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C Herold-Mende

Publications and source records attributed to C Herold-Mende.

At least 19 recordsLinked to original sources
PubMed2005

Human multidrug resistance protein 8 (MRP8/ABCC11), an apical efflux pump for steroid sulfates, is an axonal protein of the CNS and peripheral nervous system.

Dehydroepiandrosterone 3-sulfate and other neurosteroids are synthesized in the CNS and peripheral nervous system where they may modulate neuronal excitability by interacting with ligand-gated ion channels. For this modulatory activity, neurosteroids have to be locally released from either neurons or glial cells. We here identify the integral membrane protein ABCC11 (multidrug resistance protein 8) as an ATP-dependent efflux pump for steroid sulfates, including dehydroepiandrosterone 3-sulfate, and localize it to axons of the human CNS and peripheral nervous system. ABCC11 mRNA was detected in human brain by real-time polymerase chain reaction. Antibodies raised against ABCC11 served to detect the protein in brain by immunoblotting and immunofluorescence microscopy. ABCC11 was preferentially found in the white matter of the brain and co-localized with neurofilaments indicating that it is an axonal protein. Additionally, ABCC11 was localized to axons of the peripheral nervous system. For functional studies, ABCC11 was expressed in polarized Madin-Darby canine kidney cells where it was sorted to the apical membrane. This apical sorting is in accordance with the localization of ABCC11 to the axonal membrane of neurons. Inside-out plasma membrane vesicles containing recombinant ABCC11 mediated ATP-dependent transport of dehydroepiandrosterone 3-sulfate with a Km value of 21 microM. This transport function together with the localization of the ABCC11 protein in vicinity to GABAA receptors is consistent with a role of ABCC11 in dehydroepiandrosterone 3-sulfate release from neurons to sites of dehydroepiandrosterone 3-sulfate-mediated receptor modulation. Our findings may provide a basis for the characterization of mutations in the human ABCC11 gene and their linkage with neurological disorders.

ATP-Binding Cassette Transporters↗
PubMed2005

Expression of mRNAs encoding for growth factors, ECM molecules, and MMP13 in mono-cultures and co-cultures of human periodontal ligament fibroblasts and alveolar bone cells.

Although the function and effects of many growth factors and extracellular matrix (ECM) molecules have been described for several periodontal tissues in vivo and in vitro, the molecular interactions involved in the communication between cells of the periodontal ligament and the alveolar bone are poorly understood. To contribute to the identification of such interactions, we have generated co-cultures (CCs) of periodontal ligament fibroblasts (PDLs) and alveolar bone cells (ABCs) and compared mRNA expression for various growth factors, ECM molecules, and matrix metalloproteinase13 (MMP13) after 1 and 2 weeks with matched mono-cultures (MCs) by reverse transcription/polymerase chain reaction. Compared with CCs of 1 week, PDLs and ABCs after 2 weeks revealed relatively high levels of all analyzed mRNAs, viz., for EGF, HGF, VEGF, TGFbeta1, collagen-I (COL1), osteonectin (ON), fibronectin (FN1), and MMP13. At week 2, when compared with MCs, CCs showed an elevation of all tested mRNAs in PDLs and ABCs, except for TGFbeta1 and FN1, which only increased in PDLs. After 1 week, when CCs were compared with MCs, mRNAs for HGF and TGFbeta1 were less abundant in PDLs and ABCs, whereas the other genes exhibited lower expression levels in only one of the cell types. Analysis of our data indicated that the expression of mRNAs for growth factors and for COL1, ON, FN1, and MMP13 was modulated in the distinct cell types with respect to culture time and culture type. The differences in the mRNA expression patterns between CCs and MCs suggest that the respective genes are involved in the molecular interactions of PDLs and ABCs.

Adolescent↗
PubMed2005

[Pseudonormalization of diffusion weighted images: magnetic resonance imaging in an animal model (C6-glioma)].

