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Biomedical subjects

Gregory N Fuller

Publications and source records attributed to Gregory N Fuller.

At least 19 recordsLinked to original sources
PubMed2006

Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma.

PURPOSE: Activation of mitogen-activated protein kinase (MAPK) and members of the Akt pathway have been shown to promote cell proliferation, survival, and resistance to radiation. This study was conducted to determine whether any of these markers are associated with survival time and response to radiation in glioblastoma. EXPERIMENTAL DESIGN: The expression of phosphorylated (p-)Akt, mammalian target of rapamycin (p-mTOR), p-p70S6K, and p-MAPK were assessed by immunohistochemical staining in 268 cases of newly diagnosed glioblastoma. YKL-40, a prognostic marker previously examined in these tumors, was also included in the analysis. Expression data were tested for correlations with response to radiation therapy in 131 subtotally resected cases and overall survival (in all cases). Results were validated in an analysis of 60 patients enrolled in clinical trials at a second institution. RESULTS: Elevated p-MAPK expression was most strongly associated with poor response to radiotherapy, a finding corroborated in the validation cohort. For survival, higher expressions of p-mTOR, p-p70S6K, and p-MAPK were associated with worse outcome (all P < 0.03). YKL-40 expression was associated with the expressions of p-MAPK, p-mTOR, and p-p70S6K (all P < 0.02), with a trend toward association with p-Akt expression (P = 0.095). When known clinical variables were added to a multivariate analysis, only age, Karnofsky performance score, and p-MAPK expression emerged as independent prognostic factors. CONCLUSIONS: p-MAPK and activated members of the Akt pathway are markers of outcome in glioblastoma. Elevated expression of p-MAPK is associated with increased radiation resistance and represents an independent prognostic factor in these tumors.

Adipokines↗
PubMed2006

Polypyrimidine tract binding protein and Notch1 are independently re-expressed in glioma.

Polypyrimidine tract binding protein (PTB) is expressed in developing mammalian astrocytes, absent in mature adult astrocytes, and aberrantly elevated in gliomas. It is unclear whether PTB is a coincidental marker of tumor progression or a significant mediator of tumorigenesis. In developing Drosophila, the absence of the PTB homolog, hephaestus, results in increased Notch activity. Since Notch is a well-known inducer of glial cell fate, we determined whether overexpression of PTB in glial cell tumors provides a selective growth advantage by inhibiting activated Notch (Notch1IC)-mediated differentiation. To do this, we performed an immunohistochemical analysis for expression of PTB, activated Notch1 (Notch1IC), Hes1 (a Notch target), and GFAP on an extensive human tissue microarray that included 246 gliomas, 10 gliosarcomas, and 10 normal brains. Statistically significant PTB overexpression was seen in all glioma grades, with the highest increase in grade IV tumors. Notch1IC was also abnormally expressed in gliomas except in a subset of grade IV tumors in which it was absent. This decrease in Notch1IC was not associated with increased PTB expression. We conclude that PTB, and Notch1 serve as independent and functionally unlinked markers of glioma progression.

Basic Helix-Loop-Helix Proteins↗
PubMed2006

Insulin-like growth factor-binding protein 2 and 5 are differentially regulated in ovarian cancer of different histologic types.

The family of insulin-like growth factor-binding proteins (IGFBPs) comprises six members, which bind and regulate the functions of insulin-like growth factors. Overexpression of IGFBP2 and IGFBP5 contributes to the invasiveness and progression of several human cancers, but their role and clinical significance in ovarian cancer has not been investigated in detail. We examined IGFBP2 and IGFBP5 expression levels using two tissue microarrays, one containing six normal surface epithelium, six benign serous cysts, 10 serous borderline tumors, eight low-grade, and 20 high-grade serous carcinomas. The other comprising 441 ovarian cancers of different histologic types linked to a clinicopathologic database. Each tumor was sampled in duplicate with a 1.0-mm punch core needle. Immunohistochemical staining was performed using antibodies against IGFBP2 or IGFBP5. The staining intensity was scored semiquantitatively as negative (0), weak (1-10%), moderate (10-50%), or strong (50-100%) using computerized image analysis. Statistical analyses used Fisher's exact test and Kaplan-Meier method. IGFBP2 and IGFBP5 were overexpressed in high-grade serous carcinomas compared to normal surface epithelium, benign serous cysts, serous borderline tumors, or low-grade serous carcinoma. They were differentially expressed in different types of ovarian carcinomas, being more often expressed at high levels in high-grade serous carcinoma, malignant mixed mullerian tumors and undifferentiated carcinoma, and more often expressed at low levels or not at all in clear cell and mucinous carcinomas. We concluded that IGFBP2 and IGFBP5 might play a role in the development of high-grade ovarian serous carcinoma, but not in mucinous or clear cell ovarian carcinomas.

