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Unit of Molecular Pathology, International Agency for Research on Cancer (IARC), 69372 Lyon, France [H. H., S. C., P. K., H. O.], and Departments of Pathology [M. K.] and Neurosurgery [Y. Y.], University Hospital Zurich, CH-8091 Zurich, Switzerland
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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, 60S ribosomal
protein L5, PTN, and hBAP) were found to be
up-regulated more than 2-fold in 20–60% of cases, whereas 11 genes
(IFI 9-27, protein kinase CLK, TDGF1, BIN1, GAB1, TYRO3, LDH-A,
adducin 3, GUK1, CDC10, and KRT8) were
down-regulated to less than 50% of normal levels in 64–100% of
cases. Semiquantitative conventional reverse transcription-PCR was
performed for 11 genes, 9 of which showed an expression profile similar
to that obtained with cDNA expression arrays. Immunohistochemical
staining for SPARC showed cytoplasmic immunoreactivity of neoplastic
cells in all diffuse astrocytomas analyzed. These results indicate
significant changes in gene expression in diffuse astrocytomas, but it
remains to be shown which of these are causally related to the
transformation of glial cells. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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The genetic profile of low-grade astrocytomas is still far from being
complete. The most frequent genetic alterations are p53
mutations and
LOH3
on chromosome 17p, which are present in approximately two-thirds of the
cases (4
, 5)
. Overexpression of PDGFR- has been
observed in approximately 50% of low-grade astrocytomas, and this was
often associated with LOH on chromosome 17p (6)
. Loss of
chromosome 22q13.3 has been observed in up to 30% of astrocytomas
(7)
, but the putative tumor suppressor gene on this
chromosomal region has yet to be identified. Comparative genomic
hybridization studies showed frequent loss of portions of chromosomes
1p and 19q (8)
, but LOH on chromosomes 1p and 19q appears
to be rare in low-grade astrocytomas (9
, 10)
.
The objective of this study was to expand the current knowledge of altered gene expression in low-grade diffuse astrocytomas as a first step in the identification of additional oncogenes or tumor suppressor genes operative in the evolution of diffuse astrocytomas and secondary glioblastomas derived thereof.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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.
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Total RNA Isolation.
Total RNA was isolated from frozen brain tissues using the Atlas Pure
Total RNA Labeling System (Clontech, Palo Alto, CA) according to
manufacturer’s instructions. Briefly, 150–200 mg of tissue were
homogenized in 3 ml of denaturing solution. After two phenol/chloroform
extractions, RNA was precipitated with isopropanol, washed with 80%
ethanol, and air dried. To remove genomic DNA contamination, RNA was
treated with RNase-free DNase I (Clontech), and RNA was then dissolved
in RNase-free H2O and stored at -80°C until
analysis.
cDNA Probe Preparation.
For cDNA probe synthesis, 5 µg of DNase-treated total RNA together
with 1 µl of CDS primer mix (Clontech) in a total volume of 6 µl
were heated to 70°C for 10 min and then cooled on ice. A mixture
consisting of 4 µl of 5x first-strand cDNA buffer (Life
Technologies, Inc., Gaithersburg, MD), 1 µl of 100 mM
DTT, 2 µl of 10 mM dNTPs (Clontech), 1 µl of RNase
block (40 units/µl; Stratagene, La Jolla, CA) and 5 µl of
[-32P]dATP (3000 Ci/mmol, 10 µCi/µl;
ICN) was added into the tube and heated at 42°C for 2 min. One µl
of SuperScript II RNase H reverse transcriptase (200 units/µl; Life
Technologies, Inc.) was then added, and the reaction was continued at
the same temperature for 50 min, followed by heating to 70°C for 15
min for enzyme inactivation. The cDNA probe was purified with a CHROMA
SPIN-200DEPC-H2O column (Clontech). Incorporation
of 32P into the probe was determined by counting
in a liquid scintillation counter (BETAMATIC; Kontron Instruments,
Montigny le Bretonneux, France). The first two fractions showing the
highest counts were collected and used for hybridization with cDNA
array.
