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Katrin Lamszus

Publications and source records attributed to Katrin Lamszus.

At least 19 recordsLinked to original sources
PubMed2006

A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo.

PURPOSE: Expression of the receptor tyrosine kinase c-Met and its ligand scatter factor/hepatocyte growth factor (SF/HGF) are strongly increased in glioblastomas, where they promote tumor proliferation, migration, invasion, and angiogenesis. We used a novel one-armed anti-c-Met antibody to inhibit glioblastoma growth in vivo. EXPERIMENTAL DESIGN: U87 glioblastoma cells (c-Met and SF/HGF positive) or G55 glioblastoma cells (c-Met positive and SF/HGF negative) were used to generate intracranial orthotopic xenografts in nude mice. The one-armed 5D5 (OA-5D5) anti-c-Met antibody was infused intratumorally using osmotic minipumps. Following treatment, tumor volumes were measured and tumors were analyzed histologically for extracellular matrix (ECM) components and proteases relevant to tumor invasion. Microarray analyses were done to determine the effect of the antibody on invasion-related genes. RESULTS: U87 tumor growth, strongly driven by SF/HGF, was inhibited > 95% with OA-5D5 treatment. In contrast, G55 tumors, which are not SF/HGF driven, did not respond to OA-5D5, suggesting that the antibody can have efficacy in SF/HGF-activated tumors. In OA-5D5-treated U87 tumors, cell proliferation was reduced > 75%, microvessel density was reduced > 90%, and apoptosis was increased > 60%. Furthermore, OA-5D5 treatment decreased tumor cell density > 2-fold, with a consequent increase in ECM deposition and increased immunoreactivity for laminin, fibronectin, and tenascin. Microarray studies showed no increase in these ECM factors, rather down-regulation of urokinase-type plasminogen activator and matrix metalloproteinase 16 in glioblastoma cells treated with OA-5D5. CONCLUSIONS: Local treatment with OA-5D5 can almost completely inhibit intracerebral glioblastoma growth when SF/HGF is driving tumor growth. The mechanisms of tumor inhibition include antiproliferative, antiangiogenic, and proapoptotic effects.

Animals↗
PubMed2006

Contactin is expressed in human astrocytic gliomas and mediates repulsive effects.

Contactin is a cell surface adhesion molecule that is normally expressed by neurons and oligodendrocytes. Particularly high levels of contactin are present during brain development. Using subtractive cloning, we identified contactin transcripts as overexpressed in glioblastomas compared with normal brain. We confirmed contactin overexpression in glioblastomas at the protein level, and localized contactin to the surface of glial fibrillary acidic protein (GFAP)-expressing glioblastoma cells. In contrast, normal astrocytes did not express contactin. Analyzing different types of astrocytic tumors, we detected an association between increasing malignancy grade and contactin expression. Functionally, contactin had repellent effects on glioma cells in vitro, as demonstrated by adhesion and migration assays. Overexpression of contactin by transfection into glioblastoma cells did not alter the proliferation rate or adhesion to various extracellular matrix proteins as well as adhesion to cells expressing the specific contactin ligand the protein tyrosine phosphatase zeta (PTPzeta). Our findings suggest that contactin has repellent effects on glioma cells to which it is presented as a ligand, but it does not alter the proliferative or adhesive capacities of cells that overexpress the molecule. The repulsive properties of contactin may be a key factor in glioma disaggregation, and may contribute to the diffuse infiltration pattern characteristic of glioma cells in human brain.

Astrocytes↗
PubMed2006

RNA interference-mediated gene silencing of pleiotrophin through polyethylenimine-complexed small interfering RNAs in vivo exerts antitumoral effects in glioblastoma xenografts.

RNA interference (RNAi) is a powerful strategy to inhibit gene expression through specific mRNA degradation mediated by small interfering RNAs (siRNAs). In vivo, however, the application of siRNAs is severely limited by their instability and poor delivery into target cells and target tissues. Glioblastomas are the most frequent and malignant brain tumors with, so far, limited treatment options. To develop novel and more efficacious therapies, advanced targeting strategies against glioblastoma multiforme (GBM)-relevant target genes must be established in vivo. Here we use RNAi-based targeting of the secreted growth factor pleiotrophin (PTN), employing a polyethylenimine (PEI)/siRNA complex strategy. We show that the complexation of chemically unmodified siRNAs with PEI leads to the formation of complexes that condense and completely cover siRNAs as determined by atomic force microscopy (AFM). On the efficient cellular delivery of these PEI/siRNA complexes, the PTN downregulation in U87 glioblastoma cells in vitro results in decreased proliferation and soft agar colony formation. More importantly, in vivo treatment of nude mice through systemic application (subcutaneous or intraperitoneal) of PEI-complexed PTN siRNAs leads to the delivery of intact siRNAs into subcutaneous tumor xenografts and a significant inhibition of tumor growth without a measurable induction of siRNA-mediated immunostimulation. Likewise, in a clinically more relevant orthotopic mouse glioblastoma model with U87 cells growing intracranially, the injection of PEI-complexed PTN siRNAs into the CNS exerts antitumoral effects. In conclusion, we present the PEI complexation of siRNAs as a universally applicable platform for RNAi in vitro and in vivo and establish, also in a complex and relevant orthotopic tumor model, the potential of PEI/siRNA-mediated PTN gene targeting as a novel therapeutic option in GBM.

