathway. In the present study, target prediction shows that while hsa-mir-424-5p has an association with mostly 10 colon cancer hallmark genes, only their associations with MAP2 and CCND1 have been experimentally validated.
CONCLUSION: These miRNAs and their targets require further evaluation for a better understanding of their associations, ultimately with the potential to develop novel therapeutic targets.

El-Bakoush A, Olajide OA
Formononetin inhibits neuroinflammation and increases estrogen receptor beta (ERβ) protein expression in BV2 microglia.
Int Immunopharmacol. 2018; 61:325-337 [PubMed] Related Publications
Formononetin is a bioactive non-steroidal polyphenol found in a variety of plants. In this study we evaluated the effects of formononetin on neuroinflammation in LPS-stimulated BV2 microglia. Results showed that formononetin significantly reduced the production of TNF-α, IL-6 and IL-1β, nitrite and PGE

Costa Nunes F, Silva LB, Winter E, et al.
Tacrine derivatives stimulate human glioma SF295 cell death and alter important proteins related to disease development: An old drug for new targets.
Biochim Biophys Acta Gen Subj. 2018; 1862(7):1527-1536 [PubMed] Related Publications
Glioblastoma is the most common and aggressive glioma, characterized by brain invasion capability. Being very resistant to the current therapies, since even under treatment, surgery, and chemotherapy with temozolomide (TMZ), patients achieve a median survival of one year. In the search for more effective therapies, new molecules have been designed. For nervous system cancers, molecules able to cross the blood-brain barrier are handled with priority. Accordingly, tacrine was chosen for this study and the inclusion of spiro-heterocyclic rings was done in its structure resulting in new compounds. Cytotoxic activity of tacrine derivatives was assayed using glioblastoma cell line (SF295) as well as analyzing cell death mechanism. Increased caspases activities were observed, confirming apoptosis as cell death type. Some derivatives also increased reactive oxygen species formation and decreased the mitochondrial membrane potential. Moreover, compounds acted on several glioblastoma-related proteins including p53, HLA-DR, beta-catenin, Iba-1, MAP2c, Olig-2, and IDH1. Therefore, tacrine derivatives presented promising results for the development of new glioblastoma therapy, particularly to treat those patients resistant to TMZ.

Ortiz-Matamoros A, Arias C
Chronic infusion of Wnt7a, Wnt5a and Dkk-1 in the adult hippocampus induces structural synaptic changes and modifies anxiety and memory performance.
Brain Res Bull. 2018; 139:243-255 [PubMed] Related Publications
Wnt signaling plays an important role in the adult brain function and its dysregulation has been implicated in some neurodegenerative pathways. Despite the functional role of the Wnt signaling in adult neural circuits, there is currently no evidence regarding the relationships between exogenously Wnt signaling activation or inhibition and hippocampal structural changes in vivo. Thus, we analyzed the effect of the chronic infusion of Wnt agonists, Wnt7a and Wnt5a, and antagonist, Dkk-1, on different markers of plasticity such as neuronal MAP-2, Tau, synapse number and morphology, and behavioral changes. We observed that Wnt7a and Wnt5a increased the number of perforated synapses and the content of pre-and postsynaptic proteins associated with synapse assembly compared to control and Dkk-1 infusion. These two Wnt agonists also reduced anxiety-like behavior. Conversely, the canonical antagonist, Dkk-1, increased anxiety and inhibited spatial memory recall. Therefore, the present study elucidates the potential participation of Wnt signaling in the remodeling of hippocampal circuits underlying plasticity events in vivo, and provides evidence of the potential benefits of Wnt agonist infusion for the treatment of some neurodegenerative conditions.

Sharif S, Ghahremani MH, Soleimani M
Induction of morphological and functional differentiation of human neuroblastoma cells by miR-124.
J Biosci. 2017; 42(4):555-563 [PubMed] Related Publications
Neuroblastoma is the most common extracranial solid tumour in children, and differentiation is considered its most appropriate therapy. In this work, we studied effects of miR-124 overexpression on differentiation in M17 cell line as a model of neuroblastoma cancer. Influence of miR-124 overexpression on differentiation in M17 cells was studied. M17 cells were infected with lentivirus that contained miR-124 precursor sequence and followed for 2 weeks to differentiate. Ectopic expression of miR-124 in M17 cells changed the shape of spherical undifferentiated cells to cells with extended neurites that formed neuronal networks. Overexpression of MiR-124 respectively increased the expression level of markers of β-Tubulin III, MAP2, SYN, NF-M and Nestin by 16-, 5-, 4-, 2.3- and 2-folds at the messenger RNA level. MiR-124 overexpression also increased the protein levels of β-Tubulin III and MAP2. Moreover, exogenous expression of miR-124 significantly increased the intracellular calcium in differentiated M17 cells. Since miR-124 is naturally expressed in neuronal cells and is downregulated in neuroblastoma cancer cells, differentiation with this type of microRNA can be a novel treatment for neuroblastoma cancer.