PURPOSE: Previous studies on intracranial tumors indicate that a high apparent diffusion coefficient (ADC) is due to low cellularity and that lower values indicate a dense, highly cellular tumor. Diffusion is affected by three major factors: cell density, existence and distribution of vasogenic edema, and hypoxic tissue. Therefore, we studied the characteristics of diffusion-weighted magnetic resonance imaging (DWI) in a rat brain C6 glioma during tumor progression. MATERIALS AND METHODS: In male Wistar rats, C6 gliomas were implanted in the caudoputamen. At day 9, 11, 13 and 15 after tumor inoculation, conventional DWI was performed on a 2.35 Tesla small bore MRI unit (Biospec 24/40, BRUKER Medizintechnik, Ettlingen, Germany). RESULTS: On conventional T2-weighted and contrast-enhanced T1-weighted images, all tumors could well be delineated from the surrounding brain tissue and showed significant progression. On DWI, the tumors were isointense or slightly hypointense compared to the surrounding brain. On the ADC maps, the tumors could be well visualized due to increasing ADC values from day 9 to 15. The mean ADC of brain tumor tissue was 0.76 +/- 0.4 x 10 ( - 3) mm (2)/s at day 9 and 0.91 +/- 0.03 x 10 ( - 3) mm (2)/s at day 15. The mean ADC of the normal contralateral caudoputamen was 0.59 +/- 0.007 x 10 ( - 3)mm (2)/s. CONCLUSION: T2 prolongation and increased water diffusion can be balanced on DWI in C6 gliomas, resulting in isointensity on DWI (T2 shine-through washout phenomenon). ADC maps are indispensable for the correct interpretation of tumor tissue diffusion behavior.

Animals↗
PubMed2004

Cell death induction by betulinic acid, ceramide and TRAIL in primary glioblastoma multiforme cells.

BACKGROUND: Glioblastoma multiforme (WHO Grade IV, GBM) is the most malignant brain tumour with a mean survival time of less than one year. Betulinic acid, ceramide and TRAIL (TNF-related apoptosis inducing ligand) represent novel therapeutic agents for potential use in GBM. METHOD: Primary GBM cells of 21 patients with macroscopically complete tumour resection were tested in vitro for cell death induction by betulinic acid, ceramide, TRAIL and established therapeutics (BCNU, cisplatin, doxorubicin, vincristin and gamma-irradiation). FINDINGS: At peak plasma concentrations (PPC), Betulinic acid, ceramide and TRAIL induced cell death in primary GBM cells at higher rates than established cytotoxic drugs. Specific cell death > or =75% was observed in 43% (9/21), 38% (8/21), and 19% (4/21) for betulinic acid, ceramide, and TRAIL respectively, while this was only found in 5% (1/21) of gamma-irradiated and cisplatin-treated cells, and in none of the GBM cultures, where BCNU or vincristin were applied in PPC. CONCLUSION: Due to a markedly improved cell death of GBM cells as compared with established therapeutics, Betulinic acid, ceramide and TRAIL might represent potent substances for future treatment of GBM.

Adult↗
PubMed2004

Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain.

Multidrug resistance proteins (MRPs, symbol ABCC) are membrane glycoproteins that mediate the ATP-dependent export of organic anions, including cytotoxic and antiviral drugs, from cells. To identify MRP family members possibly involved in the intrinsic resistance of human brain to cytotoxic and antiviral drugs, we analyzed the expression and localization of MRP1-MRP6 in rapidly frozen perilesional samples of several regions of adult human brain obtained during neurosurgery. Quantitative polymerase chain reaction analysis showed expression of MRP1, MRP2, MRP3, MRP4, and MRP5 mRNA, whereas MRP6 mRNA was below detectability. However, immunofluorescence microscopy of cryosections from human brain showed no reactivity for the MRP2 or MRP3 proteins. The proteins MRP1, MRP4, and MRP5 were clearly localized by confocal laser scanning microscopy to the luminal side of brain capillary endothelial cells. The MRP4 and MRP5 proteins were also detected in astrocytes of the subcortical white matter. Notably, MRP5 protein was present in pyramidal neurons. MRP proteins may, thus, contribute to the cellular efflux of endogenous anionic glutathione or glucuronate conjugates (substrates for MRP1), cyclic nucleotides (substrates for MRP4 and MRP5), or glutathione (co-substrate for MRP1 and MRP4); in addition, they may play an important role in the resistance of the brain to several cytotoxic and antiviral drugs.