Animals↗
PubMed2006

RNA interference targeting protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta suppresses glioblastoma growth in vitro and in vivo.

The protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta (PTPzeta/RPTPbeta) and its ligand pleiotrophin (PTN) are overexpressed in human glioblastomas. Both molecules are involved in neuronal cell migration during CNS development. In addition, PTN can induce glioma cell migration which is at least in part mediated through binding to PTPzeta/RPTPbeta. To study the relevance of this ligand-receptor pair for glioma growth in vitro and in vivo, we transfected the human glioblastoma cell line U251-MG with small interfering RNA (siRNA) directed against PTPzeta/RPTPbeta. Stable siRNA transfection resulted in strong down-regulation of PTPzeta/RPTPbeta expression. When injected subcutaneously into nude mice, clones that expressed normal levels of PTPzeta/RPTPbeta (PTPzeta + clones) formed exponentially growing tumours, whereas tumour growth was almost completely abrogated for clones that expressed reduced PTPzeta/RPTPbeta levels (PTPzeta - clones). Similar results were obtained using an orthotopic intracerebral model. Proliferation of PTPzeta - cells in vitro was significantly reduced compared with that of control clones. Matrix-immobilized PTN stimulated the proliferation of PTPzeta + cells but not of PTPzeta - cells. Haptotactic migration induced by PTN was reduced for PTPzeta - clones compared with control clones. Our findings suggest that antagonization of PTPzeta/RPTPbeta expression can inhibit glioma growth in vivo and may thus represent a potentially promising treatment strategy.

Animals↗
PubMed2005

Inhibition of glioblastoma angiogenesis and invasion by combined treatments directed against vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and vascular endothelial-cadherin.

PURPOSE: Inhibition of angiogenesis can influence tumor cell invasion and metastasis. We previously showed that blockade of vascular endothelial growth factor receptor-2 (VEGFR-2) with the monoclonal antibody DC101 inhibited intracerebral glioblastoma growth but caused increased tumor cell invasion along the preexistent vasculature. In the present study, we attempted to inhibit glioma cell invasion using a monoclonal antibody against the epidermal growth factor receptor (EGFR), which in the context of human glioblastomas, has been implicated in tumor cell invasion. In addition, we analyzed whether blockade of vascular endothelial (VE)-cadherin as a different antiangiogenic target could also inhibit glioblastoma angiogenesis and growth. EXPERIMENTAL DESIGNS: Nude mice who received intracerebral glioblastoma xenografts were treated using monoclonal antibodies against VEGFR-2 (DC101), EGFR (C225), and VE-cadherin (E4G10) either alone or in different combinations. RESULTS: Increased tumor cell invasion provoked by DC101 monotherapy was inhibited by 50% to 66% by combined treatment with C225 and DC101. C225 inhibited glioblastoma cell migration in vitro, but had no effect on the volume of the main tumor mass or on tumor cell proliferation or apoptosis in vivo, either alone or in combination with DC101. The anti-VE-cadherin monoclonal antibody E4G10 was a weaker inhibitor of tumor angiogenesis and growth than DC101, and also caused a weaker increase in tumor cell invasion. CONCLUSIONS: Inhibition of angiogenesis achieved by blocking either VEGFR-2 or VE-cadherin can cause increased glioma cell invasion in an orthotopic model. Increased tumor cell invasion induced by potent inhibition of angiogenesis with DC101 could be inhibited by simultaneous blockade of EGFR.

Animals↗
PubMed2005

Novel mutations and repeated findings of mutations in familial Alzheimer disease.

Twenty-one unrelated patients with a history of suspected familial Alzheimer disease (FAD) were screened for mutations in PSEN1, PSEN2, and APP, the known FAD genes encoding the presenilins (PS1 and PS2) and the amyloid precursor protein (APP). The mutation detection rate was 57%. Of the nine pathogenic mutations found in 12 cases, three were in APP, one in PSEN2, and five in PSEN1, including two novel Greek mutations (L113Q and N135S). Whereas our findings suggest the possibility of single founders for the majority of mutations, we found evidence of recurrence of the APP mutations V717L and V717I.