Thom M, Liu J, Bongaarts A, et al.
Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?
Brain Pathol. 2018; 28(2):155-171 [PubMed] Free Access to Full Article Related Publications
Multinodular and vacuolating neuronal tumor (MVNT) is a new pattern of neuronal tumour included in the recently revised WHO 2016 classification of tumors of the CNS. There are 15 reports in the literature to date. They are typically associated with late onset epilepsy and a neoplastic vs. malformative biology has been questioned. We present a series of ten cases and compare their pathological and genetic features to better characterized epilepsy-associated malformations including focal cortical dysplasia type II (FCDII) and low-grade epilepsy-associated tumors (LEAT). Clinical and neuroradiology data were reviewed and a broad immunohistochemistry panel was applied to explore neuronal and glial differentiation, interneuronal populations, mTOR pathway activation and neurodegenerative changes. Next generation sequencing was performed for targeted multi-gene analysis to identify mutations common to epilepsy lesions including FCDII and LEAT. All of the surgical cases in this series presented with seizures, and were located in the temporal lobe. There was a lack of any progressive changes on serial pre-operative MRI and a mean age at surgery of 45 years. The vacuolated cells of the lesion expressed mature neuronal markers (neurofilament/SMI32, MAP2, synaptophysin). Prominent labelling of the lesional cells for developmentally regulated proteins (OTX1, TBR1, SOX2, MAP1b, CD34, GFAPδ) and oligodendroglial lineage markers (OLIG2, SMI94) was observed. No mutations were detected in the mTOR pathway genes, BRAF, FGFR1 or MYB. Clinical, pathological and genetic data could indicate that MVNT aligns more with a malformative lesion than a true neoplasm with origin from a progenitor neuro-glial cell type showing aberrant maturation.

Lauzon MA, Drevelle O, Faucheux N
Peptides derived from the knuckle epitope of BMP-9 induce the cholinergic differentiation and inactivate GSk3beta in human SH-SY5Y neuroblastoma cells.
Sci Rep. 2017; 7(1):4695 [PubMed] Free Access to Full Article Related Publications
The incidence of brain degenerative disorders like Alzheimer's disease (AD) will increase as the world population ages. While there is presently no known cure for AD and current treatments having only a transient effect, an increasing number of publications indicate that growth factors (GF) may be used to treat AD. GFs like the bone morphogenetic proteins (BMPs), especially BMP-9, affect many aspects of AD. However, BMP-9 is a big protein that cannot readily cross the blood-brain barrier. We have therefore studied the effects of two small peptides derived from BMP-9 (pBMP-9 and SpBMP-9). We investigated their capacity to differentiate SH-SY5Y human neuroblastoma cells into neurons with or without retinoic acid (RA). Both peptides induced Smad 1/5 phosphorylation and their nuclear translocation. They increased the number and length of neurites and the expression of neuronal markers MAP-2, NeuN and NSE better than did BMP-9. They also promoted differentiation to the cholinergic phenotype more actively than BMP-9, SpBMP-9 being the most effective as shown by increases in intracellular acetylcholine, ChAT and VAchT. Finally, both peptides activated the PI3K/Akt pathway and inhibited GSK3beta, a current AD therapeutic target. BMP-9-derived peptides, especially SpBMP-9, with or without RA, are promising molecules that warrant further investigation.

Li R, Zhou P, Guo Y, Zhou B
The involvement of autophagy and cytoskeletal regulation in TDCIPP-induced SH-SY5Y cell differentiation.
Neurotoxicology. 2017; 62:14-23 [PubMed] Related Publications
Exposure and toxicity to organophosphate-based flame retardants are an increasing health concern. Neurons appear to be particularly vulnerable to the effects of these chemicals. For example, in vitro studies have shown that tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) induces apoptosis and autophagy in neural cells. In the present study, we investigated the cell biological mechanisms of TDCIPP-induced neurotoxicity using undifferentiated human SH-SY5Y neuroblastoma cells as a model. Interestingly, TDCIPP treatment promoted differentiation in SH-SY5Y cells, which displayed various alterations including neurite elongation, an expansion of the numbers of neurite-bearing cells, and an increase in expression of cytoskeletal components normally enriched in neurons. Furthermore, the upregulation of microtubule-associated protein light chain 3, the degradation of p62/sequestosome 1, and the formation of autophagosomes occurred in treated cells, suggesting that TDCIPP exposure induces autophagy. However, pretreatment with the autophagy inhibitor 3-methyladenine suppressed TDCIPP-induced autophagy and reduced expression of the aforementioned cytoskeletal components. This correlated with a reduction in neurite outgrowth and numbers of neurite-bearing cells. Taken together, these results indicate that autophagy might promote TDCIPP-induced SH-SY5Y cell differentiation, which leads to an increase in expression of cytoskeletal components and neurite outgrowth. This study offers key insights into the mechanisms of neurotoxicity associated with this commonly used organophosphate.