ATP-Binding Cassette Transporters↗
PubMed2001

Metastatic growth of squamous cell carcinomas is correlated with upregulation and redistribution of hemidesmosomal components.

Bullous pemphigoid antigen-1 (BPA1) and alpha(6)beta(4)-integrin colocalize at the hemidesmosomes in basal-layer keratinocytes of normal squamous epithelia. The expression of these genes was analyzed during the process of tumor cell invasion and metastasis on frozen sections of head and neck biopsies, and the structural appearance of hemidesmosomes was analyzed by electron microscopy. Despite a diminution of hemidesmosomal structures as revealed by electron microscopy, gene expression of BPA1 and alpha(6)beta(4)-integrins was distinctly upregulated with the onset of invasive growth, demonstrated at the mRNA level by in situ hybridization. The upregulated gene expression extended to the entire proliferative zone of invasive tumors, including the tumor cells which have lost contact with the basement membrane and no longer display hemidesmosomes. The polarized localization of the BPA1 and alpha(6)beta(4) proteins to the basal aspect of the peripheral tumor cells was largely retained in invasive but nonmetastatic lesions, but was lost upon progression to metastatic growth of head and neck squamous cell carcinomas (SCC), in which pericellular staining extended into many tumor cell layers. The results of this study confirm that expression of BPA1 and alpha(6)beta(4)-integrins is elevated in carcinoma cells but is not directed to intact hemidesmosomes. Importantly, this loss of directed localization is an indicator of the capacity to metastasize.

Antigens, Surface↗
PubMed2001

Human thioredoxin reductase is efficiently inhibited by (2,2':6',2' '-terpyridine)platinum(II) complexes. Possible implications for a novel antitumor strategy.

Malignant neoplasms of the brain represent the second leading cause of cancer-related mortality in children under the age of 15. The prognosis of patients with glioblastoma multiforme, the most malignant type of gliomas, remains poor offering a median survival time of only 1 year. (2,2':6',2"-Terpyridine)platinum(II) complexes are known to possess DNA-intercalating activity and have been shown to be potential chemotherapeutic agents. In the present study we identified the selenoenzyme thioredoxin reductase (TrxR) as a major target of (2,2':6',2"-terpyridine)platinum(II) complexes. New complexes were synthesized in order to optimize this inhibition. The NADPH-reduced enzyme is inhibited almost stoichiometrically by the complexes involving a reversible competitive and an irreversible tight-binding component. For the most potent inhibitor, N,S-bis(2,2':6',2"-terpyridine)platinum(II)-thioacetimine trinitrate, the K(i) for the competitive component of the inhibition is 4 nM and the IC(50) for the tight-binding component is 2 nM after an incubation time of 5 min. The closely related but non-selenium-containing enzyme glutathione reductase is much less inhibited (by a factor of >1000). The platinum complexes were found to strongly inhibit the proliferation of three different glioblastoma cell lines as well as of two different head-and-neck squamous carcinoma cell lines. In a glioblastoma cell culture, less than 10 microM of a platinum(II) compound caused an initial drop of hTrxR activity which was followed by an increase of activity in the surviving cells. A 10 microM inhibitor added every 24 h led to 4% residual hTrxR activity but 100% glutathione reductase activity in the cells surviving for 67 h. The potential of (2,2':6',2"-terpyridine)platinum(II) complexes acting simultaneously at two different intracellular targets-hTrxR and DNA-as antitumor agents is discussed.

2,2'-Dipyridyl↗
PubMed2001

Low frequency of chromosomal imbalances in anaplastic ependymomas as detected by comparative genomic hybridization.

