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N Lau

Publications and source records attributed to N Lau.

At least 19 recordsLinked to original sources
PubMed2001

Isotype-specific Ras.GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status.

Previous studies have demonstrated that astrocytomas express elevated levels of activated Ras.GTP despite the absence of activating Ras mutations. Farnesyl transferase inhibitors (FTIs) exert their antitumor effect in part through inhibition of Ras-mediated signaling. SCH66336 is a potent FTI presently undergoing clinical trials in patients with solid tumors. We evaluated the efficacy of SCH66336 against a panel of eight human astrocytoma cell lines and three human astrocytoma explant xenograft models in NOD-SCID mice. SCH66336 demonstrated variable antiproliferative effects against the cell lines, with IC(50) ranging from 0.6 microM to 32.3 microM. Two of the three human glioblastoma multiforme (GBM) xenografts demonstrated substantial growth inhibition in response to SCH66336, with up to 69% growth inhibition after 21 days of treatment. Drug efficacy could be accurately predicted using a combination of the H-, K-, and N-isotype-specific Ras.GTP levels. These data indicate that the absence of Ras mutations does not preclude chemotherapeutic efficacy by FTIs, that Ras is likely a major target of FTIs regardless of Ras mutational status, and that isotype-specific Ras.GTP levels are a promising marker of drug efficacy.

Alkyl and Aryl Transferases↗
PubMed2001

Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas.

Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes the growth of malignant human astrocytomas. We developed a transgenic mouse astrocytoma model using the glial fibrillary acidic protein (GFAP) promoter to express oncogenic V(12)Ha-ras, specifically in astrocytes. The development of GFAP-immunoreactive astrocytomas was directly proportional to the level of V(12)Ha-ras transgene expression. Chimeras expressing high levels of V(12)Ha-ras in astrocytes died from multifocal malignant astrocytomas within 2 weeks, whereas those with moderate levels went to germ-line transmission. Ninety-five percent of these mice died from solitary or multifocal low- and high-grade astrocytomas within 2-6 months. These transgenic astrocytomas are pathologically similar to human astrocytomas, with a high mitotic index, nuclear pleomorphism, infiltration, necrosis, and increased vascularity. Derivative astrocytoma cells are tumorigenic upon inoculation in another host. The transgenic astrocytomas exhibit additional molecular alterations associated with human astrocytomas, including a decreased or absent expression of p16, p19, and PTEN as well as overexpression of EGFR, MDM2, and CDK4. Cytogenetic analysis revealed consistent clonal aneuploidies of chromosomal regions syntenic with comparable loci altered in human astrocytomas. Therefore, this transgenic mouse astrocytoma model recapitulates many of the molecular histopathological and growth characteristics of human malignant astrocytomas in a reproducible, germ-line-transmitted, and high-penetrance manner.

Animals↗
PubMed2001

Expression and hypoxic regulation of angiopoietins in human astrocytomas.

Vascular endothelial growth factor (VEGF) is a major inducer of tumor angiogenesis and edema in human astrocytomas by its interaction with cognate endothelial-specific receptors (VEGFR1/R2). Tie1 and Tie2/Tek are more recently identified endothelial-specific receptors, with angiopoietins being ligands for the latter. These angiogenic factors and receptors are crucial for the maturation of the vascular system, but their role in tumor angiogenesis, particularly in astrocytomas, is unknown. In this study, we demonstrate that the angiopoietin family member Ang1 is expressed by some of the astrocytoma cell lines. In contrast to VEGF, Ang1 is down regulated by hypoxia. Ang2 was not overexpressed. Expression profiles of low-grade astrocytoma specimens were similar to those of normal brain, with low levels of Ang1, Ang2, and VEGF expression. Glioblastoma multiforme expressed higher levels of Angl, but not to the same degree as pseudopalisading astrocytoma cells around necrotic and hypoxic zones expressed VEGF, as shown in previous studies. Ang2 expression in the highly proliferative tumor vascular endothelium was also increased, as was phosphorylated Tie2/Tek. The expression profile of these angiogenic factors and their endothelial cell receptors in human glioblastomas multiforme was similar to that in a transgenic mouse model of glioblastoma multiforme. These data suggest that both VEGF and angiopoietins are involved in regulating tumor angiogenesis in human astrocytomas.