Adenocarcinoma, Clear Cell↗
PubMed2006

Randomized, double-blind, placebo-controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation.

PURPOSE: Because raised matrix metalloprotease (MMP) levels are associated with glioma invasion and angiogenesis, we tested the efficacy of marimastat (MT) an orally active drug that can reduce MMP levels, in patients with gliomas. PATIENTS AND METHODS: A total of 162 patients with intracranial glioblastoma multiforme or gliosarcomas who had undergone surgery and radiotherapy participated in this multicenter, double-blind, placebo-controlled, parallel group study conducted at 20 institutions. Seventy-nine patients (57 male, 22 female, median age 58 years) were randomized to receive placebo (PB), and 83 patients (51 male, 32 female, median age 57 years) were randomized to receive MT, 10 mg orally twice daily, until tumor progression. RESULTS: This intention-to-treat efficacy analysis showed no statistically significant difference between MT and PB groups with respect to survival (P = 0.38, log rank test). The median survival time from protocol initiation was 37.9 weeks for the PB group and 42.9 weeks for the MT group, with a hazard ratio of 1.16 (95% CI 0.83 to 1.60). There were no statistically significant differences in quality of life between the PB and MT groups, as assessed by the FACT-BR questionnaire. Musculoskeletal toxicities led to dose modification or withdrawal in 20% of MT-treated and 1.2% of PB-treated patients. CONCLUSION: MT does not improve survival in patients with glioblastoma or gliosarcoma following surgery and radiotherapy. Therefore, single-agent MT appears unwarranted; however, MT in combination with cytotoxic chemotherapy may be warranted, as suggested by observations in our study and other studies.

Adult↗
PubMed2006

An interaction between insulin-like growth factor-binding protein 2 (IGFBP2) and integrin alpha5 is essential for IGFBP2-induced cell mobility.

In the study we report here, we tested the hypothesis that insulin-like growth factor-binding protein 2 (IGFBP2) promotes cell mobility through its interaction with integrin alpha5. Our previous microarray studies showed that IGFBP2 activates the expression of integrin alpha5. In addition, IGFBP2 has an Arg-Gly-Asp (RGD) domain, which is a known integrin binding motif. We first confirmed our microarray results by showing that the expression of integrin alpha5 is indeed up-regulated at the protein level in IGFBP2-overexpressing SNB19 glioma cells. Using co-immunoprecipitation, we confirmed that IGFBP2 does interact with integrin alpha5. To confirm that IGFBP2 interacts directly with integrin alpha5 through the RGD domain, we created an RGD --> RGE mutant (D306E) IGFBP2 and stably overexpressed the mutant IGFBP2 in the same cell line. Co-immunoprecipitation then showed that D306E-IGFBP2 had no detectable binding with integrin alpha5. We further observed that IGFBP2-overexpressing cells have extensive cell surface lamellipodia, whereas D306E-IGFBP2-overexpressing cells show abundant cell surface focal adhesions. Consistent with this, phenotype analysis then showed that IGFBP2-overexpressing cells have elevated migration rates compared with vector control; in contrast, the migration rates of the D306E-IGFBP2-overexpressing cells were not elevated and were comparable with that of vector control. Decreased expression of integrin alpha5 by small interference RNA in IGFBP2-overexpressing cells also reduced cell mobility. Therefore, we have concluded that one mechanism by which IGFBP2 activates IGFBP2-induced cell mobility is through its interaction with integrin alpha5 and this interaction is specifically mediated through the RGD domain on IGFBP2.

Base Sequence↗
PubMed2006

The SHREW1 gene, frequently deleted in oligodendrogliomas, functions to inhibit cell adhesion and migration.