We screened 26 ependymomas in 22 patients (7 WHO grade I, myxopapillary, myE; 6 WHO grade II, E; 13 WHO grade III, anaplastic, aE) using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). 25 out of 26 tumors showed chromosomal imbalances on CGH analysis. The chromosomal region most frequently affected by losses of genomic material clustered on 13q (9/26). 6/7 myE showed a loss on 13q14-q31. Other chromosomes affected by genomic losses were 6q (5/26), 4q (5/26), 10 (5/26), and 2q (4/26). The most consistent chromosomal abnormality in ependymomas so far reported, is monosomy 22 or structural abnormality 22q, identified in approximately one third of Giemsa-banded cases with abnormal karyotypes. Using FISH, loss or monosomy 22q was detected in small subpopulations of tumor cells in 36% of cases. The most frequent gains involved chromosome arms 17 (8/26), 9q (7/26), 20q (7/26), and 22q (6/26). Gains on 1q were found exclusively in pediatric ependymomas (5/10). Using FISH, MYCN proto-oncogene DNA amplifications mapped to 2p23-p24 were found in 2 spinal ependymomas of adults. On average, myE demonstrated 9.14, E 5.33, and aE 1.77 gains and/or losses on different chromosomes per tumor using CGH. Thus, and quite paradoxically, in ependymomas, a high frequency of imbalanced chromosomal regions as revealed by CGH does not indicate a high WHO grade of the tumor but is more frequent in grade I tumors.

Adolescent↗
PubMed1999

Expression of facilitative glucose transport proteins during development of squamous cell carcinomas of the head and neck.

Positron emission tomography studies on malignant head and neck tumors have shown that tumor growth and elevated glucose uptake are associated. On a molecular level, glucose uptake is mediated by specific glucose transport proteins, which exhibit an altered expression in head and neck malignant neoplasms. However, it is unknown when during development of squamous cell carcinomas an alteration of the expression of glucose transport proteins occurs. We have studied the expression of different facilitating glucose transport proteins (GLUT 1, 2, 3 and 4) by immunohistochemistry in a variety of preneoplastic and neoplastic mucosal lesions of the head and neck. We have observed weak expression of GLUT 1 in normal mucosa, a marked expression of GLUT 1 throughout preneoplastic lesions, which correlated well with the degree of dysplasia. In squamous cell carcinomas of the head and neck (HNSCC) and metastases, GLUT 1 was always expressed strongly. In contrast, GLUT 2, 3 and 4 were not detected in any of the epithelial tissues examined. The increased expression of GLUT 1 in dysplastic lesions and its sustained expression in SCC indicate that changes of GLUT 1 expression are early events during development of HNSCC. Therefore, the detection of GLUT 1 might be a reliable marker in the diagnosis of premalignant lesions of the oropharyngeal mucosa.

Aged↗
PubMed1999

[Functional expression of vascular endothelial growth factor receptor Flt-1 on squamous cell carcinoma of the head and neck].

Vascular endothelial growth factor (VEGF) is one of the most potent factors in tumor-induced neoangiogenesis. After binding to its specific receptors KDR and FLT-1 on the endothelial cell surface cell proliferation and migration are stimulated. Recently there has been some evidence for the expression of these receptors on tumor cells. We investigated the protein and mRNA expression of KDR and FLT-1 in native tissues and tumor cell cultures from squamous cell carcinomas of the head and neck (HNSCC) and analyzed their in vitro functional significance for tumor cell proliferation and migration. Apart from the expected expression of VEGF receptors on endothelial cells we observed a tumor cell-specific localization of FLT-1 in 29 tumors and KDR in 16 of 37 tumors analyzed. Functional studies in vitro revealed that the addition of VEGF to HNSCC cells inhibited the proliferation and migration of these cells in a dose-dependent manner. Our data suggest a potential negative regulatory loop for VEGF and FLT1 when tumor cells have an insufficient blood supply.

Biopsy↗
PubMed1999

[Glucose uptake in malignant tumors of the head and neck].