Cenciarelli C, Marei HE, Zonfrillo M, et al.
The interference of Notch1 target Hes1 affects cell growth, differentiation and invasiveness of glioblastoma stem cells through modulation of multiple oncogenic targets.
Oncotarget. 2017; 8(11):17873-17886 [PubMed] Free Access to Full Article Related Publications
The invasive and lethal nature of Glioblastoma multiforme (GBM) necessitates the continuous identification of molecular targets and search of efficacious therapies to inhibit GBM growth. The GBM resistance to chemotherapy and radiation it is attributed to the existence of a rare fraction of cancer stem cells (CSC) that we have identified within the tumor core and in peritumor tissue of GBM. Since Notch1 pathway is a potential therapeutic target in brain cancer, earlier we highlighted that pharmacological inhibition of Notch1 signalling by γ-secretase inhibitor-X (GSI-X), reduced cell growth of some c-CSC than to their respective p-CSC, but produced negligible effects on cell cycle distribution, apoptosis and cell invasion. In the current study, we assessed the effects of Hes1-targeted shRNA, a Notch1 gene target, specifically on GBM CSC refractory to GSI-X. Depletion of Hes1 protein induces major changes in cell morphology, cell growth rate and in the invasive ability of shHes1-CSC in response to growth factor EGF. shHes1-CSC show a decrease of the stemness marker Nestin concurrently to a marked increase of neuronal marker MAP2 compared to pLKO.1-CSC. Those effects correlated with repression of EGFR protein and modulation of Stat3 phosphorylation at Y705 and S727 residues. In the last decade Stat3 has gained attention as therapeutic target in cancer but there is not yet any approved Stat3-based glioma therapy. Herein, we report that exposure to a Stat3/5 inhibitor, induced apoptosis either in shHes1-CSC or control cells. Taken together, Hes1 seems to be a favorable target but not sufficient itself to target GBM efficaciously, therefore a possible pharmacological intervention should provide for the use of anti-Stat3/5 drugs either alone or in combination regimen.

Orellana ME, Belfort R, Antecka E, Burnier MN
Immunohistochemical analysis of retinoblastoma cell phenotype using neuronal and glial cell markers.
Arq Bras Oftalmol. 2016 Nov-Dec; 79(6):395-399 [PubMed] Related Publications
Purpose:: The cellular origin of retinoblastoma is uncertain as constituent tumor cells heterogeneously express markers of both immature and mature retinal cells. An immunohistochemical analysis of cellular origin may yield valuable insights into disease progression and treatment options. This study aimed to determine the cellular origin of retinoblastoma in a large case series and correlate these findings with histopathological prognostic factors.
Methods:: Thirty-nine retinoblastoma cases were histopathologically diagnosed and analyzed by immunohistochemistry using monoclonal antibodies against the immature neural cell marker SRY-box containing gene 2 (SOX-2), the mature neuronal cell marker microtubule-associated protein 2 (MAP2), and the mature glial cell marker glial fibrillary acidic protein (GFAP). Histopathological features were also evaluated, including patterns of growth, differentiation, vitreous seeding, and choroidal/scleral, optic nerve, and anterior chamber invasion. Two retinoblastoma cell lines, WERI-1 and Y79, were studied by immunocytochemistry using the same antibodies.
Results:: Expression of SOX-2 was strong in 97.4% of retinoblastoma cases, while MAP-2 was expressed in 59% of cases. Immunostaining for GFAP was positive only in reactive stromal astrocytes interspersed amongst tumor cells and in peritumoral tissue. There was no correlation between histopathological prognostic factors and immunohistochemical markers. Retinoblastoma cell lines showed strong positivity for SOX2 (90% of WERI-1 cells and 70% of Y79 cells) and MAP2 (90% of cells in both lines). GFAP was completely negative in both cell lines.
Conclusion:: The majority of retinoblastomas and both RB cell lines expressed an immature neural and/or a mature neuronal cell marker, but not a glial marker. These results indicate a typical neuroblast or neuronal origin and eliminate astrocyte differentiation from neural stem cells as the source of retinoblastoma.

Fiset PO, Fontebasso AM, De Jay N, et al.
Longitudinal mutational analysis of a cerebellar pilocytic astrocytoma recurring as a ganglioglioma.
Pediatr Blood Cancer. 2017; 64(2):275-278 [PubMed] Related Publications
A cerebellar pilocytic astrocytoma (PA) in a child recurred first with a PA histology and then with features of a ganglioglioma (GG). Molecular genetic analyses of the tumors confirmed a BRAF V600E mutation in all. They also all harbored a T202M mutation in ERK1, a kinase downstream of BRAF that is implicated in glial versus neuronal differentiation. The GG sample contained several variants that were not present in the PA samples; in particular, it had a truncating mutation in MAP2. These findings not only underscore the role of BRAF as oncogenic driver but also suggest that other genes may influence tumor morphology.