Hybridization and Quantitation of cDNA Arrays.
The Atlas Human Cancer 1.2 Arrays containing cDNA fragments of 1176
cancer-associated human genes/clones were purchased from Clontech.
Preliminary experiments using different hybridization temperatures
(64°C–68°C), washing conditions (64°C–68°C for different
periods of time), and exposure time (up to 14 days) showed that up to
80% of total genes spotted onto the array could be detected using
brain samples. The experimental conditions were then optimized (see
below) to yield unambiguous and reproducible X-ray signals of
approximately 250–300 genes after 6 days of exposure.
Array membranes were prehybridized with 5 µl of ExpressHyb solution
(Clontech) at 68°C with continuous rotation in a glass hybridization
roller. After prehybridization for 2 h, purified
-32P-labeled cDNA probes made from normal or
tumor RNAs were added into different rollers, and hybridization was
continued overnight at the same temperature. Arrays were subsequently
washed twice in 200 ml of wash solution 1 (2x SSC, 1% SDS) at 68°C
for 20 min with agitation and then washed once in 200 ml of wash
solution 2 (0.1x SSC, 0.5% SDS) at 68°C for 20 min with agitation.
After a final wash with 200 ml of 2x SSC for 5 min at room
temperature, the damp membranes were sealed in plastic wrap and exposed
to Kodak Biomax MS X-ray film with an intensifying screen at -80°C
for 6 days.
Array images on the X-ray film were scanned at 400 dpi by using an image scanner (X-Finity professional, Model PS4800+; PFU Limited, Japan) and then analyzed using AtlasImage 1.01a software (Clontech). We first eliminated by visual inspection false positive signals due to apparent artifacts; the intensity of each spot on the array was then calculated after background subtraction. Mean values of intensity for each gene detected from multiple arrays were generated by the computer software (an averaged array). Two averaged arrays (one from 3 normal brain tissues and another from 11 tumor samples) were then compared. For generating mean intensity from multiple arrays and for subsequent comparison between two arrays, the "global" mode was used, which normalizes data using all genes presented on the array, instead of one or several housekeeping genes, as reference. Furthermore, to assess the frequency of positive cases and the mean and range of expression levels of each gene, an averaged array of nontumorous tissues and an individual tumor array were compared. Putative functions of the genes identified were obtained by use of the AtlasInfo database.4
To assess the reproducibility of this system, we repeated hybridization for three samples using new probes synthesized from the original total RNA. The difference between experiments was within 15%, and the majority (>90%) of expression signals were reproducibly detected.
RT-Differential PCR.
First-strand cDNA was synthesized as follows: 1 µg of DNase-treated
total RNA together with 0.5 µg of
oligo(dT)12–18 (Pharmacia, Uppsala, Sweden) in a
total volume of 11 µl were heated to 70°C for 10 min and then
chilled on ice. A mixture consisting of 4 µl of 5x first-strand cDNA
buffer (Life Technologies, Inc.), 2 µl of 100 mM DTT, 1
µl of 10 mM dNTPs, and 1 µl of Rnase block (40
units/µl; Stratagene) was added into the tube and heated at 42°C
for 2 min. SuperScript II RNase H Reverse Transcriptase (200 units;
Life Technologies, Inc.) was then added, and the reaction continued at
42°C for 50 min. After a 15-min inactivation step at 70°C, the cDNA
was stored at -20°C until use.
