Research IndicatorsGraph generated 13 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (2)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: S100B (cancer-related)
Schwannomatosis, a rare form of neurofibromatosis, is characterized predominantly by multiple, often painful, schwannomas throughout the peripheral nervous system. The current standard of care for schwannomatosis is surgical resection. A major obstacle to schwannomatosis research is the lack of robust tumor cell lines. There is a great need for mechanistic and drug discovery studies of schwannomatosis, yet appropriate tools are not currently available. Schwannomatosis tumors are difficult to grow in culture as they survive only a few passages before senescence. Our lab has extensive experience in establishing primary and immortalized human Schwann cell cultures from normal tissue that retain their phenotypes after immortalization. Therefore we took on the challenge of creating immortalized human Schwann cell lines derived from tumors from schwannomatosis patients. We have established and fully characterized 2 schwannomatosis cell lines from 2 separate patients using SV40 virus large T antigen. One patient reported pain and the other did not. The schwannomatosis cell lines were stained with S100B antibodies to confirm Schwann cell identity. The schwannomatosis cells also expressed the Schwann cell markers, p75NTR, S100B, and NGF after multiple passages. Cell morphology was retained following multiple passaging and freeze/ thaw cycles. Gene expression microarray analysis was used to compare the cell lines with their respective parent tumors. No differences in key genes were detected, with the exception that several cell cycle regulators were upregulated in the schwannomatosis cell lines when compared to their parent tumors. This upregulation was apparently a product of cell culturing, as the schwannomatosis cells exhibited the same expression pattern of cell cycle regulatory genes as normal primary human Schwann cells. Cell growth was also similar between normal primary and immortalized tumor cells in culture. Accurate cell lines derived directly from human tumors will serve as invaluable tools for advancing schwannomatosis research, including drug screening.
The overall 5-year survival for melanoma is 91%. However, if distant metastasis occurs (stage IV), cure rates are < 15%. Hence, melanoma detection in earlier stages (stages I-III) maximises the chances of patient survival. We measured the expression of a panel of 17 microRNAs (miRNAs) (MELmiR-17) in melanoma tissues (stage III; n = 76 and IV; n = 10) and serum samples (collected from controls with no melanoma, n = 130; and patients with melanoma (stages I/II, n = 86; III, n = 50; and IV, n = 119)) obtained from biobanks in Australia and Germany. In melanoma tissues, members of the 'MELmiR-17' panel were found to be predictors of stage, recurrence, and survival. Additionally, in a minimally-invasive blood test, a seven-miRNA panel (MELmiR-7) detected the presence of melanoma (relative to controls) with high sensitivity (93%) and specificity (≥ 82%) when ≥ 4 miRNAs were expressed. Moreover, the 'MELmiR-7' panel characterised overall survival of melanoma patients better than both serum LDH and S100B (delta log likelihood = 11, p < 0.001). This panel was found to be superior to currently used serological markers for melanoma progression, recurrence, and survival; and would be ideally suited to monitor tumour progression in patients diagnosed with early metastatic disease (stages IIIa-c/IV M1a-b) to detect relapse following surgical or adjuvant treatment.
Kaehler KC, Politz O, Henderson D, et al.Novel DNA methylation markers with potential prognostic relevance in advanced malignant melanoma identified using COBRA assays.
Melanoma Res. 2015; 25(3):225-31 [PubMed
] Related Publications
Aberrant methylation of promoter regions involved in silencing of tumor suppressor genes is a key feature of many human cancers including melanoma. These DNA methylation events occur early in cancer development, increase with progression, and may therefore serve as biomarkers for the detection and staging of cancer. In our study, we used an epigenomic reactivation screening approach including Combined Bisulfite Restriction Analyses (COBRA) assays to identify novel methylation markers in late-stage melanoma. Two human xenograft melanoma models have been used to identify genes methylated in cancer and reactivated upon treatment with a histone deacetylase inhibitor. Gene expression analysis and promoter scanning for DNA methylation by COBRA assays and bisulfite sequencing were used to identify candidate genes. The methylation status of the CpG island promoter region of genes related to melanoma pathophysiology in skin, lymph node, and visceral metastatic metastases in 28 patients (samples n=35) were assessed. These methylation markers have been evaluated in melanoma metastasis tissue and in control samples from normal skin. The screening in in-vitro and in-vivo systems for methylated genes in melanoma samples showed 10 candidate genes. Using COBRA assays, we detected a methylation pattern in the promoter region of 10 genes with two genes (BASP1, CDH11), together with the patient's age and the log-S100B-level at biopsy, constructing a descriptor with a trend to correlate with shorter time to death.
Sun D, Li X, Ma M, et al.The predictive value and potential mechanisms of miRNA-328 and miRNA-378 for brain metastases in operable and advanced non-small-cell lung cancer.
Jpn J Clin Oncol. 2015; 45(5):464-73 [PubMed
] Related Publications
OBJECTIVE: The incidence of brain metastases greatly varies in patients with non-small-cell lung cancer, and molecular markers are considered to predict brain metastases. Therefore, this study sought to identify the predictive value and potential mechanisms of miRNA-328 and miRNA-378 for brain metastases in non-small-cell lung cancer.
METHODS: Patients who received a curable surgery for their lung cancer were screened according to our criteria. Formalin-fixed paraffin-embedded samples from the patients were examined for the expression of miRNA-328 and miRNA-378 using real-time polymerase chain reaction and the expression of N-cadherin, E-cadherin, vascular endothelial growth factor, protein kinase Cα and S100B were investigated using immunohistochemical staining.
RESULTS: In total, 86 patients were screened for this study and 23 patients were diagnosed with brain metastases during the follow-up period. Comparing patients with and without brain metastases, the expression of miRNA-328 and miRNA-378 in tumor tissues were significantly different (P = 6.2 × 10(-5) and P = 2.8 × 10(-5), respectively). For the patients with brain metastases, the expression of miRNA-328 and miRNA-378 in tumor tissues compared with para-carcinoma tissues were also significantly different (P = 2.2 × 10(-5) and P = 1.6 × 10(-5), respectively). For patients with brain metastases, the association between miRNA-328 and protein kinase Cα was significant (r = 0.591, P = 0.003), but that between miRNA-378 and protein kinase Cα was not significant (r = 0.259, P = 0.232).