Adult↗
PubMed2005

Long-term observation reveals time-course-dependent characteristics of tumour vascularisation.

Functional properties of tumour vasculature influence the process of metastasis and play a role in generating a heterogeneous metabolic microenvironment, which contributes to genetic instability and inefficiency of tumour therapies. Morphological and functional properties of tumour vasculature may vary from tumour onset to late-stage disease. The aim of this study was to identify the dynamic alteration in tumour microcirculation in a chronic observation model. Invasively-growing, non-disseminating, green fluorescent protein transfected, human bone marrow derived endothelial cells, were implanted into cranial windows of severe combined immunodeficient mice. Intravital fluorescence microscopy was performed over a period of 85 days to measure permeability, leucocyte-endothelial interaction (LEI) and tissue perfusion rate as functional parameters. Vessel density, branching pattern and scanning electron microscopy were monitored as morphological parameters. Concordant with an increasing count of transendothelial pores, the results show that the initial event following tumour cell implantation was a significant increase in the permeability of pre-existing vessels. The variations in newly formed vessels were characterised by sequentially-occurring functional and morphological alterations with the development of characteristics typical of tumour vessels, such as increased count of trifurcations and variation in vessel calibre by more than 100%. In parallel with the increasing vessel volume per area, the tissue perfusion rate increased until day 61. It is concluded from the step-specific sequential functional and morphological alterations that the efficiency of adjuvant therapies depends not only on their intrinsic efficiency but also on the timing of their initiation.

Animals↗
PubMed2005

November 2004: intradural mass of the cauda equina in a woman in her early 60s.

November 2004. A 63-year-old woman presented with slowly aggravating lower back pain and recent urinary urge incontinence. MRI revealed a sharply-delineated, partly cystic intradural mass with inhomogenous contrast-enhancement and ectatic vessels at the upper pole. An ependymoma was suspected, and the tumor was resected in toto. Histologically, at first glance, the tumor strongly resembled an ependymoma, showing a monomorphic cellular pattern, perivascular pseudorosettes and ependymal canal-like structures. However, the finding of a delicate collagen capsule, compartmentation of tumor cells into zellballen and the presence of ganglionic cells were untypical. These features were indicative of a paraganglioma with a gangliocytic component. Immunoreactivity of the tumor cells for neuroendocrine antigens, the detection of GFAP-positive sustentacular cells and the ultrastructural confirmation of neurosecretory granules substantiated this diagnosis. The clinical, radiological and morphological similarity between ependymomas, which are far more common in the cauda equina region than paragangliomas, has led to substantial diagnostic confusion in the past.

Cauda Equina↗
PubMed2005

Well-differentiated neurocytoma: what is the best available treatment?

Most neurocytomas are well differentiated, being associated with better long-term survival than the more aggressive atypical lesions. Atypical neurocytomas are characterized by an MIB-1 labeling index >3% or atypical histologic features. This analysis focuses on well differentiated neurocytomas in order to define the optimal treatment. A case with a follow-up of 132 months is presented. The patient developed two recurrences two and four years after first surgery, each showing an increasing proliferation activity. Furthermore, all published well-differentiated neurocytoma cases were reviewed for surgery, radiotherapy, and prognosis. Additional relevant data were obtained from the authors. Complete resection (CTR), complete resection plus radiotherapy (CTR + RT), incomplete resection (ITR), and incomplete resection plus radiotherapy (ITR + RT) were compared for outcome by using the Kaplan-Meier method and the log-rank test. Data were complete in 301 patients (CTR, 108; CTR + RT, 27; ITR, 81; ITR + RT, 85). Local control and survival were better after CTR than after ITR (P < 0.0001 and P = 0.0085, respectively). Radiotherapy improved local control after ITR (P < 0.0001) and after CTR (P = 0.0474), but not survival (P = 0.17 and P = 1.0, respectively). In the ITR + RT group, doses < or =54 Gy (n = 33) and >54 Gy (n = 32) were not significantly different for local control (P = 0.88) and survival (P = 0.95). The data demonstrated CTR to be superior to ITR for local control and survival. After CTR and ITR, radiotherapy improved local control, but not survival. A radiation dose of 54 Gy appeared sufficient. Application of postoperative radiotherapy should be decided individually, taking into account the risk of local failure, the need for another craniotomy, and potential radiation toxicity.

Adolescent↗
PubMed2005

Neural stem cell migration toward gliomas in vitro.