Koseoglu MM, Ozdilek BA, Djakbarova U, Gulusur A
Targeting Ras Activity Prevented Amyloid Beta-Induced Aberrant Neuronal Cell Cycle Re-Entry and Death.
Curr Alzheimer Res. 2016; 13(11):1267-1276 [PubMed] Related Publications
Several studies suggest that soluble Amyloid β (Aβ) oligomer-induced aberrant neuronal cell cycle re-entry is the initial trigger for a significant part of the neuronal degeneration and loss in Alzheimer's disease (AD). In this study, we investigated the role of Ras, which is a well-known protooncoprotein, in soluble Aβ oligomer-induced aberrant neuronal cell cycle activation and subsequent cell loss using retinoic acid differentiated human SH-SY5Y neuroblastoma cells as model system. In line with previous literature, we showed that in vitro preparations of soluble Aβ42 oligomers triggered cell cycle activation but not cell proliferation. As a new finding, we showed that Farnesylthiosalicylic acid (FTS), a specific chemical Ras inhibitor, prevented soluble Aβ42 oligomer preparation-induced cell cycle activation. Moreover, we showed that the expression of dominant negative mutant H-Ras (S17N) prevented soluble Aβ42 oligomer preparation-induced cell cycle activation, confirming the specific role of Ras in this pathway. As a possible better mimic of the situation in the AD brain, we prepared soluble oligomers from Aβ42 : Aβ40 (3:7) peptide mixture and showed that this oligomer preparation similarly induced cell cycle activation which was also inhibited by the Ras inhibitor. Finally, we showed that FTS prevented soluble Aβ42 oligomer preparationinduced cell death in our retinoic acid differentiated SH-SY5Y cells. Overall, our results strongly suggest that Ras activity is required for soluble Aβ oligomer-induced aberrant neuronal cell cycle reentry and subsequent neuronal loss, which are considered important mechanisms in AD pathogenesis.

Cenciarelli C, Marei HE, Felsani A, et al.
PDGFRα depletion attenuates glioblastoma stem cells features by modulation of STAT3, RB1 and multiple oncogenic signals.
Oncotarget. 2016; 7(33):53047-53063 [PubMed] Free Access to Full Article Related Publications
Platelet derived growth factor receptors (PDGFRs) play an important role in tumor pathogenesis, and they are frequently overexpressed in glioblastoma (GBM). Earlier we have shown a higher protein expression of PDGFR isoforms (α and β) in peritumoral-tissue derived cancer stem cells (p-CSC) than in tumor core (c-CSC) of several GBM affected patients. In the current study, in order to assess the activity of PDGFRα/PDGF-AA signaling axis, we performed time course experiments to monitor the effects of exogenous PDGF-AA on the expression of downstream target genes in c-CSC vs p-CSC. Interestingly, in p-CSC we detected the upregulation of Y705-phosphorylated Stat3, concurrent with a decrement of Rb1 protein in its active state, within minutes of PDGF-AA addition. This finding prompted us to elucidate the role of PDGFRα in self-renewal, invasion and differentiation in p-CSC by using short hairpin RNA depletion of PDGFRα expression. Notably, in PDGFRα-depleted cells, protein analysis revealed attenuation of stemness-related and glial markers expression, alongside early activation of the neuronal marker MAP2a/b that correlated with the induction of tumor suppressor Rb1. The in vitro reduction of the invasive capacity of PDGFRα-depleted CSC as compared to parental cells correlated with the downmodulation of markers of epithelial-mesenchymal transition phenotype and angiogenesis. Surprisingly, we observed the induction of anti-apoptotic proteins and compensatory oncogenic signals such as EDN1, EDNRB, PRKCB1, PDGF-C and PDGF-D. To conclude, we hypothesize that the newly discovered PDGFRα/Stat3/Rb1 regulatory axis might represent a potential therapeutic target for GBM treatment.

Rosiak K, Smolarz M, Stec WJ, et al.
IDH1R132H in Neural Stem Cells: Differentiation Impaired by Increased Apoptosis.
PLoS One. 2016; 11(5):e0154726 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The high frequency of mutations in the isocitrate dehydrogenase 1 (IDH1) gene in diffuse gliomas indicates its importance in the process of gliomagenesis. These mutations result in loss of the normal function and acquisition of the neomorphic activity converting α-ketoglutarate to 2-hydroxyglutarate. This potential oncometabolite may induce the epigenetic changes, resulting in the deregulated expression of numerous genes, including those related to the differentiation process or cell survivability.
METHODS: Neural stem cells were derived from human induced pluripotent stem cells following embryoid body formation. Neural stem cells transduced with mutant IDH1R132H, empty vector, non-transduced and overexpressing IDH1WT controls were differentiated into astrocytes and neurons in culture. The neuronal and astrocytic differentiation was determined by morphology and expression of lineage specific markers (MAP2, Synapsin I and GFAP) as determined by real-time PCR and immunocytochemical staining. Apoptosis was evaluated by real-time observation of Caspase-3 activation and measurement of PARP cleavage by Western Blot.
RESULTS: Compared with control groups, cells expressing IDH1R132H retained an undifferentiated state and lacked morphological changes following stimulated differentiation. The significant inhibitory effect of IDH1R132H on neuronal and astrocytic differentiation was confirmed by immunocytochemical staining for markers of neural stem cells. Additionally, real-time PCR indicated suppressed expression of lineage markers. High percentage of apoptotic cells was detected within IDH1R132H-positive neural stem cells population and their derivatives, if compared to normal neural stem cells and their derivatives. The analysis of PARP and Caspase-3 activity confirmed apoptosis sensitivity in mutant protein-expressing neural cells.
CONCLUSIONS: Our study demonstrates that expression of IDH1R132H increases apoptosis susceptibility of neural stem cells and their derivatives. Robust apoptosis causes differentiation deficiency of IDH1R132H-expressing cells.