Angiopoietin-1↗
PubMed2000

Expression and regulation of neuropilin-1 in human astrocytomas.

Vascular endothelial growth factor (VEGF), through activation of its endothelial receptors VEGFR-1 and VEGFR-2, is an important positive modulator of tumor angiogenesis and edema in solid tumors such as malignant astrocytomas. Neuropilin-1 (Npn-1) is a transmembrane receptor expressed by both endothelial and non-endothelial cells, including tumor cells. Npn-1 has been postulated to function as a co-factor in activation of the biologically relevant VEGFR-2, by the most abundant VEGF165 isoform. However, the function of Npn-1 in normal and pathological angiogenesis, its expression pattern in relation to VEGF in tumors such as astrocytomas and whether it is similarly or differentially regulated compared to VEGF remain unknown. In our study, the expression pattern of Npn-1 and VEGF by human astrocytoma cell lines and specimens was closely correlated and associated with malignant astrocytomas. Mitogens, such as epidermal growth factor and activation of p21-Ras, previously demonstrated to be relevant in astrocytoma proliferation and induction of VEGF, also induce Npn-1 expression. Hypoxia, the main physiological inducer of VEGF expression, decreased Npn-1 expression. Increased Npn-1 expression was also demonstrated in a transgenic mouse astrocytoma model. Astrocytomas are an ideal system for furthering our understanding of the functional relevance, if any, of Npn-1 in tumor angiogenesis.

Animals↗
PubMed2000

A risk factor screening and assessment protocol for schizophrenia and related psychosis.

OBJECTIVE: The Psychological Assistance Service (PAS) opened in Newcastle, New South Wales in 1997 as a clinical service for the assessment and treatment of young people at high risk of psychosis and those experiencing a first psychotic episode. The aim of this paper is to describe the assessment protocol of PAS, which is strongly influenced by the neurodevelopmental perspective on early onset psychosis. METHOD: The systematic assessment of patients referred to PAS using a protocol over a 2 week period is described. The protocol includes a narrative history, structured diagnostic interview, quantitative assessment of symptoms and other clinical features, a neurological examination and comprehensive neuropsychological test battery. RESULTS: The clinic has received over 250 referrals in a 2 year period and accepted 116 patients for a full assessment, of whom 60 were deemed to be 'at-risk' of psychosis and 56 were experiencing their first psychotic episode. Both groups were similar with respect to gender and there were minor age differences. The first-episode group experienced more reality distortion, schizotypal and negative symptoms. While both groups showed some neuropsychological and neurological impairment, there were no statistically significant differences between the groups on these variables except for a test of executive functioning in which the first-episode group was more impaired than the 'at-risk' group. A low rate of conversion to psychosis occurred in the 'at-risk' group. CONCLUSIONS: The minor differences between the two groups may have been related to relatively small sample sizes, although some similarities between the groups were to be expected. The low rate of conversion to psychosis in the 'at-risk' group is discussed. Further analyses using larger samples are necessary to determine the validity of the various 'at-risk' categories and this will involve following a sufficiently large sample over an adequate time. The most efficient way of doing this would be to pool data across centres with comparable early intervention programs.

Adolescent↗
PubMed2000

Loss of neurofibromin is associated with activation of RAS/MAPK and PI3-K/AKT signaling in a neurofibromatosis 1 astrocytoma.

Neurofibromatosis 1 (NF1) is a common autosomal dominant cancer predisposition syndrome, in which 15% to 20% of affected individuals develop astrocytomas. Neurofibromin, the protein product of the NF1 gene, functions as a tumor suppressor, largely by inhibiting Ras activity. While loss of neurofibromin has been implicated in the molecular pathogenesis of other NF1-associated tumors, there is no formal evidence demonstrating loss of neurofibromin function in NF1-associated astrocytomas. In this report, we describe an NF1 patient from whom both astrocytoma tumor tissue as well as corresponding non-neoplastic white matter were available for analysis. Loss of neurofibromin expression was observed in the tumor and was associated with elevated levels of Ras-GTP. However, elevated Ras-GTP levels were not the result of oncogenic Ras mutations, altered p120-GAP function, growth factor receptor activation, or abnormal p53, Rb, or p16 expression. Furthermore, increased Raf-MAPK and PI3-K/Akt activity was detected in the NF1 astrocytoma compared with the corresponding normal white matter. These results support a role for neurofibromin as the critical GAP in the molecular pathogenesis of NF1 astrocytomas.