Differential PCR was performed by coamplification of the gene in question together with a reference gene (ß-actin or GAPDH) using cDNA template generated as described above and corresponding gene-specific primer sets. The primer sequences are as follows: (a) 5'-GCCTTCTGCAACTCCGACATC-3' (sense) and 5'-CGTGTACATCTTGCCATCATA-3' (antisense) for TIMP3; (b) 5'-CAAGAAGCCCTGCCTGATGAG-3' (sense) and 5'-GGGGTCCTGGCACACGCACAT-3' (antisense) for SPARC; (c) 5'-GCTCTGCTCGCCCTCCTACG-3' (sense) and 5'-AAGCCGCTCCACATACAGTC-3' (antisense) for c-myc; (d) 5'-AGCCATGCCCGCATTAGCTC-3' (sense) and 5'-AAAGGAATGCAACTTCCCAA-3' (antisense) for EGFR; (e) 5'-AGAACCGAAGCAAGCCAAAGA-3' (sense) and 5'-GCTGCTCATCCCCAGAGG-3' (antisense) for AAD14; (f) 5'-GTCACCCACCTCAACATTTCA-3' (sense) and 5'-CATCGCTGCCGTCTCAA-3' (antisense) for LRP; (g) 5'-GGTCCTCGTCAACGCAGTGTA-3' (sense) and 5'-TGGCAGACAGCGGAGTGG-3' (antisense) for GDNPF; (h) 5'-ATCAACATCCACAGCGAGACC-3' (sense) and 5'-CAGAGCCGAATACCAGTGACA-3' (antisense) for IFI 9-27; (i) 5'-GACCTGCTGTGGATGGATT-3' (sense) and 5'-ACCTTCTGGGCTTTGATGAG-3' (antisense) for BIN1; (j) 5'-CCTGGCCGACAACCTGTAT-3' (sense) and 5'-TCCATTCGCAGACAAGTAAAGC-3' (antisense) for TRYO3; (k) 5'-GCAGTATCCTTGGGGTATTGCT-3' (sense) and 5'-TCTTCTTCCATTTGTGCCAGAG-3' (antisense) for CDC10; (l) 5'-CAACCGCGAGAAGATGACC-3' (sense) and 5'-TCCAGGGCGACATAGCACA-3' (antisense) for ß-actin; and (m) 5'-AACGTGTCAGTGGTGGACCTG-3' (sense) and 5'-AGTGGGTGTCGCTGTTGAAGT-3' (antisense) for GAPDH. PCR was carried out in a total volume of 10 µl containing 0.5 µl of cDNA solution, 0.5 unit of Taq DNA polymerase (Sigma, St. Louis, MO), 1–2 mM MgCl2, 0.2 mM each dNTP, 0.1–0.2 µM sense and antisense primers, 10 mM Tris-HCl (pH 8.3), and 50 mM KCl in a Robot Thermal Cycler (Stratagene) as follows: (a) initial denaturation for 5 min at 94°C; (b) 29–35 cycles with denaturation at 94°C for 30 s, annealing at 56°C–61°C for 1 min, and extension at 72°C for 1 min; and (c) a final extension step for 5 min at 72°C. After PCR, 7 µl of products were run on a 2% agarose gel and stained with ethidium bromide; the intensity of target and reference genes was quantified using the 1D Image Analysis Software (Kodak Digital Science). Change of gene expression was then calculated as a ratio of the intensity of tumor to control samples after normalization using a factor derived from the relative intensity of the reference gene in tumor and control samples.
Immunohistochemistry.
Formalin-fixed, paraffin-embedded sections of 11 low-grade astrocytomas
analyzed in the cDNA expression array were deparaffinized in xylene and
rehydrated in graded ethanol. Endogenous peroxidase activity was
blocked with 0.3% hydrogen peroxide in methanol for 30 min at room
temperature. The sections were microwaved in antigen unmasking solution
(Vector Laboratories, Burlingame, CA) for 3 x 5 min.
After incubation with 5% skimmed milk for 1 h at room
temperature, the sections were incubated overnight at 4°C with the
primary monoclonal antibody against SPARC (10.9 mg/ml; Hematological
Technologies Inc., Essex Junction, VT; 1:15,000 dilution). The reaction
was visualized using Vectastain Elite ABC kit (Vector Laboratories) and
3,3'-diaminobenzidine solution (Vector Laboratories). The sections were
then counterstained with hematoxylin. Formalin-fixed, paraffin-embedded
sections of human breast tumors were used as positive controls
(11)
. Sections without primary antibody were served as
negative controls.