Cabrera JR, Lucas JJ
MAP2 Splicing is Altered in Huntington's Disease.
Brain Pathol. 2017; 27(2):181-189 [PubMed] Related Publications
Dendritic alteration of striatal medium spiny neurons is one of the earliest morphological abnormalities in Huntington's disease (HD). The main microtubule-associated protein in dendrites is MAP2. The low-molecular weight isoforms of MAP2 (LMW-MAP2) are the juvenile forms resulting from exclusion of the sequence encoded by exons E7-E9 and are downregulated after the early stages of neuronal development when E7-E9 exon-including high-molecular weight isoforms (HMW-MAP2) are favored. Splicing alteration has recently been proposed to contribute to HD in view of two pathogenic missplicing events resulting in a highly toxic N-terminal version of mutant huntingtin and in a detrimental imbalance in MAP Tau isoforms with three or four tubulin-binding repeats. Both splicing events are postulated targets of the SR splicing factor SRSF6 which has recently been reported to be dramatically altered in HD. SR proteins often regulate functionally related sets of genes and SRSF6 targets are enriched in genes involved in brain organogenesis including several actin-and tubulin-binding proteins. Here we hypothesized that MAP2 might be target of SRSF6 and altered in HD. By SRSF6 knockdown in neuroblastoma cells, we demonstrate that splicing of MAP2 E7-E9 exons is affected by SRSF6. We then show a disbalance in LMW and HMW MAP2 mRNA isoforms in HD striatum in favor of the juvenile LMW forms together with a decrease in total MAP2 mRNA. This is accompanied by a global decrease in total MAP2 protein due to almost total disappearance of HMW-MAP2 isoforms with preservation of LMW-MAP2 isoforms. Accordingly, the predominant dendritic MAP2 staining in striatal neuropil of control subjects is absent in HD cases. In these, MAP2-immunoreactivity is faint and restricted to neuronal cell bodies often showing a sharp boundary at the base of dendrites. Together, our results highlight the importance of splicing alteration in HD and suggest that MAP2 alteration contributes to dendritic atrophy.

Hashemi M, Fallah A, Aghayan HR, et al.
A New Approach in Gene Therapy of Glioblastoma Multiforme: Human Olfactory Ensheathing Cells as a Novel Carrier for Suicide Gene Delivery.
Mol Neurobiol. 2016; 53(8):5118-28 [PubMed] Related Publications
Olfactory ensheathing cells (OECs) of human olfactory mucosa are a type of glial-like cells that possess good migratory and tropism properties. We believe that neuronal-derived vehicle may have better capability to receive to the site of injury. In addition to, obtaining of such vehicle from the patient reduces risk of unwanted complications. So, in this study, we investigate whether human olfactory ensheathing cells can be used as a cell source for the first time in gene delivery to assay the tumoricidal effect of herpes simplex virus thymidine kinase gene (HSV-tk) on glioblastoma multiforme (GBM). We obtained OECs from superior turbinate of human nasal cavity mucosa, and cell phenotype was confirmed by the expression of cell-specific antigens including low-affinity nerve growth factor receptor (p75 neurotrophin receptor), microtubule-associated protein-2 (MAP2), and S100 calcium binding protein B (S100-beta) using immunocytochemistry. Then, these cells were transduced by lentiviral vector for transient and stable expression of the herpes simplex virus thymidine kinase gene (OEC-tk). The migratory capacity of OEC-tk, their potency to convert prodrug ganciclovir to toxic form, and cytotoxic effect on astrocyte cells were assayed in vitro. The OECs showed fibroblast-like morphology and expressed specific antigens such as p75 neurotrophin receptor, S100-beta, and MAP2. Our results indicated that OECs-tk were able to migrate toward primary cultured human glioblastoma multiforme and affected survival rate of tumor cells according to exposure time and concentration of ganciclovir. Also, OECs-HSV-tk was capable of inducing apoptosis in tumor cells. Our findings suggest that human OECs could employ as a possible tool to transfer anticancer agent in gene therapy of brain tumor.

Gate D, Danielpour M, Bannykh S, Town T
Characterization of cancer stem cells and primary cilia in medulloblastoma.
CNS Neurol Disord Drug Targets. 2015; 14(5):600-11 [PubMed] Related Publications
Medulloblastoma, a tumor of the cerebellum, is the most common pediatric central nervous system malignancy. These tumors are etiologically linked to mutations in the Sonic hedgehog (Shh) pathway, which signals through the primary, non-motile cilium. The growth of these aggressive tumors relies on self-renewal of tumor-propagating cells known as cancer stem cells (CSCs). Previous reports have implicated CD133-expressing cells as CSCs in brain tumors, while those expressing CD15 have been shown to propagate medulloblastoma. Here, we demonstrate that CD133+ and CD15+ cells are distinct medulloblastoma populations. CD15+ cells comprise approximately 0.5-1% of total human medulloblastoma cells, display CSC properties in culture and are detected in the Smoothened A1 transgenic mouse model of medulloblastoma. Additionally, we report on a medulloblastoma patient with enriched CD15+ cells in recurrent vs primary medulloblastoma. We also demonstrate that human medulloblastoma cells critically rely on establishment of primary cilia to drive Shh-mediated cell division. Primary cilia are found in external granule cells of human fetal cerebellum and in 12/14 medulloblastoma samples. Yet, CD15+ medulloblastoma cells lack primary cilia, suggesting that this CSC population signals independently of Shh. These results are important when considering the effects of current and prospective treatment modalities on medulloblastoma CSC populations.