CONCLUSIONS: The expression of miRNA-328 and miRNA-378 in tumor tissues can be used to predict brain metastases in patients with non-small-cell lung cancer. miRNA-328 might promote brain metastases by regulating the expression of protein kinase Cα. However, the mechanisms of miRNA-378 to promote brain metastases should be studied in the future.
In this study we describe the molecular and cellular characterization of a zebrafish mutant that develops tumors in the optic pathway. Heterozygous Tg(flk1:RFP)is18 transgenic adults develop tumors of the retina, optic nerve and optic tract. Molecular and genetic mapping demonstrate the tumor phenotype is linked to a high copy number transgene array integrated in the lincRNA gene lincRNAis18/Zv9_00007276 on chromosome 3. TALENs were used to isolate a 147 kb deletion allele that removes exons 2-5 of the lincRNAis18 gene. Deletion allele homozygotes are viable and do not develop tumors, indicating loss of function of the lincRNAis18 locus is not the trigger for tumor onset. Optic pathway tumors in the Tg(flk1:RFP)is18 mutant occur with a penetrance of 80-100% by 1 year of age. The retinal tumors are highly vascularized and composed of rosettes of various sizes embedded in a fibrous matrix. Immunohistochemical analysis showed increased expression of the glial markers GFAP and BLBP throughout retinal tumors and in dysplastic optic nerve. We performed transcriptome analysis of pre-tumorous retina and retinal tumor tissue and found changes in gene expression signatures of radial glia and astrocytes (slc1a3), activated glia (atf3, blbp, apoeb), proliferating neural progenitors (foxd3, nestin, cdh2, her9/hes1), and glioma markers (S100β, vim). The transcriptome also revealed activation of cAMP, Stat3 and Wnt signal transduction pathways. qRT-PCR confirmed >10-fold overexpression of the Wnt pathway components hbegfa, ascl1a, and insm1a. Together the data indicate Müller glia and/or astrocyte-derived progenitors could contribute to the zebrafish Tg(flk1:RFP)is18 optic pathway tumors.
Kolar K, Freitas-Andrade M, Bechberger JF, et al.Podoplanin: a marker for reactive gliosis in gliomas and brain injury.
J Neuropathol Exp Neurol. 2015; 74(1):64-74 [PubMed
] Related Publications
Reactive astrogliosis is associated with many pathologic processes in the central nervous system, including gliomas. The glycoprotein podoplanin (PDPN) is upregulated in malignant gliomas. Using a syngeneic intracranial glioma mouse model, we show that PDPN is highly expressed in a subset of glial fibrillary acidic protein-positive astrocytes within and adjacent to gliomas. The expression of PDPN in tumor-associated reactive astrocytes was confirmed by its colocalization with the astrocytic marker S100β and with connexin43, a major astrocytic gap junction protein. To determine whether the increase in PDPN is a general feature of gliosis, we used 2 mouse models in which astrogliosis was induced either by a needle injury or ischemia and observed similar upregulation of PDPN in reactive astrocytes in both models. Astrocytic PDPN was also found to be coexpressed with nestin, an intermediate filament marker for neural stem/progenitor cells. Our findings confirm that expression of PDPN is part of the normal host response to brain injury and gliomas, and suggest that it may be a novel cell surface marker for a specific population of reactive astrocytes in the vicinity of gliomas and nonneoplastic brain lesions. The findings also highlight the heterogeneity of glial fibrillary acidic protein-positive astrocytes in reactive gliosis.
Dubey M, Bugiani M, Ridder MC, et al.Mice with megalencephalic leukoencephalopathy with cysts: a developmental angle.
Ann Neurol. 2015; 77(1):114-31 [PubMed
] Related Publications
OBJECTIVE: Megalencephalic leukoencephalopathy with cysts (MLC) is a genetic disease characterized by infantile onset white matter edema and delayed onset neurological deterioration. Loss of MLC1 function causes MLC. MLC1 is involved in ion-water homeostasis, but its exact role is unknown. We generated Mlc1-null mice for further studies.
METHODS: We investigated which brain cell types express MLC1, compared developmental expression in mice and men, and studied the consequences of loss of MLC1 in Mlc1-null mice.
RESULTS: Like humans, mice expressed MLC1 only in astrocytes, especially those facing fluid-brain barriers. In mice, MLC1 expression increased until 3 weeks and then stabilized. In humans, MLC1 expression was highest in the first year, decreased, and stabilized from approximately 5 years. Mlc1-null mice had early onset megalencephaly and increased brain water content. From 3 weeks, abnormal astrocytes were present with swollen processes abutting fluid-brain barriers. From 3 months, widespread white matter vacuolization with intramyelinic edema developed. Mlc1-null astrocytes showed slowed regulatory volume decrease and reduced volume-regulated anion currents, which increased upon MLC1 re-expression. Mlc1-null astrocytes showed reduced expression of adhesion molecule GlialCAM and chloride channel ClC-2, but no substantial changes in other known MLC1-interacting proteins.
INTERPRETATION: Mlc1-null mice replicate early stages of the human disease with early onset intramyelinic edema. The cellular functional defects, described for human MLC, were confirmed. The earliest change was astrocytic swelling, substantiating that in MLC the primary defect is in volume regulation by astrocytes. MLC1 expression affects expression of GlialCAM and ClC-2. Abnormal interplay between these proteins is part of the pathomechanisms of MLC.