Adult↗
PubMed1999

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects.

While 25% of human cancers harbor oncogenic Ras mutations, such mutations are not found in astrocytomas. We have previously demonstrated that the activation of receptor tyrosine kinases expressed by malignant human astrocytoma cells and specimens results in functional upregulation of the Ras signalling pathway and increased levels of activated Ras*GTP. Farnesyl transferase inhibitors (FTIs) are promising anti-cancer agents in early clinical trials, which may exert their effect through pharmacological inhibition of the Ras signalling pathway. In this study we establish the anti-tumorigenic properties of the FTI L-744,832 against a panel of malignant human astrocytoma cell lines. Furthermore, we demonstrate the multiple mechanisms by which L-744,832 exerts its effect. L-744,832 demonstrates both cytostatic and cytotoxic effects on astrocytoma cells, and cells expressing a truncated constitutively phosphorylated Epidermal Growth Factor Receptor common in high-grade astrocytomas (EGFRvIII/p140EGF-R) demonstrate increased sensitivity to the agent. L-744,832 is capable of inducing apoptosis in astrocytoma cells under anchorage-dependent conditions; this process occurs in a p53-independent manner and is associated with increased expression of Bax and Bak. L-744,832 also induces cell cycle arrest at both the G1/M and G2/S checkpoints; this process is also independent of p53 mutational status. Cell cycle arrest in drug-treated cells can be accompanied by induction of p21WAF1/CIP1, but this induction is not necessary for the cell cycle inhibitory effects, nor is it dependent on functional p53. Finally, angiogenesis in astrocytomas has been shown to be dependent on secretion of Vascular Endothelial Growth Factor (VEGF) by tumour cells, particularly under hypoxic conditions. L-744,832 potently inhibits the secretion of VEGF under hypoxic conditions. These combinations of mechanisms suggest that these tumours, despite the absence of oncogenic Ras mutations, will be amenable to growth inhibition by FTIs, through a combination of anti-proliferative, pro-apoptotic, and anti-angiogenic effects.

Alkyl and Aryl Transferases↗
PubMed1999

Normoxic and hypoxic regulation of vascular endothelial growth factor (VEGF) by astrocytoma cells is mediated by Ras.

Vascular endothelial growth Factor (VEGF) has been identified as a key angiogenic factor involved in the growth and malignant progression of tumours. Glioblastoma multiforme (GBM) are the most common primary human brain tumours, histo-pathologically characterized by intense tumour angiogenesis. GBMs do not harbour oncogenic Ras mutations, but there is a functional up-regulation of Ras signaling through activation of receptor tyrosine kinases overexpressed by these tumours. We demonstrate that Ras pathway activation regulates VEGF secretion in astrocytoma cell lines. Ras pathway inhibition was carried out using genetic and pharmacologic techniques. Astrocytoma cells that were transfected to express the dominant inhibitory mutant H-Ras(N17) demonstrated a reduction in VEGF secretion under both normoxic and hypoxic conditions. Cells treated with the farnesyl transferase inhibitor L-744,832 demonstrated similar reductions in VEGF secretion. Furthermore, astrocytoma cells expressing a constitutively phosphorylated and truncated EGF-R common in GBMs (EGFRvIII or p140(EGF-R)) demonstrate further elevations in Ras activation, resulting in a further increase in VEGF secretion. We have previously demonstrated that activation of Ras plays a vital role in transducing mitogenic signals in human malignant astrocytoma cells. Our present results further extend the role of Ras activation in modulating tumour angiogenesis in these tumours. We propose that Ras may contribute to the angiogenic switch in astrocytomas.