Marrelli M, Paduano F, Tatullo M
Human periapical cyst-mesenchymal stem cells differentiate into neuronal cells.
J Dent Res. 2015; 94(6):843-52 [PubMed] Related Publications
It was recently reported that human periapical cysts (hPCys), a commonly occurring odontogenic cystic lesion of inflammatory origin, contain mesenchymal stem cells (MSCs) with the capacity for self-renewal and multilineage differentiation. In this study, periapical inflammatory cysts were compared with dental pulp to determine whether this tissue may be an alternative accessible tissue source of MSCs that retain the potential for neurogenic differentiation. Flow cytometry and immunofluorescence analysis indicated that hPCy-MSCs and dental pulp stem cells spontaneously expressed the neuron-specific protein β-III tubulin and the neural stem-/astrocyte-specific protein glial fibrillary acidic protein (GFAP) in their basal state before differentiation occurs. Furthermore, undifferentiated hPCy-MSCs showed a higher expression of transcripts for neuronal markers (β-III tubulin, NF-M, MAP2) and neural-related transcription factors (MSX-1, Foxa2, En-1) as compared with dental pulp stem cells. After exposure to neurogenic differentiation conditions (neural media containing epidermal growth factor [EGF], basic fibroblast growth factor [bFGF], and retinoic acid), the hPCy-MSCs showed enhanced expression of β-III tubulin and GFAP proteins, as well as increased expression of neurofilaments medium, neurofilaments heavy, and neuron-specific enolase at the transcript level. In addition, neurally differentiated hPCy-MSCs showed upregulated expression of the neural transcription factors Pitx3, Foxa2, Nurr1, and the dopamine-related genes tyrosine hydroxylase and dopamine transporter. The present study demonstrated for the first time that hPCy-MSCs have a predisposition toward the neural phenotype that is increased when exposed to neural differentiation cues, based on upregulation of a comprehensive set of proteins and genes that define neuronal cells. In conclusion, these results provide evidence that hPCy-MSCs might be another optimal source of neural/glial cells for cell-based therapies to treat neurologic diseases.

Havránek T, Bačová Z, Štrbák V, et al.
Prolactin increases expression of cytoskeletal proteins in SK-N-SH cells.
Folia Biol (Praha). 2014; 60(6):281-5 [PubMed] Related Publications
Although many studies have demonstrated the role of prolactin in the central nervous system, there is a considerable lack of known effects of prolactin on the parameters of neurogenesis and neuronal differentiation. The aim of the present study was to test whether prolactin changes gene expression and protein levels of nestin and microtubule-associated protein 2 (MAP2) in neuroblastoma (SK-N-SH) and glioblastoma (U-87MG) cells. Nestin and MAP2 represent cytoskeletal proteins associated with neuronal differentiation and they contribute to radial growth of the axons, dendrites and glial processes. SK-N-SH and U-87MG cells were exposed to prolactin (10 nM) for 48 h. Total mRNA was extracted. After reverse transcription, qPCR with specific primers for nestin and MAP2 was performed. The levels of proteins were measured by the In-Cell Western assay. Mitochondrial activity test was used to evaluate the viability of cells under the influence of prolactin. Incubation with 10 nM prolactin did not change the viability, either in SK-N-SH or in U-87MG cells. Prolactin significantly increased the gene expression and protein levels of both nestin and MAP2 in SK-N-SH cells, while no significant changes were observed in U-87MG cells. The presented data suggest that prolactin is linked to the regulation of cytoskeletal proteins in the neuronal type of cells and might be important for their differentiation.

Zogovic N, Tovilovic-Kovacevic G, Misirkic-Marjanovic M, et al.
Coordinated activation of AMP-activated protein kinase, extracellular signal-regulated kinase, and autophagy regulates phorbol myristate acetate-induced differentiation of SH-SY5Y neuroblastoma cells.
J Neurochem. 2015; 133(2):223-32 [PubMed] Related Publications
We explored the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), extracellular signal-regulated kinase (ERK), and autophagy in phorbol myristate acetate (PMA)-induced neuronal differentiation of SH-SY5Y human neuroblastoma cells. PMA-triggered expression of neuronal markers (dopamine transporter, microtubule-associated protein 2, β-tubulin) was associated with an autophagic response, measured by the conversion of microtubule-associated protein light chain 3 (LC3)-I to autophagosome-bound LC3-II, increase in autophagic flux, and expression of autophagy-related (Atg) proteins Atg7 and beclin-1. This coincided with the transient activation of AMPK and sustained activation of ERK. Pharmacological inhibition or RNA interference-mediated silencing of AMPK suppressed PMA-induced expression of neuronal markers, as well as ERK activation and autophagy. A selective pharmacological blockade of ERK prevented PMA-induced neuronal differentiation and autophagy induction without affecting AMPK phosphorylation. Conversely, the inhibition of autophagy downstream of AMPK/ERK, either by pharmacological agents or LC3 knockdown, promoted the expression of neuronal markers, thus indicating a role of autophagy in the suppression of PMA-induced differentiation of SH-SY5Y cells. Therefore, PMA-induced neuronal differentiation of SH-SY5Y cells depends on a complex interplay between AMPK, ERK, and autophagy, in which the stimulatory effects of AMPK/ERK signaling are counteracted by the coinciding autophagic response. Phorbol myristate acetate (PMA) induces the expression of dopamine transporter, microtubule-associated protein 2, and β-tubulin, and subsequent neuronal differentiation of SH-SY5Y neuroblastoma cells through AMP-activated protein kinase (AMPK)-dependent activation of extracellular signal-regulated kinase (ERK). The activation of AMPK/ERK axis also induces the expression of beclin-1 and Atg7, and increases LC3 conversion, thereby triggering the autophagic response that counteracts differentiation process.