Elevated levels of the tumor marker S100B are observed in malignant melanoma, and this EF-hand-containing protein was shown to directly bind wild-type (wt) p53 in a Ca(2+)-dependent manner, dissociate the p53 tetramer, and inhibit its tumor suppression functions. Likewise, inhibiting S100B with small interfering RNA (siRNA(S100B)) is sufficient to restore wild-type p53 levels and its downstream gene products and induce the arrest of cell growth and UV-dependent apoptosis in malignant melanoma. Therefore, it is a goal to develop S100B inhibitors (SBiXs) that inhibit the S100B-p53 complex and restore active p53 in this deadly cancer. Using a structure-activity relationship by nuclear magnetic resonance approach (SAR by NMR), three persistent binding pockets are found on S100B, termed sites 1-3. While inhibitors that simultaneously bind sites 2 and 3 are in place, no molecules that simultaneously bind all three persistent sites are available. For this purpose, Cys84 was used in this study as a potential means to bridge sites 1 and 2 because it is located in a small crevice between these two deeper pockets on the protein. Using a fluorescence polarization competition assay, several Cys84-modified S100B complexes were identified and examined further. For five such SBiX-S100B complexes, crystallographic structures confirmed their covalent binding to Cys84 near site 2 and thus present straightforward chemical biology strategies for bridging sites 1 and 3. Importantly, one such compound, SC1982, showed an S100B-dependent death response in assays with WM115 malignant melanoma cells, so it will be particularly useful for the design of SBiX molecules with improved affinity and specificity.
Zhang Q, Zhu M, Cheng W, et al.Downregulation of 425G>a variant of calcium-binding protein S100A14 associated with poor differentiation and prognosis in gastric cancer.
J Cancer Res Clin Oncol. 2015; 141(4):691-703 [PubMed
] Related Publications
PURPOSE: Altered level of S100 calcium-binding proteins is involved in tumor development and progression. However, their role in gastric cancer (GC) is not well documented. We investigated the expression pattern of S100 proteins and differentiation or prognosis as well as possible mechanisms in GC.
METHODS: RT-PCR, Western blot analysis, and immunohistochemistry were used to determine the mRNA and protein expression of S100 family genes in GC. The polymorphisms of promoter and 5'-UTR of S100A14 gene were identified and related to luciferase reporter gene activity. Association of S100A14 expression with clinicopathologic features and survival in GC was analyzed.
RESULTS: We detected upregulated S100A2, S100A6, S100A10, and S100A11 expression and downregulated S100P and S100B expression in GC. Particularly, we detected differential mRNA and protein expression of S100A14 in GC cell lines and primary tumors. Furthermore, S100A14 expression change was related to a differentiated GC phenotype, with an expression in 31/40 (77.5 %) samples of well-differentiated tumors and 29/85 (34.1 %) samples of poorly differentiated tumors (P < 0.001). Moreover, 5-year survival was better in GC cases with positive than negative S100A14 level (P = 0.02). The genetic variant 425G>A on the 5'-UTR of S100A14 was associated with reduced S100A14 expression in GC cells.
CONCLUSION: Decreased expression of S100A14 with presence of its genetic variant 425G>A may be associated with an undifferentiated phenotype and poor prognosis in GC.
Qin B, Panickar KS, Anderson RACinnamon polyphenols attenuate the hydrogen peroxide-induced down regulation of S100β secretion by regulating sirtuin 1 in C6 rat glioma cells.
Life Sci. 2014; 102(1):72-9 [PubMed
] Related Publications
AIMS: It is well established that the brain is particularly susceptible to oxidative damage due to its high consumption of oxygen. The objective of this study was to investigate the protective effects of a water soluble polyphenol-rich extract of cinnamon and the possible mechanisms, under conditions of oxidative stress-induced by hydrogen peroxide, in rat C6 glioma cells.
MAIN METHODS: After 24h of H2O2 incubation, the secretion and intracellular expression of S100β were determined by immunoprecitation/immunoblotting and immunofluorescence imaging.
KEY FINDINGS: Cinnamon polyphenols (CP) counteracted the oxidative effects of H2O2 on S100β secretion and expression. CP also enhanced the impaired protein levels of sirtuins 1, 2, and 3, which are deacetylases important in cell survival. H2O2 also induced the overexpression of the proinflammatory factors, TNF-α, phospho-NF-κB p65, as well as of Bcl-xl, Bax and Caspase-3, which are all the members of the Bcl-2 family. CP not only suppressed the expression of these proteins but also attenuated the phosphorylation induced by H2O2. CP also upregulated the decreased Bcl-2 protein levels in H2O2 treated C6 cells. The effects of CP on H2O2-induced downregulation of S100β secretion were blocked by SIRT1 siRNA demonstrating that SIRT1 plays a regulatory role in CP-mediated prevention by H2O2.
SIGNIFICANCE: These data demonstrate that Cinnamon polyphenols may exert neuroprotective effects in glial cells by the regulation of Bcl-2 family members and enhancing SIRT1 expression during oxidative stress.
Meghnani V, Vetter SW, Leclerc ERAGE overexpression confers a metastatic phenotype to the WM115 human primary melanoma cell line.
Biochim Biophys Acta. 2014; 1842(7):1017-27 [PubMed
] Related Publications
The formation of melanoma metastases from primary tumor cells is a complex phenomenon that involves the regulation of multiple genes. We have previously shown that the receptor for advanced glycation end products (RAGE) was up-regulated in late metastatic stages of melanoma patient samples and we hypothesized that up-regulation of RAGE in cells forming a primary melanoma tumor could contribute to the metastatic switch of these cells. To test our hypothesis, we overexpressed RAGE in the WM115 human melanoma cell line that was established from a primary melanoma tumor of a patient. We show here that overexpression of RAGE in these cells is associated with mesenchymal-like morphologies of the cells. These cells demonstrate higher migration abilities and reduced proliferation properties, suggesting that the cells have switched to a metastatic phenotype. At the molecular level, we show that RAGE overexpression is associated with the up-regulation of the RAGE ligand S100B and the down-regulation of p53, ERK1/2, cyclin E and NF-kB. Our study supports a role of RAGE in the metastatic switch of melanoma cells.
Welinder C, Jönsson G, Ingvar C, et al.Feasibility study on measuring selected proteins in malignant melanoma tissue by SRM quantification.