Screening for p53 Mutations.
Exons 5–8 of the p53 gene were screened for mutations in
all 11 low-grade astrocytomas using single-strand conformational
polymorphism followed by direct sequencing as described previously
(5)
.
Statistical Analyses.
Student’s unpaired t test was carried out to compare data
in tumors with and without p53 mutations.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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3
4
and Fig. 2
are restricted to genes that showed altered
expression in at least 20% of cases. A total of 24 genes showed
significant expression change: 6 genes were detectable only in tumors;
7 genes were overexpressed; and 11 genes were down-regulated (Tables 2
3
4)
. Examples of array autoradiographs are shown in Fig. 1
.
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. The overall gene expression profiles of these tumors
showed patterns similar to those of fibrillary astrocytomas (Fig. 1)
.
Using the criteria set-up above, no genes were identified as
significantly differentially expressed between the two subtypes when
comparing two averaged arrays generated from pooled data from the
respective subtypes.
Low-grade Astrocytomas with and without p53
Mutation.
Single-strand conformational polymorphism analysis followed by direct
DNA sequencing revealed that 8 of 11 (73%) low-grade astrocytomas
contained a p53 mutation (Table 1)
. Except for GDNPF
(intensity x 1000, 9.23 ± 4.60 for wild type
versus 6.36 ± 0.82 for mutant;
P = 0.006) and LDH-A (T/N, 0.29 ± 0.03 for wild type versus 0.36 ± 0.11 for mutant;
P = 0.04), gene expression profiles showed no
statistically significant differences between tumors with and without
p53 mutations (Fig. 2)
.
RT-Differential PCR.
To confirm the mRNA expression data obtained by cDNA expression array,
we performed semiquantitative RT-PCR for 11 of the genes listed in
Tables 2
3
4
. Although the extent of change detected by the two methods
varied, probably due to the difference in sensitivity, expression
change of nine of the genes detected by RT-PCR showed the same tendency
as in cDNA array experiments (Fig. 3)
. The expression of two genes (BIN1 and CDC10)
did not differ significantly between tumors and nontumorous brain
tissues by RT-PCR (data not shown). The increase versus
control levels was 2.5-fold for EGFR (range, 1.1–3.3),
3.5-fold for SPARC (range, 2.1–4.6), 8.5-fold for TIMP3 (range,
2.3–17.2), 1.7-fold for GDNPF (range, 0.7–2.2), and 1.7-fold for LRP
(range, 1.0–2.4). The decrease versus control levels was
18% (range, 3–75%) for IFI 9-27 and 68% (range, 57–93%) for
TYRO3.
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, whereas the adjacent normal brain tissue was negative.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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3
4)
.
The genes identified have putative functions in a variety of cellular
processes. They can be classified into three major categories:
(a) cell growth and transformation, cell cycle control, and
apoptosis (c-myc, EGFR, PDGFR-, TDGF1, PTN, BIN1,
GAB1, and GDNPF); (b) cytokine, protein kinase, signal
transduction and cell surface receptors, and associated proteins
(IFI 9-27, AAD14, CLK, LDH-A, LRP, GUK1, CDC10, DR-nm23, and
nm-23-H4); (c) cell adhesion and basement
membrane and ECM proteins (SPARC, TIMP3, adducin 3, TYRO3,
and KRT8) (Tables 2
3
4)
. It is notable that this study has
identified several genes, such as PDGFR-, c-myc,
EGFR, LRP, and SPARC, for which overexpression has been
previously reported in astrocytic brain tumors, demonstrating the
suitability and power of cDNA array technology in the identification of
transformation-associated genes.
PDGFR- overexpression in low-grade astrocytomas was first detected
by in situ hybridization (12
, 13)
. In the
present study, PDGFR- overexpression was seen in 2 of 10 low-grade
astrocytomas (Table 3
; Fig. 2B
). Hermanson et al.