3T3 Cells↗
PubMed1999

Expression of activated epidermal growth factor receptors, Ras-guanosine triphosphate, and mitogen-activated protein kinase in human glioblastoma multiforme specimens.

OBJECTIVE: Amplification of the epidermal growth factor receptor (EGFR) is a common event in the molecular pathogenesis of high-grade astrocytic tumors, occurring in 50% of glioblastoma multiforme (GBM) cases. A subset of GBMs also express a constitutively phosphorylated truncated receptor (EGFRvIII). Expression of transfected EGFRvIII in cells has been reported to activate the Ras-mitogen-activated protein kinase pathway and to provide a growth advantage. Novel therapeutic agents targeting signal transduction pathways are entering early clinical trials; determination of which GBMs express EGFRvIII might help identify patients who might benefit from these biological agents. METHODS: A cohort of 15 flash-frozen surgical specimens (12 GBMs, 2 gliosarcomas, and 1 adult low-grade glioma) were evaluated for EGFR and EGFRvIII expression and for EGFR activation status using immunohistochemical (IHC) analysis, Western blotting, and reverse transcription-polymerase chain reaction assays. Levels of activated Ras-guanosine triphosphate were measured using a nonradioactive luciferase-based technique. Mitogen-activated protein kinase activation was determined using a myelin basic protein assay. IHC analysis was performed on paraffin-embedded, formalin-fixed, pathological specimens. Normal control samples included white matter specimens distal to tumors (n = 5), a sample obtained during a lobectomy for treatment of epilepsy (n = 1), and cultured fetal human astrocytes (n = 1). RESULTS: We demonstrated higher levels of activated Ras and mitogen-activated protein kinase in GBM specimens, compared with normal brain tissue or the low-grade glioma. There was a very good correlation between results obtained using specialized molecular techniques and those obtained using routine IHC techniques. Screening for EGFRvIII expression may be of prognostic importance, because patients with EGFRvIII-positive tumors exhibited shorter life expectancies (mean survival time for patients with EGFRvIII-positive tumors, 4.5 +/- 0.6 mo; mean survival time for patients with EGFRvIII-negative tumors, 11.2 +/- 0.9 mo). CONCLUSION: We demonstrated that routine IHC techniques using commercially available antibodies are capable of identifying which GBM specimens express EGFRvIII and whether the EGFRs are activated. Such a molecular classification of GBMs might allow us to determine which patients might benefit from biologically targeted therapies. In addition, characterization of specimens with respect to their EGFRvIII status seems to be of prognostic value.

Adult↗
PubMed1999

Glucose intolerance and 23-year risk of coronary heart disease and total mortality: the Honolulu Heart Program.

OBJECTIVE: The associations between glucose intolerance measured at the study entry date and the 23-year incidence of coronary heart disease (CHD), CHD mortality, and total mortality were examined at the Honolulu Heart Program. RESEARCH DESIGN AND METHODS: This prospective study followed a cohort of 8,006 Japanese-American men who were 45-68 years old and living on the island of Oahu, HI, in 1965. Baseline glucose was measured in a nonfasting state 1 h after a 50-g glucose load. History and use of medication for diabetes was obtained during an interview. The cohort was divided into four categories of glucose tolerance: low-normal, high-normal, asymptomatic hyperglycemia, and known diabetes. RESULTS: During the 23 years of follow-up, 864 incident cases of CHD, 384 deaths from CHD, and 2,166 total deaths occurred. The relative risks (RRs) were obtained using Cox proportional hazards modeling, with the low-normal category as a reference. The RRs were adjusted for age only, as well as for age, BMI, hypertension, cholesterol, triglycerides, smoking, alcohol, and a Japanese diet index. The age-adjusted and risk factor-adjusted RRs for all outcomes were significant for the asymptomatic hyperglycemic and known diabetes groups (P<0.05). The age-adjusted RRs for CHD incidence and total mortality were marginally significant in the high-normal group, but the RRs were not significant when adjusted for risk factors. CONCLUSIONS: These results suggest a dose-response relation of glucose intolerance at baseline with CHD incidence, CHD mortality, and total mortality, independent of other risk factors, in this cohort of middle-aged and older Japanese-American men.