J Proteome Res. 2014; 13(3):1315-26 [PubMed
] Related Publications
Currently there are no clinically recognized molecular biomarkers for malignant melanoma (MM) for either diagnosing disease stage or measuring response to therapy. The aim of this feasibility study was to develop targeted selected reaction monitoring (SRM) assays for identifying candidate protein biomarkers in metastatic melanoma tissue lysate. In a pilot study applying the SRM assay, the tissue expression of nine selected proteins [complement 3 (C3), T-cell surface glycoprotein CD3 epsilon chain E (CD3E), dermatopontin, minichromosome maintenance complex component (MCM4), premelanosome protein (PMEL), S100 calcium binding protein A8 (S100A8), S100 calcium binding protein A13 (S100A13), transgelin-2 and S100B] was quantified in a small cohort of metastatic malignant melanoma patients. The SRM assay was developed using a TSQ Vantage triple quadrupole mass spectrometer that generated highly accurate peptide quantification. Repeated injection of internal standards spiked into matrix showed relative standard deviation (RSD) from 6% to 15%. All nine target proteins were identified in tumor lysate digests spiked with heavy peptide standards. The multiplex SRM peptide assay panel was then measured and quantified on a set of frozen MM tissue samples obtained from the Malignant Melanoma Biobank collected in Lund, Sweden. All nine proteins could be accurately quantified using the new SRM assay format. This study provides preliminary data on the heterogeneity of biomarker expression within MM patients. The S100B protein, which is clinically used as the pathology identifier of MM, was identified in 9 out of 10 MM tissue lysates. The use of the targeted SRM assay provides potential advancements in the diagnosis of MM that can aid in future assessments of disease in melanoma patients.
The Notch pathway is a highly conserved signaling system essential for modulating neurogenesis and promoting astrogenesis. Similarly, the cAMP signaling cascade can promote astrocytic commitment in several cell culture models, such as the C6 glioma cell line. These cells have the capacity to differentiate into oligodendrocytes or astrocytes, characteristics that allow their use as a glial progenitor model. In this context, we explore here the plausible involvement of cAMP in Notch-dependent signal transactions. The exposure of C6 cells to a non-hydrolysable cAMP analogue resulted in a sustained augmentation of Notch activity, as detected by nuclear translocation of its intracellular domain portion (NICD) and transcriptional activity. The cAMP effect is mediated through the activation of the γ-secretase complex, responsible for Notch cleavage and is sensitive to inhibitors of the cAMP-dependent protein kinase, PKA. As expected, Notch cleavage and nuclear translocation resulted in the up-regulation of the mRNA levels of one of its target genes, the transcription factor Hair and enhancer of split 5. Moreover, the glutamate uptake activity, as well as the expression of astrocytic markers such as glial fibrillary acidic protein, S100β protein and GLAST was also enhanced in cAMP-exposed cells. Our results clearly suggest that during the process of C6 astrocytic differentiation, cAMP activates the PKA/γ-secretase/NICD/RBPJ(κ) pathway and Notch1 expression, leading to transcriptional activation of the genes responsible for glial progenitor cell fate decision.
Ducourneau VR, Dolique T, Hachem-Delaunay S, et al.Cancer pain is not necessarily correlated with spinal overexpression of reactive glia markers.
Pain. 2014; 155(2):275-91 [PubMed
] Related Publications
Bone cancer pain is a common and disruptive symptom in cancer patients. In cancer pain animal models, massive reactive astrogliosis in the dorsal horn of the spinal cord has been reported. Because astrocytes may behave as driving partners for pathological pain, we investigated the temporal development of pain behavior and reactive astrogliosis in a rat bone cancer pain model induced by injecting MRMT-1 rat mammary gland carcinoma cells into the tibia. Along with the development of bone lesions, a gradual mechanical and thermal allodynia and hyperalgesia as well as a reduced use of the affected limb developed in bone cancer-bearing animals, but not in sham-treated animals. Dorsal horn Fos expression after nonpainful palpation of the injected limb was also increased in bone cancer-bearing animals. However, at any time during the evolution of tumor, there was no increase in glial fibrillary acidic protein (GFAP) immunoreactivity in the dorsal horn. Further analysis at 21days after injection of the tumor showed no increase in GFAP and interleukin (IL) 1β transcripts, number of superficial dorsal horn S100β protein immunoreactive astrocytes, or immunoreactivity for microglial markers (OX-42 and Iba-1). In contrast, all these parameters were increased in the dorsal horn of rats 2weeks after sciatic nerve ligation. This suggests that in some cases, bone cancer pain may not be correlated with spinal overexpression of reactive glia markers, whereas neuropathic pain is. Glia may thus play different roles in the development and maintenance of chronic pain in these 2 situations.
Malignant melanoma continues to be an extremely fatal cancer due to a lack of viable treatment options for patients. The calcium-binding protein S100B has long been used as a clinical biomarker, aiding in malignant melanoma staging and patient prognosis. However, the discovery of p53 as a S100B target and the consequent impact on cell apoptosis redirected research efforts towards the development of inhibitors of this S100B-p53 interaction. Several approaches, including computer-aided drug design, fluorescence polarization competition assays, NMR, x-ray crystallography and cell-based screens have been performed to identify compounds that block the S100B-p53 association, reactivate p53 transcriptional activities and induce cancer cell death. Eight promising compounds, including pentamidine, are presented in this review and the potential for future modifications is discussed. Synthesis of compound derivatives will likely exhibit increased S100B affinity and mimic important S100B-target dynamic properties that will result in high specificity.
Miki Y, Gion Y, Mukae Y, et al.Morphologic, flow cytometric, functional, and molecular analyses of S100B positive lymphocytes, unique cytotoxic lymphocytes containing S100B protein.