(6)
reported that a high level of PDGFR- expression was
significantly correlated with LOH on chromosome 17p in astrocytic brain
tumors. This is corroborated by our observation that the two low-grade
astrocytomas with more than 2-fold overexpression of PDGFR-
contained a p53 mutation (Fig. 2)
.
Overexpression of the c-myc oncoprotein has previously been
detected by immunohistochemistry in 5% of low-grade, 33% of
intermediate-grade, and 76% of high-grade astrocytic gliomas
(14)
. In the present study, we show that in normal brain
tissue, the c-myc mRNA level was below the detection limit
by cDNA array hybridization and RT-PCR (Fig. 3)
, whereas 73% of the
low-grade astrocytomas showed c-myc expression (Figs. 2A
and 3)
, supporting the view that c-myc
overexpression may be involved in the pathogenesis of low-grade
astrocytomas.
EGFR amplification and overexpression are genetic hallmarks
of primary (de novo) glioblastomas (15
, 16)
. In
contrast, EGFR amplification (analyzed by Southern blot or
differential PCR) and EGFR overexpression (analyzed by
immunohistochemistry; Ref. 16
) are rarely detected in
low-grade astrocytomas (17
, 18)
and the secondary
glioblastomas derived thereof (5
, 16)
. In the present
study, we found that in normal brain tissue, EGFR mRNA was
not detectable by cDNA expression array and was only detectable at low
levels by RT-PCR. A small up-regulation of EGFR expression
(1.1–3.3-fold) was observed in all low-grade astrocytomas analyzed
(Fig. 3)
. This level of EGFR overexpression is significantly
lower than that observed in primary glioblastomas, and it remains to be
shown whether it plays a significant role in the development of
low-grade astrocytomas.
LRP is a multifunctional cell surface receptor involved in lipoprotein
metabolism and cellular lipid uptake. It can bind specifically to
2-macroglobulin-proteinase complexes and
regulates proteinase activity, which is necessary for cellular
migration and invasive processes (19
, 20)
. It may also
function in cell growth and repair (21)
. A recent study
using RT-PCR and immunohistochemistry showed that LRP was overexpressed
in 4 of 25 high-grade gliomas and that this often occurred in
association with EGFR amplification (21)
. In
the present study, LRP up-regulation was observed in 60% of low-grade
astrocytomas (Table 3)
, indicating that this gene is already involved
in early stages of gliomagenesis.
SPARC and TIMP3 identified in this study are involved in cell adhesion
and cell-ECM interactions. SPARC is a
Mr 43,000 secreted glycoprotein
that interacts with the ECM components. In endothelial cells and
fibroblasts, SPARC acts as a negative mediator of spreading and is
associated with pathophysiological events requiring tissue remodeling
and de novo formation of basement membranes
(22)
. SPARC also regulates and coordinates endothelial
cell proliferation and migration during wound healing and angiogenesis
(23
, 24)
. Immunohistochemistry showed that SPARC is
expressed in normal steroidogenic cells, chondrocytes, placental
trophoblasts, vascular smooth muscle cells, and endothelial cells
(11)
. Strong reactivity was also found in fibrocytes and
endothelial cells involved in tissue repair (11)
. SPARC is
highly expressed in a variety of human neoplasms, including colorectal
cancer (22)
, ovarian cancer (25)
, melanomas
(23
, 26)
, meningiomas (27)
, and gliomas
(28)
. Using subtractive hybridization, immunoblotting, and
immunohistochemistry, Rempel et al. (28)
recently showed that SPARC is overexpressed in the majority of
low-grade astrocytomas, anaplastic astrocytomas, and glioblastomas. In
this study, RT-PCR revealed that SPARC expression was up-regulated by
2.1–4.6-fold in all low-grade astrocytomas (Fig. 3)
, lending further
evidence to the view that SPARC is an invasion-related candidate gene
in low-grade astrocytomas (28)
.