Yan Y, Zhao J, Cao C, et al.
Tetramethylpyrazine promotes SH-SY5Y cell differentiation into neurons through epigenetic regulation of Topoisomerase IIβ.
Neuroscience. 2014; 278:179-93 [PubMed] Related Publications
Tetramethylpyrazine (TMP) is an active compound extracted from the traditional Chinese medicinal herb Chuanxiong. Recently, it has been reported that TMP enhances neurogenesis, and promotes neural stem cell differentiation toward neurons. However, its molecular basis remains unknown. Topoisomerase IIβ (TopoIIβ) is a nuclear enzyme with an essential role in neuronal development. This study aimed to investigate whether TopoIIβ is involved in TMP-induced neuronal differentiation. We examined the effect of TMP on neuronal differentiation of SH-SY5Y cells. It was found that TMP inhibited cell proliferation and induced G0/G1 cell cycle arrest. TMP promoted SH-SY5Y cells to differentiate toward post-mitotic neurons characterized by long, out-branched neurites and up-regulated neuronal markers, microtubule-associated protein 2 (MAP2) and tau. Meanwhile, we demonstrated that TopoIIβ was highly expressed following TMP treatment. To unravel how TMP affects TopoIIβ expression, two chromatin active markers, acetylated histone H3 (Ac-H3) and acetylated histone H4 (Ac-H4) were examined in this study. Our data showed that the levels of Ac-H3 and Ac-H4 were positively correlated with TopoIIβ expression in the processes of neuronal differentiation. We further performed chromatin immunoprecipitation (ChIP) analysis and identified that TMP enhanced the recruitment of Ac-H3 and Ac-H4 to the TopoIIβ gene promoter region. Therefore, we concluded that TMP may stimulate neuronal differentiation of SH-SY5Y cells through epigenetic regulation of TopoIIβ. These results suggest a novel molecular mechanism underlying TMP-promoted neuronal differentiation.

Guo H, Cao C, Chi X, et al.
Specificity protein 1 regulates topoisomerase IIβ expression in SH-SY5Y cells during neuronal differentiation.
J Neurosci Res. 2014; 92(10):1374-83 [PubMed] Related Publications
Topoisomerase IIβ (top IIβ) is a nuclear enzyme with an essential role in neural development. The regulation of top IIβ gene expression during neural differentiation is poorly understood. Functional analysis of top IIβ gene structure displayed a GC box sequence in its transcription promoter, which binds the nuclear transcription factor specificity protein 1 (Sp1). Sp1 regulates gene expression via multiple mechanisms and is essential for early embryonic development. This study seeks to determine whether Sp1 regulates top IIβ gene expression during neuronal differentiation. For this purpose, human neuroblastoma SH-SY5Y cells were induced to neuronal differentiation in the presence of all-trans retinoic acid (RA) for 5 days. After incubation with 10 μM RA for 3-5 days, a majority of the cells exited the cell cycle to become postmitotic neurons, characterized by the presence of longer neurite outgrowths and expression of the neuronal marker microtubule-associated protein-2 (MAP2). Elevated Sp1 and top IIβ mRNA and protein levels were detected and found to be positively correlated with the differentiation stage. Chromatin immunoprecipitation assay demonstrated an increased recruitment of Sp1 to the top IIβ promoter after RA treatment. Mithramycin A, a compound that interferes with Sp1 binding to GC-rich DNA sequences, downregulated the expression of top IIβ, resulting in reduced expression of MAP2 and decreased neurite length compared with the control group. Our results indicate that Sp1 regulates top IIβ expression by binding to the GC box of the gene promoter during neuronal differentiation in SH-SY5Y cells.

Ahn S, Kang SY, Suh YL
Supratentorial ependymoma with glial component of two different histologies and neuropil-like islands: a case report.
Clin Neuropathol. 2014 Mar-Apr; 33(2):128-34 [PubMed] Related Publications
Glioneuronal tumors with neuropil-like islands (GTNIs) are a basically infiltrating astrocytoma or mixed oligoastrocytoma, containing large neuropil-like islands (NIs). Recently, we experienced a peculiar case of supratentorial ependymoma with NIs. A 29-month-old girl presented with seizure and a brain magnetic resonance image revealed a huge heterogeneous mass in the left lateral ventricle. Histologically, glial components of the tumor showed two different histologies: anaplastic ependymoma and myxopapillary ependymomatous features. The latter was admixed with numerous NIs. Immunohistochemically, the glial components expressed GFAP and a paranuclear dot pattern of EMA and CD99, whereas the NIs were positive for synaptophysin and MAP2. KI-67 was high in the anaplastic ependymoma, but very low in the fascicles of spindle cells and NIs. Quantitative PCR confirmed mRNA expression of five genes related to neuronal differentiation in both the glial and neuronal components of this tumor. Our case suggests that ependymoma with NIs may be in a spectrum of GTNIs.