Eur J Haematol. 2013; 90(2):99-110 [PubMed
] Related Publications
Little is known about the S100B⁺ lymphocytes, which are unique human peripheral blood lymphocytes (PBL) containing the S100B protein. It has recently been shown that S100B is released from various types of S100B⁺ cells and exhibits varied cytokine-like activities. In this study, we precisely characterized the S100B⁺ lymphocytes of healthy adults with respect to the proportion in the whole PBL, immunophenotypes, function, and their S100B mRNA expression and also evaluated their S100B-releasing activity upon stimulation. S100B⁺ lymphocytes were detected in all individuals examined, and the proportion of S100B⁺ lymphocytes in the whole PBL ranged from 0.42% to 16.15% (mean, 4.21%). In addition, two subtypes of S100B ⁺ lymphocytes, a CTL subtype (CD3⁺ CD8⁺ CD16⁻) and a NK subtype (CD3⁻ CD3⁻ CD16⁺), were detected. The majority of the CTL subtype of S100B⁺ lymphocytes expressed the αβ-T-cell receptor. Surprisingly, S100B mRNA was detected not only in S100B⁺ lymphocytes, but also in every S100B⁺ lymphocytes, although the expression levels of S100B mRNA in S100B⁻ lymphocytes were much lower than those of S100B⁺ lymphocytes. The CTL subtype of S100B⁺ lymphocytes exhibited blastic morphological changes, proliferated and released S100B upon stimulation with phytohemagglutinin. The NK subtype of S100B⁺ lymphocytes exhibited morphological NK activity when cocultivated with NK-sensitive target, K-562 cells. Thus, the CTL subtype of S100B⁺ lymphocytes exhibit the biological characteristics of T cells, while the NK subtype of S100B⁺ lymphocytes exhibit the characteristics of NK cells. These results suggest that S100B⁺ lymphocytes are a particular subtype of cytotoxic lymphocytes that play a unique role in antitumor immunity.
Krenacs T, Kiszner G, Stelkovics E, et al.Collagen XVII is expressed in malignant but not in benign melanocytic tumors and it can mediate antibody induced melanoma apoptosis.
Histochem Cell Biol. 2012; 138(4):653-67 [PubMed
] Related Publications
The 180 kDa transmembrane collagen XVII is known to anchor undifferentiated keratinocytes to the basement membrane in hemidesmosomes while constitutively shedding a 120 kDa ectodomain. Inherited mutations or auto-antibodies targeting collagen XVII cause blistering skin disease. Collagen XVII is down-regulated in mature keratinocytes but re-expressed in skin cancer. By recently detecting collagen XVII in melanocyte hyperplasia, here we tested its expression in benign and malignant melanocytic tumors using endodomain and ectodomain selective antibodies. We found the full-length collagen XVII protein in proliferating tissue melanocytes, basal keratinocytes and squamous cell carcinoma whereas resting melanocytes were negative. Furthermore, the cell-residual 60 kDa endodomain was exclusively detected in 62/79 primary and 15/18 metastatic melanomas, 8/9 melanoma cell lines, HT199 metastatic melanoma xenografts and atypical nests in 8/63 dysplastic nevi. The rest of 19 nevi including common, blue and Spitz subtypes were also negative. In line with the defective ectodomain, sequencing of COL17A1 gene revealed aberrations in the ectodomain coding region including point mutations. Collagen XVII immunoreaction-stained spindle cell melanomas, showed partly overlapping profiles with those of S100B, Melan A and HMB45. It was concentrated at vertical melanoma fronts and statistically associated with invasive phenotype. Antibody targeting the extracellular aa507-529 terminus of collagen XVII endodomain promoted apoptosis and cell adhesion, while inhibiting proliferation in HT199 cells. These results suggest that the accumulation of collagen XVII endodomain in melanocytic tumors is associated with malignant transformation to be a potential marker of malignancy and a target for antibody-induced melanoma apoptosis.
Karamchandani JR, Nielsen TO, van de Rijn M, West RBSox10 and S100 in the diagnosis of soft-tissue neoplasms.
Appl Immunohistochem Mol Morphol. 2012; 20(5):445-50 [PubMed
] Related Publications
Despite a well-characterized lack of specificity, pathologists routinely employ S100 in the diagnosis of neural crest-derived tumors. Recent studies have shown that Sox10 is a reliable marker of neural crest differentiation that is consistently expressed in schwannian and melanocytic tumors. We sought to validate these results in a larger series of soft tissue neoplasms of both neural crest and non-neural crest origin, and to further characterize the sensitivity and specificity of Sox10 for use in clinical diagnosis. We evaluated Sox10 and S100 mRNA levels in 122 cases of peripheral nerve sheath tumors and synovial sarcoma and used immunohistochemistry for Sox10 and S100 protein expression in 1012 tissue specimens. This study includes 174 tissue microarray cases previously reported by Nonaka and colleagues, which include cases of melanoma, dermatofibrosarcoma protuberans, neurofibroma, synovial sarcoma, clear-cell sarcoma, malignant peripheral nerve sheath tumor (MPNST), perineurioma, and schwannoma. Synovial sarcomas expressed significantly higher levels of S100B than Sox10 (P=7.9×10), and no significant Sox10 mRNA expression was identified in synovial sarcoma (n=40), whereas 18/40 cases showed comparatively increased levels of S100 mRNA. The majority of schwannomas (n=26) and neurofibromas (n=28) showed relatively an increased expression of both Sox10 and S100 mRNA. MPNSTs (n=28) showed variable levels of Sox10 and S100 mRNA expression, and these expression levels were highly correlated (Pearson correlation coefficient r=0.79). In contrast, immunohistochemistry performed on a larger and more varied number of cases highlighted significant differences between the 2 proteins. We identified 5 non-neural, nonmelanocytic sarcoma types in which a subset of cases showed S100 protein expression: synovial sarcoma (12/79, 15%), Ewing sarcoma (3/14, 21%), rhabdomyosarcoma (4/17, 24%), chondrosarcoma (3/4, 75%), and extraskeletal myxoid chondrosarcoma (5/11, 45%). For each of these entities, we identified cases with strong and diffuse S100 staining. Of these cases, only 1 case of rhabdomyosarcoma showed focal Sox10 positivity. In 78 cases of MPNST, S100 increased the sensitivity (31/78, 40%) as compared with Sox10 (21/78, 27%), but the majority of these cases were negative for both Sox10 and S100 (44/78, 56%). Sox10 proved superior to S100 in the detection of desmoplastic melanoma (7/9, 78%) and clear-cell sarcoma (4/7, 57%). We also report for the first time Sox10 expression in 26 cases of granular cell tumor, further supporting the neural crest derivation of this tumor. Excluding MPNST, S100 and Sox10 showed similar sensitivity in tumors of neural crest origin (140/148, 95% and 137/148, 93%, respectively). In summary, Sox10 shows an increased specificity for tumors of neural crest origin compared with S100: Sox10 was positive in only 5 of 668 cases (99% specificity) in nonschwannian, nonmelanocytic tumors, whereas S100 was positive in 53 of 668 cases (91% specificity). Sox10 should be used in the place of or along with S100 in soft tissue tumor diagnosis.