Aged↗
PubMed1997

Proliferation of human malignant astrocytomas is dependent on Ras activation.

Overexpression and activation of receptor tyrosine kinases, such as platelet derived growth factor receptors (PDGFRs) and epidermal growth factor receptor (EGFR), leads to proliferation of human malignant astrocytoma cells. Although oncogenic mutations affecting Ras are not prevalent in human malignant astrocytomas, we have investigated whether levels of activated Ras.GTP might be elevated in these tumors secondary to the mitogenic signals originating from activated receptor tyrosine kinases. In support of this hypothesis high levels of Ras.GTP, similar to those found in oncogenic Ras transformed fibroblasts, were present in four established human malignant astrocytoma cell lines which express PDGFRs and EGFR, and 20 operative malignant astrocytoma specimens. Stimulation of PDGFR's and EGFR's induced tyrosine phosphorylation of the Shc adaptor protein and its association with Grb2, suggesting a mechanism by which Ras may be activated in human malignant astrocytoma cells. Furthermore, blocking Ras activation by expression of the Ha-Ras-Asn17 dominant-negative mutant, or by farnesyl transferase inhibitors, decreased in vitro proliferation of the human astrocytoma cell lines. These results support the hypothesis that proliferative signals from receptor tyrosine kinases expressed by human malignant astrocytoma cells utilize the Ras mitogenic pathway. Pharmacological inhibitors of the Ras pathway may therefore be of therapeutic value in these presently terminal tumors.

Alkyl and Aryl Transferases↗
PubMed1997

Signal transduction pathways and their relevance in human astrocytomas.

Aberrations in a number of signal transduction pathways have been identified as playing a key role in the molecular pathogenesis of astrocytomas and their progression to high grade glioblastoma multiforme (GBM). GBMs are characterized by overexpression of the Platelet Derived Growth Factor Receptors (PDGFR) and their ligands (PDGF), as well as the Epidermal Growth Factor Receptor (EGF-R). These receptors activate the Ras pathway, a key cellular signal transduction pathway, culminating in the activation of a wide range of Ras-dependent cellular events. GBMs have also been found to either overexpression or lose expression of various Protein Kinase C (PKC) isoforms. Major strides are being made in developing pharmacological agents which specifically inhibit these growth factor receptors and intracellular signal transduction pathways. Elucidating the role of these pathways in GBMs is thus of major clinical importance, as these novel molecularly-targeted agents may prove of use in the clinical management of GBMs in the future.

Astrocytoma↗
PubMed1997

Meningiomas: role of vascular endothelial growth factor/vascular permeability factor in angiogenesis and peritumoral edema.

OBJECTIVE: Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) is a potent angiogenic growth factor implicated in the tumor angiogenesis/metastasis of a number of human cancers. Activation of receptors for VEGF/VPF is specifically mitogenic to endothelial cells and increases their permeability. Although extensive literature exists regarding VEGF/VPF in human astrocytomas, little is known about its potential biological role(s) in meningiomas. Our interest in meningiomas was initiated by the observation that some meningiomas are extremely vascular and are occasionally associated with a considerable degree of peritumoral brain edema, both potentially related to the biological attributes of VEGF/VPF. METHODS: As a first test of this hypothesis, we examined a cohort of 18 meningiomas for expression of VEGF/VPF at the messenger ribonucleic acid and protein levels and correlated expression with pathological characteristics, vascularity, and degree of peritumoral edema. RESULTS: The majority of meningiomas expressed VEGF/VPF at both the messenger ribonucleic acid and protein levels. Corresponding serial sections were stained with an endothelial cell marker to obtain a microvascular density count, which positively correlated (P = 0.0005) with expression of VEGF/VPF. Furthermore, meningiomas with a large amount of peritumoral edema, as determined from the preoperative computed tomographic scans or magnetic resonance imaging scans, had elevated expression of VEGF/VPF (P = 0.05). CONCLUSION: These data suggest that VEGF/VPF may play a role in both meningioma vascularity and peritumoral edema.

Adult↗
PubMed1997

Expression and activation of epidermal growth factor receptors in meningiomas.