Various in vivo studies demonstrated a migration tendency of neural stem cells (NSCs) toward gliomas, making these cells a potential carrier for delivery of therapeutic genes to disseminated glioma cells. We analyzed which factors determine NSC migration and invasion in vitro. Conditioned media prepared from 10 different human glioma cell lines, as well as 13 different tumor-associated growth factors, were analyzed for their chemotactic effects on murine C17.2 NSCs. The growth factor receptor status was analyzed by reverse transcriptase-polymerase chain reaction. Invasion of NSCs into multicellular tumor spheroids generated from 10 glioma cell lines was quantified. NSCs displayed a heterogeneous migration pattern toward glioma spheroids as well as toward glioma-cell-conditioned medium. Chemotactic migration was stimulated up to fivefold by conditioned medium as compared to controls. In coculture assays, NSC invasion varied from single cell invasion into glioma spheroids to complete dissemination of NSCs into glioma spheroids of different cell lines. Among 13 different growth factors, scatter factor/hepatocyte growth factor (SF/HGF) was the most powerful chemoattractant for NSCs, inducing a 2.5-fold migration stimulation. An antibody against SF/HGF inhibited migratory stimulation induced by conditioned media. NSC migration can be stimulated by various growth factors, similar to glioma cell migration. The extent to which NSCs infiltrate three-dimensional glioma cell aggregates appears to depend on additional factors, which are likely to include cell-to-cell contacts and interaction with extracellular matrix proteins.

Animals↗
PubMed2004

Technical note: A toy as tool: a low-cost image analysis system for the evaluation of tumor size in experimental small animal models.

Image analysis systems are an essential tool in measurements of size of intraparenchymal tumors or lesions in experimental small animal models. Conventional image analysis systems are relatively expensive. We therefore compared the performance of a professional image analysis system with an inexpensive setup by evaluating tumor size in an orthotopic glioma mouse model. The maximum cross-sectional tumor area of H&E stained brain-slides of two groups of mice (treatment and control group) was measured by two independent investigators using a professional image analysis system (Leica DM IRB microscope) with the Leica Quantimet 500c software, and a low-cost-system (Intel QX3 microscope) with a non-commercial image analysis software. Mean tumor volumes were calculated and the results from each of the image analysis systems, investigators, and treatment effects were compared. The tumor volumes as measured with the low-cost and the professional system differed between -3.7 and +7.5% (P = 0.69-0.99). Measurements made by investigator A and B differed between -7.0 and +3.9% (P = 0.69-0.88). Treatment in all cases significantly reduced the tumor volume between 58.4 and 62.7% (P = 0.0002 or 0.0003), regardless of the investigator or the used image analysis system. We therefore conclude that the QX3 low-cost microscope in combination with a non-commercial image-analysis software represents an inexpensive solution to reliably analyze the size of regions of interest, if they provide a sufficient contrast. However, the low-cost setup due to its low resolution definitely limits a detailed analysis of histologic features.

Animals↗
PubMed2004

Angiogenesis-related growth factors in brain tumors.

Numerous growth factors have been implicated in glioma angiogenesis. This chapter focuses on the role of scatter factor/hepatocyte growth factor, fibroblast growth factor, platelet-derived growth factor and transforming growth factor beta. We review the expression pattern of these factors in gliomas, their functional contribution to tumor angiogenesis - also in relation to vascular endothelial growth factor, and the effects resulting from their inhibition or overexpression in gliomas in vivo.

Animals↗
PubMed2004

Identification of the adult human hemangioblast.

Recent studies show that human CD133(+) (previously known as AC133(+)) cells from mobilized peripheral blood consist of stem cells with either hematopoietic or endothelial potential. To test whether this population also contains individual precursors with both capacities, the defining characteristics of the elusive adult hemangioblast, we developed a culture system that allows single-cell analyses of differentiation. In the presence of vascular endothelial growth factor (VEGF), stem cell growth factor (SCGF), and FLT-3 ligand, CD133(+)-enriched cells were first expanded and the amplified cells were transduced with a vector encoding an enhanced green fluorescent protein (EGFP) marker gene. Single EGFP(+) cells were then cocultured with corresponding non-transduced cells from the same experiment, yielding 50-100 marked cells in 8% of the wells after 2 weeks. The resultant cells were divided and differentiated with either granulocyte colony-stimulating factor (G-CSF) or with SCGF and VEGF. These culture conditions resulted in the formation of neutrophil or endothelial cells, respectively, as identified morphologically and by phenotypic staining. Dual differentiation of EGFP(+) cells could be observed in one-quarter of clones from single-seeded cells, suggesting that 2% of EGFP(+) cells were in fact human hemangioblasts. These cells could be expanded for at least 28 days without losing this dual capacity. Hence, this culture system may be of clinical relevance in the development of cellular therapies for disorders involving hematopoiesis and the vascular system. In addition, our results provide important information related to the development of the vasculature and the potential role of hemangioblasts in vasculogenesis in adult humans.