Invasive aspergillosis (IA) is a major threat to the successful outcome of hematopoietic stem cell transplantation (HSCT), although individual risk varies considerably. Recent evidence has established a pivotal role for a danger sensing mechanism implicating the S100B/receptor for advanced glycation end products (RAGE) axis in antifungal immunity. The association of selected genetic variants in the S100B/RAGE axis with susceptibility to IA was investigated in 223 consecutive patients undergoing HSCT. Furthermore, studies addressing the functional consequences of these variants were performed. Susceptibility to IA was significantly associated with two distinct polymorphisms in RAGE (-374T/A) and S100B (+427C/T) genes, the relative contribution of each depended on their presence in both transplantation counterparts [patient SNP(RAGE), adjusted hazard ratio (HR), 1.97; P = 0.042 and donor SNP(RAGE), HR, 2.03; P = 0.047] or in donors (SNP(S100B), HR, 3.15; P = 7.8e-(4)) only, respectively. Functional assays demonstrated a gain-of-function phenotype of both variants, as shown by the enhanced expression of inflammatory cytokines in RAGE polymorphic cells and increased S100B secretion in vitro and in vivo in the presence of the S100B polymorphism. These findings point to a relevant role of the danger sensing signaling in human antifungal immunity and highlight a possible contribution of a genetically-determined hyperfunction of the S100B/RAGE axis to susceptibility to IA in the HSCT setting.
Huang MY, Wang HM, Tok TS, et al.EVI2B, ATP2A2, S100B, TM4SF3, and OLFM4 as potential prognostic markers for postoperative Taiwanese colorectal cancer patients.
DNA Cell Biol. 2012; 31(4):625-35 [PubMed
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Undetected micrometastasis may play a key role in the early relapse of colorectal cancer (CRC) patients. The aim of this study was to detect circulating tumor cells (CTCs) for predicting early relapse of CRC patients by a weighted enzymatic chip array (WEnCA) and analyze 15 candidate genes associated with CRC carcinogenesis. The genes of 105 postoperative CRC patients were analyzed by membrane array and direct sequencing. We constructed a WEnCA platform including five prognosis-related genes and analyzed the detection rate of WEnCA for CTCs in 30 clinically confirmed CRC relapse patients. Postoperative relapse was significantly correlated with gene overexpression, including EVI2B (p=0.001, OR=4.622), ATP2A2 (p=0.006, OR=4.688), S100B (p=0.001, OR=11.521), TM4SF3 (p=0.001, OR=6.756), and OLFM4 (p=0.008, OR=3.545). Using WEnCA (weighting score of each gene: 5 to EVI2B, 5 to ATP2A2, 12 to S100B, 7 to TM4SF3, and 4 to OLFM4), we could detect CTCs presenting these genotypes in relapsed CRC patients. The sensitivity, specificity, and accuracy were 94.7%, 93.5%, and 97%, respectively. The results of the present study suggest that EVI2B, ATP2A2, S100B, TM4SF3, and OLFM4 could be potential prognostic markers for CRC patients.
Distant metastasis of colorectal cancer (CRC) occurs mainly in the liver and is the major cause of death. This study explored the overexpression of liver metastasis-associated mRNAs in human CRC by using a well-established, weighted enzymatic chip array platform. Analysis of 10 CRC tissue specimens compared with their normal adjacent tissues revealed that ATP2A2, ELAVL4, hTERT, KCTD2, MUC1, OLFM4, S100B, and TM4SF4 genes were upregulated (gene expression ratio of cancer tissue to paired normal tissue was >2) by microarray and bioinformatics analysis. A gene chip including eight candidate genes was constructed to investigate the circulating tumor cells in blood specimens of 103 preoperative CRC patients and further validated by reverse transcriptase-polymerase chain reaction. Liver metastasis was significantly correlated with overexpression of S100B (p=0.001, OR=9.217), TM4SF3 (p=0.011, OR=4.385), and OLFM4 (p=0.015, OR=3.438). These results suggest that S100B, TM4SF3, and OLFM4 overexpression may affect metastatic behavior of tumor cells in Taiwanese CRC patients.
Jiang W, Jia Q, Liu L, et al.S100B promotes the proliferation, migration and invasion of specific brain metastatic lung adenocarcinoma cell line.
Cell Biochem Funct. 2011; 29(7):582-8 [PubMed
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Brain metastasis frequently occurs in cancer patients and is associated with a poor prognosis. We previously reported that S100B was highly expressed in PC14/B, a specific brain metastatic lung adenocarcinoma cell line, which suggests that it is associated with brain metastasis of lung cancer. However, the role of S100B in brain metastasis remains to be elucidated. In this study, using PC14/B cell line, we found that siRNA mediated depletion of S100B in PC14/B cells led to notable differences in cell proliferation, apoptosis, cell cycle progression, colony formation ability, cell migratory and invasive activity compared with the mock-transfected cells. Therefore, our data suggest that S100B promotes the brain metastasis of lung adenocarcinoma by promoting cell proliferation, preventing apoptosis and increasing cell migration and invasion.
Dagdan E, Morris DW, Campbell M, et al.Functional assessment of a promoter polymorphism in S100B, a putative risk variant for bipolar disorder.