TIMP3 is a member of the TIMP family, which is a group of multifunctional secreted proteins that play pivotal roles in the regulation of ECM metabolism by inhibiting the activity of various MMPs. Deregulation of either TIMPs or MMPs leads to unbalance of activities between these two types of enzymes, and this is considered to be related to the invasive phenotype of human neoplasms, including gliomas (29 , 30) . In addition to their inhibitory activity on metalloproteinases, some of the TIMP family proteins have other distinct properties such as growth factor function and promotion of oncogenic transformation (31, 32, 33) . Simultaneous overexpression of TIMP2 and MMPs has been observed in recurrent gliomas more frequently than in primary tumors (34) , suggesting that overexpression of these genes contributes to the invasive and more aggressive nature of the recurrent gliomas. TIMP3 overexpression has been observed in all breast carcinomas analyzed (32 , 33) . However, a recent study (35) showed an aberrant methylation pattern in the TIMP3 promoter region in several primary tumors, including brain tumors, suggesting a tumor suppressor role for TIMP3. In this study, we found that TIMP3 was overexpressed (2.3–17.2-fold by RT-PCR) in all low-grade astrocytomas. A recent study using serial analysis of gene expression reported a 13-fold increase in TIMP4 expression in glioblastomas (36) . These results suggest that TIMP3 and TIMP4 and the interplay between TIMPs and MMPs may play a significant role in the pathogenesis of astrocytic brain tumors.
Several additional genes were found to be up-regulated. DR-nm23,
nm23-H4, 60S ribosomal protein L5, and PTN have been implicated in the
pathogenesis, angiogenesis, and metastasis of nonneural tumors (Tables 2
and 3)
. The possible role of AAD14, hBAP, and GNDPF in the multistep
process of malignant transformation is currently unknown.
IFI 9-27 regulates B-cell development and activation, mediates
antiproliferative activity of IFN- and -
, and may be implicated
in cell growth control (37, 38, 39)
. IFI 9-27 triggers
aggregation and inhibits proliferation of leukemic B cells
(38)
. In this study, we show that IFI 9-27 is
down-regulated in all low-grade astrocytomas analyzed. RT-PCR confirmed
that expression of this gene was reduced to 3–50% of control levels
in approximately 50% of the low-grade astrocytomas, whereas
nontumorous brain tissue showed a high level of expression (Fig. 3)
. It
remains to be elucidated whether this down-regulation of IFI 9-27 is a
causative event in the pathogenesis of low-grade astrocytomas. Several
other down-regulated genes such as TDGF1, BIN1, GAB1, TYRO3,
LDH-A, adducin 3, and KRT8 (Table 4)
have been
implicated in the pathogenesis of nonneural tumors. A role for protein
kinase CLK, adducin 3, GUK1, and CDC10 in tumorigenesis has not been
reported previously.
It should be pointed out that the cDNA array methodology examines the mRNA level rather than protein concentrations that can be regulated not only by transcriptional but also by posttranscriptional mechanisms. Thus, some genes with small changes in mRNA level (<2-fold in this study) but with significant change in protein level may have not been identified in this study.
The results obtained in this study demonstrate the complexity of
genes/pathways that may be involved in the development of low-grade
astrocytomas (Tables 2
3
4)
and point to some interesting candidate
genes worth further investigation. Whether these up- or down-regulated
genes are causally related to the transformation of glial cells remains
to be investigated.
In summary, the establishment of gene expression profiles in low-grade astrocytomas using cDNA array technology has demonstrated significant expression changes in a number of genes implicated in various cellular pathways related to the control of cell growth, differentiation, and tumor invasion. It provides information for additional molecular studies aimed at a clarification of their role in the development of astrocytic brain tumors.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by a grant from the Foundation for
Promotion of Cancer Research, Japan. 