Positron emission tomography (PET) studies have shown an elevated glucose uptake in squamous cell carcinomas of the head and neck (HNSCC). On a cellular level glucose uptake is mediated by specific glucose transport proteins. We have used immunohistochemistry ot study the expression of different facilitative glucose transport proteins (GLUT) in the normal mucosa and in HNSCC. A weak expression of GLUT 1 was observed in epithelial cells of the normal mucosa. However, the expression of GLUT 1 was strongly elevated in epithelial cells of HNSCC. GLUT2, 3 and 4 were not detected in any of the epithelial tissues examined. An increased expression of GLUT 3 was found in inflammatory cells. The storage of glycogen showed a negative correlation to the GLUT 1 expression. While an increased glycogen storage was accompanied by a decreased GLUT 1 expression in highly differentiated epithelial cells, glycogen loss was associated with a strong GLUT 1 expression in less differentiated cells. The present study with PET indicates that the elevated glucose uptake of HNSCC is closely related to an increased expression of GLUT 1 in epithelial tumor cells.

Adult↗
PubMed1999

[Expression and localization profile of tenascin in squamous cell carcinomas of the head and neck].

Tenascin is a glycoprotein of the extracellular matrix and is mainly expressed in association with a high proliferative and migratory activity. This characteristic has made it a successfully used target molecule in the treatment of glioblastoma. An application of anti-tenascin therapy concept in squamous cell carcinomas of the head and neck (HNSCC) mainly depends on the expression pattern of tenascin in a tumor type. In the present study, we analyzed the messenger (m) RNA and protein expression of tenascin in HNSCC tumors when compared to normal mucosa and determined its cellular localization and correlation with various clinical parameters, including tumor staging. In native tissue tenascin protein was localized in the entire extracellular matrix surrounding the tumor. Normal mucosa showed only a weak and interrupted basement membrane staining. In situ hybridization revealed a very faint tenascin mRNA signal in basal cells of normal mucosa and a strong signal in tumor cells. This tumor cell-specific expression of tenascin was confirmed at the protein level in HNSCC cultures. However, there was no correlation of tenascin expression with tumor staging or tumor cell proliferation. Our data clearly show that tenascin is selectively expressed in HNSCC and therefore could be useful for a therapeutic intervention in these tumors.

Carcinoma, Squamous Cell↗
PubMed1999

[Cytokine expression of transforming growth factor-beta2 and interleukin-10 in squamous cell carcinomas of the head and neck. Comparison of tissue expression and serum levels].

Transforming growth factor-beta (TGF-beta) and interleukin 10 (Il-10) are cytokines that have a strong immunosuppressive ability. Their secretion by tumor cells is able to suppress an immunological response against tumor. Both factors have been shown to enhance tumor growth in glioblastomas and carcinoma of the breast. We determined the expression pattern of TGF-beta and Il-10 in squamous cell carcinomas of the head and neck (HNSCC) and a possible association with tumor stage and their pre-treatment cytokine serum levels. Cytokine expression in primary tumors and metastases of 21 patients with HNSCC was investigated by immunohistochemistry. To assess the TGF-beta2 and Il-10 levels in tumor patients before therapy 49 serum specimens were analyzed by ELISA. TGF-beta2 was detected in 95% of all tumor tissues analyzed and Il-10 in 79% of all tumors. TGF-beta2 was localized in tumor cells and tumor borders, while Il-10 was preferentially found in peritumoral connective tissue. Metastasizing tumors showed elevated pretreatment serum levels for TGF-beta2 and Il-10. There was no correlation between TGF-beta2 and Il-10 expression in tumor tissue and pretreatment serum levels. Our data show that the majority of HNSCC analyzed express TGF-beta2 and Il-10. A correlation between pretherapy elevated cytokine serum levels and tumor grade was shown.

Biopsy↗
PubMed1999

Defects of basement membrane and hemidesmosome structure correlate with malignant phenotype and stromal interactions in HaCaT-Ras xenografts.