Allelic loss of the short arm of chromosome 1 has been observed frequently in oligodendroglioma (60-80%). We evaluated 177 oligodendroglial tumor samples and defined a consensus region of deletion of approximately 630 kb. This region contains a single gene, SHREW1, which encodes a novel transmembrane protein in adherens junctions. Whereas a mutation was not detected in the coding region of the SHREW1 gene in oligodendrogliomas, restoration of SHREW1 expression resulted in suppression of cell adhesion and migration. Thus, SHREW1 inactivation may play a role in the development of oligodendroglial tumors.

Cell Adhesion↗
PubMed2006

Pathway alterations during glioma progression revealed by reverse phase protein lysate arrays.

The progression of gliomas has been extensively studied at the genomic level using cDNA microarrays. However, systematic examinations at the protein translational and post-translational levels are far more limited. We constructed a glioma protein lysate array from 82 different primary glioma tissues, and surveyed the expression and phosphorylation of 46 different proteins involved in signaling pathways of cell proliferation, cell survival, apoptosis, angiogenesis, and cell invasion. An analysis algorithm was employed to robustly estimate the protein expressions in these samples. When ranked by their discriminating power to separate 37 glioblastomas (high-grade gliomas) from 45 lower-grade gliomas, the following 12 proteins were identified as the most powerful discriminators: IBalpha, EGFRpTyr845, AKTpThr308, phosphatidylinositol 3-kinase (PI3K), BadpSer136, insulin-like growth factor binding protein (IGFBP) 2, IGFBP5, matrix metalloproteinase 9 (MMP9), vascular endothelial growth factor (VEGF), phosphorylated retinoblastoma protein (pRB), Bcl-2, and c-Abl. Clustering analysis showed a close link between PI3K and AKTpThr308, IGFBP5 and IGFBP2, and IBalpha and EGFRpTyr845. Another cluster includes MMP9, Bcl-2, VEGF, and pRB. These clustering patterns may suggest functional relationships, which warrant further investigation. The marked association of phosphorylation of AKT at Thr308, but not Ser473, with glioblastoma suggests a specific event of PI3K pathway activation in glioma progression.

Adult↗
PubMed2006

Expression of the receptor tyrosine kinase Tie2 in neoplastic glial cells is associated with integrin beta1-dependent adhesion to the extracellular matrix.

The abnormal function of tyrosine kinase receptors is a hallmark of malignant gliomas. Tie2 receptor tyrosine kinase is a specific endothelial cell receptor whose function is positively regulated by angiopoietin 1 (Ang1). Recently, Tie2 has also been found in the nonvascular compartment of several tumors, including leukemia as well as breast, gastric, and thyroid cancers. There is, however, little information on the function of the Ang1/Tie2 pathway in the non-stromal cells within human tumors. We found that surgical glioblastoma specimens contained a subpopulation of Tie2+/CD31- and Tie2+/GFAP+ cells, suggesting that Tie2 is indeed expressed outside the vascular compartment of gliomas. Furthermore, analysis of a tissue array consisting of 116 human glioma samples showed that Tie2 expression in the neoplastic glial cells was significantly associated with progression from a lower to higher grade. Importantly, Ang1 stimulation of Tie2+ glioma cells resulted in increased adherence of the cells to collagen I and IV, suggesting that Tie2 regulates glioma cell adhesion to the extracellular matrix. Conversely, the down-regulation of Tie2 levels by small interference RNA or the addition of soluble Tie2 abrogated the Ang1-mediated effect on cell adhesion. In studying the expression of cell adhesion molecules, we found that Tie2 activation was related to the up-regulation of integrin beta1 levels and the formation of focal adhesions. These results, together with the reported fact that malignant gliomas express high levels of Ang1, suggest the existence of an autocrine loop in malignant gliomas and that a Tie2-dependent pathway modulates cell-to-extracellular matrix adhesion, providing new insights into the highly infiltrative phenotype of human gliomas.

Cell Adhesion↗
PubMed2006

Overexpression of IGFBP5, but not IGFBP3, correlates with the histologic grade of human diffuse glioma: a tissue microarray and immunohistochemical study.