Am J Med Genet B Neuropsychiatr Genet. 2011; 156B(6):691-9 [PubMed
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Calcium-binding protein S100B has been implicated in the pathology of bipolar affective disorder (BPAD) and schizophrenia (SZ). S100B protein levels are elevated in serum of patients with both disorders compared to controls. We previously reported genetic association of a SNP in the promoter of S100B, rs3788266, with a psychotic form of BPAD. To test for genotypic effects of rs3788266 in vivo, S100B serum protein levels were measured in 350 Irish and German subjects of known S100B genotype. The functional effect of rs3788266 on S100B promoter activity was studied using the luciferase reporter system in U373MG glioblastoma and SH-SY5Y neuroblastoma cell lines. Allelic effects of rs3788266 on protein complex formation at the S100B promoter were investigated by an electrophoretic mobility shift assay. Higher mean serum S100B levels were associated with the risk G allele of rs3788266 in BPAD cases (P = 0.0001), unaffected relatives of BPAD cases (P < 0.0001) and unrelated controls (P < 0.0001). Consistent with the in vivo findings, luciferase gene expression was significantly increased in the presence of the G allele compared to the A allele in SH-SY5Y (P = <0.0001), and in U373MG (P = <0.0008) cell lines. The binding affinity of both SH-SY5Y and U373MG protein complexes for the S100B promoter was significantly stronger in the presence of G allele compared to the A allele promoter fragments. These data support rs3788266 as a functional promoter variant in the S100B gene where the presence of the G allele promotes increased gene expression and is associated with increased serum levels of the protein.
Tucker T, Riccardi VM, Brown C, et al.S100B and neurofibromin immunostaining and X-inactivation patterns of laser-microdissected cells indicate a multicellular origin of some NF1-associated neurofibromas.
J Neurosci Res. 2011; 89(9):1451-60 [PubMed
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Neurofibromatosis 1 (NF1) is an autosomal dominant disease that predisposes individuals to developing benign neurofibromas. Some features and consequences of NF1 appear to result from partial deficiency of neurofibromin (Nfn), the NF1 gene protein product, as a result of haploinsufficiency for the NF1 gene. Other features and consequences of NF1 appear to involve total deficiency of Nfn, which arises as a result of either loss of function of the second NF1 allele or excess degradation of Nfn produced by the second allele in a particular clone of cells. We used immunofluorescence to assess the presence of Nfn in putative Schwann cells (S100B(+) ) and non-Schwann cells (S100B(-) ) in 36 NF1-derived benign neurofibromas classified histologically as diffuse or encapsulated. The S100B(+) /Nfn(-) cell population made up only 18% ± 10% (mean ± standard deviation) of the neurofibroma cells in both the diffuse and encapsulated neurofibromas. The proportion of S100B(+) /Nfn(+) cells was significantly higher and the proportion of S100B(-) /Nfn(-) cells was significantly lower in diffuse neurofibromas than in encapsulated neurofibromas. We isolated S100B(+) /Nfn(+) , S100B(+) /Nfn(-) , and S100B(-) /Nfn(+) cells by laser microdissection and, using X-chromosome inactivation profiles, assessed clonality for each cell type. We showed that, although some neurofibromas include a subpopulation of S100B(+) /Nfn(-) cells consistent with clonal expansion of a Schwann cell progenitor that has lost function of both NF1 alleles, other neurofibromas do not show evidence of monoclonal proliferation of Schwann cells. Our findings suggest that, although clonal loss of neurofibromin function is probably involved in the development of some NF1-associated neurofibromas, other pathogenic processes also occur.
Orgaz JL, Benguria A, Sanchez-Martinez C, et al.Changes in the gene expression profile of A375 human melanoma cells induced by overexpression of multifunctional pigment epithelium-derived factor.
Melanoma Res. 2011; 21(4):285-97 [PubMed
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Pigment epithelium-derived factor (PEDF) is a broad-spectrum angiogenesis inhibitor that displays potent antimetastatic activity in multiple tumor types. We have previously shown that PEDF prevents primary tumor growth and metastatic spread of human melanoma in mouse experimental models. Consistent with these observations, PEDF expression is lost at the late stages of melanoma progression, allowing melanoma cells to become angiogenic, migratory, and invasive. PEDF's ability to modify the interplay between the host and tumor tissues strongly supports its use as a therapeutic agent for the treatment of metastatic melanoma. However, transition to the clinic requires a more detailed knowledge of the molecular mechanisms underpinning PEDF's activity. In this study, we describe changes in the gene expression profile of A375 human melanoma cells induced by PEDF overexpression. PEDF modulated diverse categories of genes known to be involved in angiogenesis and migration. It downregulated cytokines such as interleukin-8 and extracellular matrix proteins such as collagen IV, while it upregulated fibronectin. Multiple transcripts previously described as contributing to the acquisition of malignant phenotype by melanoma were also diminished by PEDF overexpression, among which we validated galectin 3 and jagged 1. In addition, PEDF downregulated S100β and melanoma inhibitory activity, which are widely used in the pathological diagnosis of melanoma. Interestingly, PEDF increased the expression of melanophilin and decreased rab27A, which are relevant targets for melanosome transport; suggesting that PEDF could directly impinge on melanocytic lineage-specific processes. Our study identifies new molecular targets and signaling pathways that may potentially contribute to determine PEDF's ability to restrict the aggressiveness of A375 human melanoma cells.
BACKGROUND: Cutaneous melanoma is an aggressive disease. S100beta is an established biomarker of disease progression; however, the mechanism of its regulation in melanoma is undefined.
METHODS: Expression of HOXC11 and SRC-1 was examined by immunohistochemistry and immunofluorescence. Molecular and cellular techniques were used to investigate regulation of S100beta, including, western blot, qPCR, ChIP and migration assays.
RESULTS: Expression levels of the transcription factor HOXC11 and its coactivator SRC-1 were significantly elevated in malignant melanoma in comparison with benign nevi (P<0.001 and P=0.017, respectively, n=80), and expression of HOXC11 and SRC-1 in the malignant tissue associated with each other (P<0.001). HOXC11 recruitment to the promoter of S100beta was observed in the primary melanoma cell line SKMel28. S100beta expression was found to be dependant on both HOXC11 and SRC-1. Treatment with the Src/Abl inhibitor, dasatinib, reduced HOXC11-SRC-1 interaction and prevented recruitment of HOXC11 to the S100beta promoter. Dasatinib inhibited both mRNA and protein levels of S100beta and reduced migration of the metastatic cell line MeWo.