Benign and malignant HaCaT-ras clones, derived from immortalized HaCaT cells were grown as nude mouse surface transplants rendering a human tumor progression model. Searching for malignancy-related alterations, the deposition, localization and mRNA of basement membrane and hemidesmosome components were analysed by immunofluorescence, in situ hybridization and electron microscopy. Initially, at 1 week epithelia of benign and malignant cells revealed a similarly low polarity and an enlarged 'activated basal' compartment, reflected by partial dislocation and extended pericellular staining of the hemidesmosome constituent integrin alpha 6 beta 4 seen by immunofluorescence. Whereas benign grafts eventually normalized, closely resembling grafts of HaCaT cells, malignant growth was correlated with a persisting epithelial activation state and continuing higher expression of alpha 6 (by immunofluorescence and in situ hybridization). The basement membrane components bullous pemphigoid antigen 1, laminin-5 and collagen IV exhibited a largely linear distribution at 1 week. However, in the malignant cell transplants initially minor basement membrane discontinuities became more severe at around 2 weeks, associated with close stromal cell contacts, angiogenesis and invasion. Most striking were basement membrane alterations seen by electron microscopy. At 1 week stretches of basement membrane had developed in malignant transplants, though to a much lesser extent than in benign specimens. With invasion these basement membrane structures mostly disappeared despite persistent although variable immunofluorescence, suggesting high turnover without ultrastructural assembly. The hemidesmosome structures were defective throughout, completely lacking anchoring plaques with keratin filaments, whereas they were still associated with basement membrane deposits. Thus, malignant HaCaT-ras transplants, while initially resembling regenerating wounds, revealed an increasing loss of tissue polarity and basement membrane structures, which seemed to be accelerated upon stromal cell contacts.

Animals↗
PubMed1999

Expression and functional significance of vascular endothelial growth factor receptors in human tumor cells.

Vascular endothelial growth factor (VEGF) is one of the key factors in tumor neoangiogenesis, acting through its receptors KDR (VEGFR-2) and fit-1 (VEGFR-1) expressed on endothelial cells. Our data demonstrate that VEGFR-1 and to a lesser extent VEGFR-2 are expressed in a number of human tumor tissues and derived cells in culture. VEGFR-1 protein is expressed in 26 of 42 glioma tissues, 22 of which show a coexpression of VEGFR-1 with VEGFR-2; 1 glioma tissue expresses exclusively VEGFR-2. In the derived glioma cell cultures, we found VEGFR-1 mRNA expression in 6 of 11 cultures, with one coexpressing VEGFR-1 and VEGFR-2. Of four established glioma cell lines, two expressed VEGFR-1. In addition VEGFR-1 protein expression was demonstrated in 30 of 37 tumor tissues of squamous cell carcinomas of the head and neck, with VEGFR-2 coexpression in 15 tissues and an expression of VEGFR-2 alone in 1 tissue. Derived tumor cell cultures showed mRNA expression of VEGFR-1 alone in seven of seven cases. Established melanoma cell lines expressed VEGFR-1 mRNA in four of five lines, with VEGFR-2 coexpression in two lines. Concerning the functional significance of VEGF receptor expression, VEGF treatment of VEGFR-1-expressing tumor cells induced the inhibition of cell proliferation by 25 to 55% and the inhibition of tumor cell migration by 29 to 55%. Thus our data indicate that the coexpression of VEGF and VEGFR-1 in tumor cells could have an inhibitory effect on tumor cell proliferation and migration, a mechanism possibly induced as a response to a deficiency in nutrient and oxygen supply.

Base Sequence↗
PubMed1998

[Prognosis of brain tumors: epidemiology, survival time and clinical course].

Although the frequency of primary brain tumors is relatively small compared to other tumors such as breast or lung carcinoma, brain tumors affect a particularly young and healthy patient population and possess a high portion of cancer mortality in these age groups. Generally brain tumor diseases influence the professional capacity in younger people and cause significant socioeconomical costs. Prognosis and clinical deterioration of primary brain tumors are determined by histopathological diagnosis first, by tumor location and -volume second. The clinical malignancy of brain tumors, caused by histopathological findings, has not essentially been changed in the last years despite more effective therapies. In contrast refinement in technical standards and computer-assisted micro-surgery makes a valuable progress in the treatment of biological benign brain tumors. Most of these patients recover normal efficiency including former working capability. On the other hand therapeutical nihilism is not supposed to be a sufficient answer to primary brain tumors, because in selected cases a longer lasting stabilization of the disease is possible. In future only through better understanding of the biology of brain tumors and much more effective therapies we can hope to make significant progress in the treatment of these tumors.

Astrocytoma↗