AC133 Antigen↗
PubMed2004

Meningioma pathology, genetics, and biology.

Over the past 5 to 10 years, important advances were made in the understanding of meningioma biology. Progress in molecular genetics probably represents the most important accomplishment in the comprehensive knowledge of meningioma pathogenesis. Several genes could be identified as targets for mutation or inactivation. Additional chromosomal regions were found to be commonly deleted or amplified, suggesting the presence of further tumor suppressor genes or proto-oncogenes, respectively, in these regions. Histopathologically, the most important innovation is represented by the revised WHO classification in the year 2000. Meningioma grading criteria in the new classification scheme are more precise and objective, and should thus improve consistency in predicting tumor recurrence and aggressive behavior. This review focuses mainly on the advances in molecular biology that were achieved in recent years. It summarizes the most important aspects of meningioma classification as the basis to place biological observations into a correlative context, and, further, includes mechanisms of angiogenesis and edema formation as well as the role of hormone receptors in meningiomas.

Animals↗
PubMed2004

Epidural hematoma after spinal anesthesia in a patient with undiagnosed epidural lymphoma.

UNLABELLED: The incidence of hemorrhagic complications after neuroaxial anesthesia is very infrequent. We report a case of a woman developing epidural bleeding 3 wk after performing an uneventful spinal anesthesia at the lumbar level L3-4 for removal of a wire loop in her left knee. No hemostasis altering medication had been taken before and after spinal puncture. The hematoma presenting at the lumbar level L2-3 had to be removed via laminectomy. Pathological examination of the hematoma revealed a highly vascularized centroblastic non-Hodgkin's lymphoma that was not diagnosed before surgery. The patient did not develop any neurological deficits. IMPLICATIONS: We report a case of a women developing epidural bleeding 3 wk after performing an uneventful spinal anesthesia for removal of a wire loop in her left knee. Pathological examination of the neurosurgically removed hematoma revealed a highly vascularized epidural centroblastic non-Hodgkin lymphoma.

Anesthesia, Spinal↗
PubMed2004

Receptor protein tyrosine phosphatase zeta as a therapeutic target for glioblastoma therapy.

Astrocytomas are the most frequent brain tumour type in adults. The most common astrocytoma is the glioblastoma (GBM), which is also the most malignant and refractory to treatment--ultimately leading to the patient's death within a year of diagnosis. Neither the classical nor more experimental therapeutic approaches have significantly improved the clinical outcome of this disease. Expression profile analysis of primary tumours has provided recent insight into the identification of new GBM therapeutic targets. These proteins serve as excellent candidates to either inhibit the target molecule's functions (e.g., angiogenesis, migration or proliferation) or, coupled with a toxin or radionucleotide, to bind and exterminate the tumour cells. The receptor protein tyrosine phosphatase zeta (RPTPzeta) and one of its main ligands, pleiotropin (Ptn), are overexpressed in GBMs, thus making them potentially very good targets for the development of new immunotherapeutics. This review will summarise recent advances in GBM therapies focusing on RPTPzeta as a target for immunotherapeutics.

Animals↗
PubMed2003

A role for receptor tyrosine phosphatase zeta in glioma cell migration.

Glioblastomas (GBM) are the most frequent and malignant human brain tumor type. Typically striking in adulthood, tumor progression is rapid, relentless, and ultimately leads to the patient's death within a year of diagnosis. The identification of transcriptionally regulated genes can lead to the discovery of targets for antibody or small-molecule-mediated therapy, as well as diagnostic markers. We prepared cDNA arrays that are specifically enriched for genes expressed in human brain tumors and profiled gene expression patterns in 14 individual tumor samples. Out of 25,000 clones arrayed, greater than 200 genes were found transcriptionally induced in glioblastomas compared to normal human brain tissue including the receptor tyrosine phosphatasezeta (RPTPzeta) and one of its ligands, pleiotrophin (Ptn). We confirmed by Northern blot analysis and immunohistochemistry that RPTPzeta is enriched in tumor samples. Knockdown of RPTPzeta by RNA interference studies established a functional role of RPTPzeta in cell migration. Our results suggest a novel function for RPTPzeta in regulating glioblastoma cell motility and point to the therapeutic utility of RPTPzeta as a target for antibody-mediated therapy of brain tumors.

Blotting, Northern↗