2 To whom requests for reprints should be
addressed, at Unit of Molecular Pathology, IARC, 150 cours Albert
Thomas, 69372 Lyon Cedex 08, France. Phone: 33-472-73-85-34; Fax:
33-472-73-85-64; E-mail: ohgaki{at}iarc.fr
3 The abbreviations used are: LOH, loss of
heterozygosity; PDGFR, platelet-derived growth factor receptor; dNTP,
deoxynucleotide triphosphate; RT, reverse transcription; T/N,
tumor:normal ratio; LRP, Low-density lipoprotein receptor-related
protein 1; ECM, extracellular matrix; MMP, matrix metalloproteinase.
4 http://atlasinfo.clontech.com.
Received 6/ 8/00. Accepted 10/25/00.
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REFERENCES |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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 A. Giese, R. Bjerkvig, M.E. Berens, and M. Westphal Cost of Migration: Invasion of Malignant Gliomas and Implications for Treatment J. Clin. Oncol., April 15, 2003; 21(8): 1624 - 1636. [Abstract] [Full Text] [PDF]
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V.-M. Wasenius, S. Hemmer, E. Kettunen, S. Knuutila, K. Franssila, and H. Joensuu Hepatocyte Growth Factor Receptor, Matrix Metalloproteinase-11, Tissue Inhibitor of Metalloproteinase-1, and Fibronectin Are Up-Regulated in Papillary Thyroid Carcinoma: A cDNA and Tissue Microarray Study Clin. Cancer Res., January 1, 2003; 9(1): 68 - 75. [Abstract] [Full Text] [PDF]
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 M. Maekawa, M. Inomata, M. S. Sasaki, A. Kaneko, M. Ushiama, K. Sugano, J. Takayama, and T. Kanno Electrophoretic Variant of a Lactate Dehydrogenase Isoenzyme and Selective Promoter Methylation of the LDHA Gene in a Human Retinoblastoma Cell Line Clin. Chem., November 1, 2002; 48(11): 1938 - 1945. [Abstract] [Full Text] [PDF]
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 Y. Li, J. M. Knisely, W. Lu, L. M. McCormick, J. Wang, J. Henkin, A. L. Schwartz, and G. Bu Low Density Lipoprotein (LDL) Receptor-related Protein 1B Impairs Urokinase Receptor Regeneration on the Cell Surface and Inhibits Cell Migration J. Biol. Chem., October 25, 2002; 277(44): 42366 - 42371. [Abstract] [Full Text] [PDF]
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J. Wischhusen, G. Jung, I. Radovanovic, C. Beier, J. P. Steinbach, A. Rimner, H. Huang, J. B. Schulz, H. Ohgaki, A. Aguzzi, et al. Identification of CD70-mediated Apoptosis of Immune Effector Cells as a Novel Immune Escape Pathway of Human Glioblastoma Cancer Res., May 1, 2002; 62(9): 2592 - 2599. [Abstract] [Full Text] [PDF]
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S. Ramaswamy and T. R. Golub DNA Microarrays in Clinical Oncology J. Clin. Oncol., April 1, 2002; 20(7): 1932 - 1941. [Abstract] [Full Text] [PDF]
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D. S. Rickman, M. P. Bobek, D. E. Misek, R. Kuick, M. Blaivas, D. M. Kurnit, J. Taylor, and S. M. Hanash Distinctive Molecular Profiles of High-Grade and Low-Grade Gliomas Based on Oligonucleotide Microarray Analysis Cancer Res., September 1, 2001; 61(18): 6885 - 6891. [Abstract] [Full Text] [PDF]
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 E. A. Maher, F. B. Furnari, R. M. Bachoo, D. H. Rowitch, D. N. Louis, W. K. Cavenee, and R. A. DePinho Malignant glioma: genetics and biology of a grave matter Genes & Dev., June 1, 2001; 15(11): 1311 - 1333. [Full Text] [PDF]
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, tumors with
mutant p53. Note the heterogeneity of gene expression
among low-grade astrocytomas and the absence of significant differences
between tumors with and without p53 mutation.