Insulin-like growth factor binding proteins (IGFBPs) comprise a family of proteins that bind and regulate the functions of IGFs. One of the IGFBPs, IGFBP2, has recently been shown to be overexpressed in glioblastoma. Overexpression of IGFBP2 contributes to the invasiveness of glioblastoma and correlates with histologic grade and survival in patients with diffuse gliomas, suggesting that IGFBP2 expression may contribute to the glioma formation and/or progression. The expression of other IGFBP family members in gliomas has, however, not been examined in detail. This study was designed to evaluate the expression of IGFBP3 and IGFBP5 in diffuse gliomas using immunohistochemistry applied to a tissue array constructed from 259 gliomas, including ten gliosarcomas. Expression of IGFBP5 correlated significantly with glioma histologic grade. 83% (58/70) of glioblastomas (WHO Grade IV) were positive for IGFBP5, which was significantly higher than WHO Grade III gliomas (41%, 41/101) or WHO Grade II gliomas (18%, 13/72) (p<0.001). In contrast, IGFBP3 was expressed in 17%, 23%, and 17% of WHO Grade IV, Grade III, and Grade II gliomas, respectively (p>0.05). There was no significant difference in IGFBP3 expression among different grades of glioma. Our study thus demonstrates that the expression of IGFBP5, but not IGFBP3, increases with glioma anaplastic progression. The strong correlation between overexpression of IGFBP5 and histologic grade suggests that, in addition to IGFBP2, IGFBP5 may also play a role in glioma progression.

Biomarkers, Tumor↗
PubMed2006

Intermittent lumbar puncture in rats: a novel method for the experimental study of opioid tolerance.

Spinal subarachnoid opioid administration in rats has been a very important method for studying the pharmacological effects of opioids, including analgesia and tolerance. Intrathecal catheterization, either through the cervical or lumbar approach, has been the predominant method used to deliver opioids spinally. However, these methods have potential undesirable complications. To help mitigate these problems, we have developed a method of intermittent lumbar puncture in rats to study the effects of chronic spinal opioid administration. This method avoids catheter-associated morbidity. We demonstrate that this method can be readily used to induce spinal opioid tolerance without causing morbidity. Intermittent lumbar puncture should prove to be a useful technique for investigating mechanisms of spinal opioid analgesia and opioid tolerance development.

Analgesics, Opioid↗
PubMed2006

Sustained angiopoietin-2 expression disrupts vessel formation and inhibits glioma growth.

Systematic analyses of the expression of angiogenic regulators in cancer models should yield useful information for the development of novel therapies for malignant gliomas. In this study, we analyzed tumor growth, vascularization, and angiopoietin-2 (Ang2) expression during the development of U-87 MG xenografts. We found that tumoral angiogenesis in this model follows a multistage process characterized by avascular, prolific peripheral angiogenesis, and late vascular phases. On day 4, we observed an area of central necrosis, a peripheral ring of Ang2-positive glioma cells, and reactive Ang2-positive vascular structures in the tumor/brain interface. When the tumor had developed a vascular network, Ang2 was expressed only in peripheral vascular structures. Because Ang2 expression was downmodulated in the late stages of development, probably to maintain a stable tumoral vasculature, we next studied whether sustained Ang2 expression might impair vascular development and, ultimately, tumor growth. Ang2 prevented the formation of capillary-like structures by and impaired angiogenesis in a chorioallantoic membrane chicken model. Finally, we tested the effect of sustained Ang2 expression on U-87 MG xenograft development. Ang2 significantly prolonged the survival of intracranial U-87 MG tumor-bearing animals. Examination of Ang2-treated xenografts revealed areas of tumor necrosis and vascular damage. We therefore conclude that deregulated Ang2 expression during gliomagenesis hindered successful angiogenesis and that therapies that sustain Ang2 expression might be effective against malignant gliomas.

Angiopoietin-2↗
PubMed2006

Origin of chordoid glioma of the third ventricle.