Previous studies have demonstrated expression of epidermal growth factor receptors (EGFRs) in human cerebral meningiomas. However, the activation status of the EGFRs and whether they activate cytoplasmic mitogenic signaling pathways are not known. In this study, using Northern blot analysis and the polymerase chain reaction, the authors report expression of epidermal growth factor, transforming growth factor-alpha, and EGFR messenger RNA in 27 meningioma specimens. Using Western blot and immunohistochemical analyses of the meningioma samples, the authors demonstrate that the EGFRs expressed by these meningiomas are activated. These activated EGFRs interact with and phosphorylate Shc, an SH2 domain-containing adapter protein that is important in transducing mitogenic signals from EGFRs to the nucleus via activation of the Ras signaling pathway. These results support the concept that activation of EGFRs in human meningiomas by autocrine/paracrine stimulation may contribute to their proliferation.

ErbB Receptors↗
PubMed1996

Increased neurofibromatosis 1 gene expression in astrocytic tumors: positive regulation by p21-ras.

The neurofibromatosis 1 (NF1) gene has been implicated in astrocyte growth regulation in several studies. To determine whether loss of NF1 expression is associated with progression towards malignancy in sporadic astrocytomas from individuals without NF1, twenty-eight fresh astrocytoma operative specimens (low and high grade tumors) and seven primary human astrocytoma cell lines were examined for NF1 mRNA and protein expression. In all astrocytomas examined, increased NF1 expression was observed in the tumors relative to normal resting astrocytes. This increased neurofibromin expression correlated with elevated levels of activated p21-ras measured in both the fresh tumor specimens and the primary cell lines. Furthermore, when levels of activated p21 ras were decreased in astrocytoma cells expressing the ras inhibitory Asn-17 dominant-negative mutant, levels of neurofibromin expression decreased. In addition, fibroblasts induced to express oncogenic activated p21-ras(val12) had increased expression of NF1. These results suggested that neurofibromin expression is increased in human astrocytic tumors as a result of positive feedback regulation by increased levels of activated p21-ras.

Animals↗
PubMed1996

Ras-GTP levels are elevated in human NF1 peripheral nerve tumors.

Neurofibromin, the gene product of NF1, is a Ras GTPase Activating Protein. The absence of neurofibromin leads to increased levels of Ras-GTP, which contributes to the proliferation of NF1 neurogenic sarcoma cell lines. Whether this pathogenic mechanism is applicable to benign and malignant peripheral nerve tumours from NF1 and non NF1 patients is not known, due to lack of a tissue based assay. We have adapted a colorimetric enzymatic assay for determining levels of Ras bound guanine nucleotides in tissues. Ras-GTP levels were increased in NF1 neurogenic sarcomas (15 times) and benign NF1 neurofibromas (four times), compared to non NF1 schwannomas. Neurofibromin was not expressed in NF1 sarcomas, in support of its important negative Ras regulatory role in the pathogenesis of NF1 peripheral nerve tumors.

Base Sequence↗
PubMed1996

Acute presentation of a neurogenic sarcoma in a patient with neurofibromatosis type 1: a pathological and molecular explanation. Case report.

Neurofibromatosis type 1 (NF1) is the most common familial cancer-predisposing syndrome in humans, for which the gene (NF1) and its gene product (neurofibromin) have been identified. The majority of tumors occurring in patients with NF1 are benign neurofibromas, sarcomatous transformation is uncommon and most often occurs within the larger plexiform neurofibromas. Such malignant transformation in a known neurofibroma is often heralded by either radiological evidence of growth or a progression in clinical symptoms (pain and neurological deficit). This progression in symptoms is usually gradual in onset, typically occurring over a period of months. In this report the authors document a neurogenic sarcoma presenting with rapid clinical and radiological growth. The pathological basis of this acute presentation was increased cellular proliferation, with invasion of blood vessels resulting in tumor infarction. The molecular basis of neurofibroma development in NF1 is loss of expression of the NF1 gene and its gene product, neurofibromin, resulting in elevated levels of Ras-guanosine triphosphate. Subsequent molecular events result in sarcomatous transformation.

Adult↗