CONCLUSION: We have defined a signalling mechanism regulating S100beta in melanoma, which can be modulated by dasatinib. Profiling patients for expression of key markers of this network has the potential to increase the efficacy of dasatinib treatment.
Plexiform neurofibromas are peripheral nerve sheath tumors initiated by biallelic mutation of the NF1 tumor suppressor gene in the Schwann cell lineage. To understand whether neurofibroma formation is possible after birth, we induced Nf1 loss of function with an inducible proteolipid protein Cre allele. Perinatal loss of Nf1 resulted in the development of small plexiform neurofibromas late in life, whereas loss in adulthood caused large plexiform neurofibromas and morbidity beginning 4 months after onset of Nf1 loss. A conditional EGFP reporter allele identified cells showing recombination, including peripheral ganglia satellite cells, peripheral nerve S100β+ myelinating Schwann cells, and peripheral nerve p75+ cells. Neurofibromas contained cells with Remak bundle disruption but no recombination within GFAP+ nonmyelinating Schwann cells. Extramedullary lympho-hematopoietic expansion was also observed in PlpCre;Nf1fl/fl mice. These tumors contained EGFP+/Sca-1+ stromal cells among EGFP-negative lympho-hematopoietic cells indicating a noncell autonomous effect and unveiling a role of Nf1-deleted microenvironment on lympho-hematopoietic proliferation in vivo. Together these findings define a tumor suppressor role for Nf1 in the adult and narrow the range of potential neurofibroma-initiating cell populations.
PURPOSE: With the rising incidence of melanoma, more patients are undergoing surveillance for disease recurrence. Our purpose was to study levels of proteins that might be secreted in the blood of patients with metastatic melanoma that can be used for monitoring these individuals.
METHODS: Genome-wide gene expression data were used to identify abundantly expressed genes in melanoma cells that encode for proteins likely to be present in the blood of cancer patients, based on high expression levels in tumors. ELISA assays were employed to measure proteins in plasma of 216 individuals; 108 metastatic melanoma patients and 108 age- and gender-matched patients with resected stage I/II disease split into equal-sized training and test cohorts.
RESULTS: Levels of seven markers, CEACAM (carcinoembryonic antigen-related cell adhesion molecule), ICAM-1 (intercellular adhesion molecule 1), osteopontin, MIA (melanoma inhibitory activity), GDF-15 (growth differentiation factor 15), TIMP-1 (tissue inhibitor of metalloproteinase 1), and S100B, were higher in patients with unresected stage IV disease than in patients with resected stage I/II disease. About 81% of the stage I/II patients in the training set had no marker elevation, whereas 69% of the stage IV patients had elevation of at least one marker (P < 0.0001). Receiver operating characteristic curves for the markers in combination in these two patient populations had an area under curve (AUC) of 0.79 in the training set and 0.8 in the test set. A CART (Classification and Regression Trees) model developed in the training set further improved the AUC in the test set to 0.898.
CONCLUSIONS: Plasma markers, particularly when assessed in combination, can be used to monitor patients for disease recurrence and can compliment currently used lactate dehydrogenase and imaging studies; prospective validation is warranted.
Aizawa T, Hasegawa K, Ohkumo T, et al.Neural stem cell-like gene expression in a mouse ependymoma cell line transformed by human BK polyomavirus.
Cancer Sci. 2011; 102(1):122-9 [PubMed
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Ependymomas often show characteristics similar to those of neural stem cells in vivo and in vitro. However, few ependymoma cell lines that exhibit neural stem cell-like properties have been reported. In this study, we have characterized a novel cell line, designated Vn19, established from ependymoma that arose in mice inoculated intracerebrally with human BK polyomavirus. Transplanted Vn19 cells in nude mice ubiquitously expressed viral large T antigen in the nucleus and coexpressed neuronal and glial marker proteins in vivo. Remarkably, individual Vn19 cells in dispersed cultures simultaneously expressed marker proteins of neural stem cells (nestin, Bmi1, CD133), neurons (βIII tubulin, neurofilament-M) and glial cells (glial fibrillary acidic protein, A2B5, S100β, O4). Ubiquitous and homogenous expression of these multilineage marker proteins was also observed in cloned Vn19 cells. The Vn19 cells formed neurosphere-like aggregates when cultured in the presence of growth factors. Quantitative RT-PCR analysis revealed that expression of mRNA for nestin, neurofilament-H and glial fibrillary acidic protein significantly increased in Vn19 cells cultured under growth factor-deprived conditions. Among MAGE (melanoma antigen) family genes, MAGE-A (A1-8), MAGE-B (B1-3), MAGE-D1, MAGE-E1, MAGE-G1 (necdin-like 2) and MAGE-H1 were expressed in the Vn19 cells, in which neither necdin nor MAGEL2 was detectable. These results suggest that this murine ependymoma cell line recapitulates the gene expression profile in ependymal cells undergoing malignant transformation.
Bernardini C, Lattanzi W, Businaro R, et al.Transcritpional effects of S100B on neuroblastoma cells: perturbation of cholesterol homeostasis and interference on the cell cycle.
Gene Expr. 2010; 14(6):345-59 [PubMed
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S100B is a Ca2+ binding protein mainly secreted by astrocytes in the vertebrate brain that is considered a multifunctional cytokine and/or a damage-associated molecular pattern (DAMP) protein and a marker of brain injury and neurodegeneration when measured in different body fluids. It has been widely shown that this protein can exert diverse effects in neural cultures depending on its concentration, having detrimental effects at micromolar concentrations. The molecular mechanisms underlying this effect are still largely unknown. This study attempts to delineate the genome-wide gene expression analysis of the events associated with exposure to micromolar concentration of S100B in a human neuroblastoma cell line. In this experimental condition cells undergo a severe perturbation of lipid homeostasis along with cell cycle arrest. These mechanisms might reasonably mediate some aspects of the S100B-related detrimental effects of S100B, although obvious differences between mature neurons and neuroblastoma cells have to be considered.