CONTEXT: Chordoid glioma is a relatively recently described unique glial neoplasm that has been formally codified by the World Health Organization in Pathology and Genetics of Tumours of the Nervous System, in which it is included along with astroblastoma and gliomatosis cerebri under the rubric "Tumors of Uncertain Origin." Many examples of chordoid glioma come to clinical attention only at a relatively large size and occupy a large portion of the third ventricle. Accordingly, the anatomic origin of chordoid glioma has been unclear and debated. OBJECTIVE: To examine the regional anatomic origin of chordoid glioma. DATA SOURCES: The clinical, imaging, histologic, immunophenotypic, and ultrastructural data in previously published case series and individual case reports of chordoid glioma were reviewed in conjunction with the study of a new case of chordoid glioma that presented at a relatively small size, thereby facilitating neuroanatomic localization. CONCLUSIONS: Chordoid glioma exhibits features of specialized ependymal differentiation on ultrastructural examination, and all examples reported in the literature to date have displayed a highly stereotypical suprasellar anatomic localization and an ovoid shape, as seen on neuroimaging studies and gross anatomy. Neuroanatomic, radiologic, and clinical evidence supports an anatomic origin for chordoid glioma from the vicinity of the lamina terminalis.

Biomarkers, Tumor↗
PubMed2006

Pulmonary artery sarcoma: a clinicopathologic and immunohistochemical study of 12 cases.

We report 12 cases of pulmonary artery sarcoma. The mean age at diagnosis was 48.4 years. Based on histomorphologic features and immunohistochemical findings, 2 tumors were classified as rhabdomyosarcoma, 4 as leiomyosarcoma, 1 as osteogenic sarcoma, 1 as angiosarcoma, and 4 as high-grade sarcoma. All patients underwent surgery. In addition, 7 patients received neoadjuvant or adjuvant therapy. Five patients died 3 to 23 months after surgery. Three patients were still alive at 8, 27, and 68 months at last follow-up. Another 3 patients were alive at 2, 15, and 40 months and then lost to follow-up. The 2 patients with the longest survival (40 months and 68 months) had a diagnosis of leiomyosarcoma. Both patients with rhabdomyosarcoma died at 3 months after surgery. Pulmonary artery sarcoma is an uncommon entity with a poor prognosis. The role of early diagnosis, histologic classification, surgical treatment, and adjuvant therapy in patient outcome is discussed.

Adult↗
PubMed2005

Attenuated expression of DFFB is a hallmark of oligodendrogliomas with 1p-allelic loss.

Allelic loss of chromosome 1p is frequently observed in oligodendroglioma. We screened 177 oligodendroglial tumors for 1p deletions and found 6 tumors with localized 1p36 deletions. Several apoptosis regulation genes have been mapped to this region, including Tumor Protein 73 (p73), DNA Fragmentation Factor subunits alpha (DFFA) and beta (DFFB), and Tumor Necrosis Factor Receptor Superfamily Members 9 and 25 (TNFRSF9, TNFRSF25). We compared expression levels of these 5 genes in pairs of 1p-loss and 1p-intact tumors using quantitative reverse-transcriptase PCR (QRTPCR) to test if 1p deletions had an effect on expression. Only the DFFB gene demonstrated decreased expression in all tumor pairs tested. Mutational analysis did not reveal DFFB mutations in 12 tested samples. However, it is possible that DFFB haploinsufficiency from 1p allelic loss is a contributing factor in oligodendroglioma development.

Chromosomes, Human, Pair 1↗
PubMed2005

A mutation-created novel intra-exonic pre-mRNA splice site causes constitutive activation of KIT in human gastrointestinal stromal tumors.

We report a new mechanism of aberrant pre-mRNA splicing resulting in constitutive activation of a mis-spliced oncoprotein (KIT) leading to malignancy (gastrointestinal stromal tumor) in contrast to loss of function of mis-spliced proteins resulting in diverse human diseases in the literature. The mechanisms of three consecutive molecular events, deletion of noncoding and coding regions encompassing the 3' authentic splice site, creation of a novel intra-exonic pre-mRNA 3' splice acceptor site leading to in-frame loss of 27 nucleotides (nine amino acids; Lys550-Lys558), and the mechanism of constitutive activation of the mis-spliced KIT are elucidated. Loss of a peptide in a critical location unleashed the protein from autoinhibition (as evidenced by three-dimensional structural analysis), causing KIT to become constitutively activated and resulting in the GIST phenotype. We also demonstrated that only one of the following two exonic splicing enhancers is sufficient for inclusion of the KIT exon 11 in vivo: AACCCATGT (nucleotides 2-10 from the 5' end, which are recognized by SC35, SRp55, and SF2/ASF) or GGTTGTTGAGG (nucleotides 27-37 from the 5' end, which are recognized by SC35 and SRp55), suggestive of exonic enhancer redundancy.