Luciani P, Deledda C, Benvenuti S, et al.
Exendin-4 induces cell adhesion and differentiation and counteracts the invasive potential of human neuroblastoma cells.
PLoS One. 2013; 8(8):e71716 [PubMed] Free Access to Full Article Related Publications
Exendin-4 is a molecule currently used, in its synthetic form exenatide, for the treatment of type 2 diabetes mellitus. Exendin-4 binds and activates the Glucagon-Like Peptide-1 Receptor (GLP-1R), thus inducing insulin release. More recently, additional biological properties have been associated to molecules that belong to the GLP-1 family. For instance, Peptide YY and Vasoactive Intestinal Peptide have been found to affect cell adhesion and migration and our previous data have shown a considerable actin cytoskeleton rearrangement after exendin-4 treatment. However, no data are currently available on the effects of exendin-4 on tumor cell motility. The aim of this study was to investigate the effects of this molecule on cell adhesion, differentiation and migration in two neuroblastoma cell lines, SH-SY5Y and SK-N-AS. We first demonstrated, by Extra Cellular Matrix cell adhesion arrays, that exendin-4 increased cell adhesion, in particular on a vitronectin substrate. Subsequently, we found that this molecule induced a more differentiated phenotype, as assessed by i) the evaluation of neurite-like protrusions in 3D cell cultures, ii) the analysis of the expression of neuronal markers and iii) electrophysiological studies. Furthermore, we demonstrated that exendin-4 reduced cell migration and counteracted anchorage-independent growth in neuroblastoma cells. Overall, these data indicate for the first time that exendin-4 may have anti-tumoral properties.

Bond WS, Akinfenwa PY, Perlaky L, et al.
Tumorspheres but not adherent cells derived from retinoblastoma tumors are of malignant origin.
PLoS One. 2013; 8(6):e63519 [PubMed] Free Access to Full Article Related Publications
Verification that cell lines used for cancer research are derived from malignant cells in primary tumors is imperative to avoid invalidation of study results. Retinoblastoma is a childhood ocular tumor that develops from loss of functional retinoblastoma protein (pRb) as a result of genetic or epigenetic changes that affect both alleles of the RB1 gene. These patients contain unique identifiable genetic signatures specifically present in malignant cells. Primary cultures derived from retinoblastoma tumors can be established as non-adherent tumorspheres when grown in defined media or as attached monolayers when grown in serum-containing media. While the RB1 genotypes of tumorspheres match those of the primary tumor, adherent cultures have the germline RB1 genotype. Tumorspheres derived from pRb-negative tumors do not express pRb and express the neuroendocrine tumor markers synaptophysin and microtubule-associated protein 2 (MAP2). Adherent cells are synaptophysin-negative and express pRb, the epithelial cell marker cytokeratin that is expressed in the retinal pigmented epithelium and the vascular endothelial cell marker CD34. While tumorspheres are of malignant origin, our results cast doubt on the assumption that adherent tumor-derived cultures are always valid in vitro models of malignant cells and emphasize the need for validation of primary tumor cultures.

Lo Furno D, Pellitteri R, Graziano AC, et al.
Differentiation of human adipose stem cells into neural phenotype by neuroblastoma- or olfactory ensheathing cells-conditioned medium.
J Cell Physiol. 2013; 228(11):2109-18 [PubMed] Related Publications
Olfactory ensheathing cells (OECs) are known to be capable of continuous neurogenesis throughout lifetime and are a source of multiple trophic factors important in central nervous system regeneration. B104 neuroblastoma cells are recognized to induce differentiation of neural stem cells into oligodendrocyte precursor cells. Therefore, the aim of this study was to verify if conditioned medium (CM) obtained from OECs or B104 cells was capable of inducing differentiation of adipose tissue-derived mesenchymal stem cells (AT-MSCs) to a neuronal phenotype. In order to this goal, immunocytochemical procedures and flow cytometry analysis were used and some neural markers, as nestin, protein gene product 9.5 (PGP 9.5), microtubule-associated protein 2 (MAP2), glial fibrillary acidic protein (GFAP), and neuron cell surface antigen (A2B5) were examined 24 h and 7 days after the treatment. The results showed that both OECs- or B104-CM treated AT-MSCs express markers of progenitor and mature neurons (nestin, PGP 9.5 and MAP2) in time-dependent manner, display morphological features resembling neuronal cells, and result negative for GFAP and A2B5, astrocyte and oligodendrocyte markers, respectively. This study demonstrated that AT-MSCs can be influenced by the environment, indicating that these cells can respond to environmental cues also versus a neuronal phenotype.

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