Alternative Splicing↗
PubMed2005

Inactivation of the invasion inhibitory gene IIp45 by alternative splicing in gliomas.

The invasion inhibitory protein 45 (IIp45) we recently identified was underexpressed in glioblastoma multiforme, the most malignant form of glioma. The IIp45 gene is located at chromosome 1p36 where frequent deletions have been reported in various types of tumors, including gliomas, raising the possibility that IIp45 may be a classic tumor suppressor gene that can be inactivated by frequent point mutations. To test this hypothesis, we sequenced the IIp45 gene in 59 diffuse glioma samples of different grades and histologic subtypes and identified a possible point mutation or a rare polymorphism in only one sample (1.7%), suggesting that IIp45 is not a classic tumor suppressor gene such as p53. Instead, reverse transcription-PCR and subsequent sequencing results revealed a tumor-specific IIp45 spliced isoform (IIp45S) in 20 of 59 (34%) gliomas examined, particularly in glioblastoma multiformes, including native tissue samples (15 of 25; 60%) and cell lines (5 of 5; 100%). The alternative splicing event is independent of 1p36 deletion, which is not common in glioblastoma multiforme. The IIp45S transcript was not detected in any of 18 normal organs, including fetal and adult brain. We determined that the IIp45S isoform results from exclusion of IIp45 exon 7 and encodes a variant protein that carries a COOH terminus different from that of IIp45 due to a frame-shift mutation. IIp45S protein was undetectable in glioma tissues, although IIp45S mRNA was prevalent. We found that IIp45S, once translated, is rapidly degraded by an ubiquitin-proteasome mechanism. Thus, the IIp45 gene is inactivated by a tumor-specific alternative splicing that generates an aberrant and unstable IIp45 isoform in infiltrative gliomas.

Alternative Splicing↗
PubMed2005

Loss of the AP-2alpha transcription factor is associated with the grade of human gliomas.

PURPOSE: The activator protein (AP)-2alpha transcription factor plays a crucial role in the progression of several human tumors, including malignant melanoma, prostate, and breast cancer. Loss of AP-2alpha results in deregulation of several genes with AP-2alpha binding motifs such as E-cadherin, p21WAF1, MMP-2, MCAM/MUC18, VEGF, and c-KIT. The purpose of our study was to determine AP-2alpha expression distribution among grades of gliomas and any possible effect on prognosis. EXPERIMENTAL DESIGN: A tissue microarray was assembled from all surgical glioma cases with available tissue samples at M.D. Anderson Cancer Center since 1986 to include 72 glioblastomas, 49 anaplastic astrocytomas, 9 low-grade astrocytoma, 37 oligodendrogliomas, 37 anaplastic oligodendrogliomas, 15 mixed oligoastrocytomas, 20 anaplastic mixed oligoastrocytomas, and 7 gliosarcomas. The microarray included normal brain tissue, and AP-2alpha expression was determined by immunohistochemistry. RESULTS: AP-2alpha expression was lost on 99% (P < 0.001) and 98% (P < 0.001) of glioblastomas and anaplastic astrocytomas, respectively, compared with grade 2 astrocytomas and normal brain, all of which (100%) maintained expression of AP-2alpha. The loss of AP-2alpha was a negative prognostic indicator within the overall category of gliomas by univariate analysis (rate ratio, 4.30; 95% confidence interval, 2.60-7.10; P < 0.001). However, there was no significant effect of loss of AP-2alpha expression on survival observed after adjustment for patient age, Karnofsky Performance Scale score, tumor grade, and extent of resection (rate ratio, 1.2; 95% confidence interval, 0.6-2.2; P = 0.6). CONCLUSIONS: AP-2alpha expression correlates inversely with glioma grade, suggesting a direct role in glioma tumorigenicity, possibly through subsequent deregulation of target genes. Of all the previously characterized markers of progression, the loss of AP-2alpha would be the most common (96.2%) molecular marker as an astrocytic tumor evolves from grade 2 to 3.

Adolescent↗