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Departments of Radiation Oncology [A. C. K., N. C. D., K. M. H., C. S., L. S., Q. T. L., A. J. G.] and Otolaryngology/Head and Neck Surgery [D. J. T., H. I.], Stanford University School of Medicine, Stanford, California 94305-5468, and Division of Oncology Research, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104 [C. K., S. E.]
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ABSTRACT |
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Introduction |
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Tumor hypoxia has been directly measured in a variety of human cancers including head and neck carcinomas, cervical carcinomas, and soft tissue sarcomas. Brizel et al. and Nordsmark et al. showed that, in head and neck carcinomas, hypoxia correlated with a lower probability of disease-free survival (4 , 5) and that, in soft tissue sarcomas, hypoxia was associated with increased incidence of distant metastases (6) . Hockel et al. (7) also found that hypoxia in cervical carcinomas resulted in increased local and distant failures. Interestingly, hypoxia predicted for distant failure not only in patients treated with radiotherapy but also in those treated with surgery alone. These studies suggest that hypoxia alters fundamental, physiologically important pathways that result in more aggressive tumor behavior in a wide variety of tumors.
We hypothesized that the development of an increased malignant
phenotype can at least partially be attributed to changes in hypoxic
gene expression. Under hypoxic conditions, the major transcription
factor affecting gene regulation is
HIF-13
(8)
. This factor regulates a diverse family of genes
including VEGF (9)
, the urokinase receptor
(10)
, tyrosine hydoxylase (11)
, endothelin 1
(12)
, nitric oxide synthase (13)
,
erythropoietin (14)
, and numerous glycolytic enzymes
(15)
. HIF-1 binds as a heterodimer consisting of an
oxygen-sensitive HIF-1
(helix-loop-helix protein, HLH) subunit
(16, 17, 18)
and a constitutively expressed oxygen insensitive
ARNT/HIF-1ß (aryl hydrocarbon receptor nuclear translocator) subunit
(17
, 18)
. HIF-1-deficient embryonic stem (ES) cells
that are null at this locus fail to induce HIF-1 target
genes when exposed to hypoxia (19
, 20)
. The HIF-1
heterodimer binds to a 6-bp [5'-ACGTG(C/G)-3'] hypoxia responsive
element (HRE) that functions as a transcriptional enhancer in
hypoxia-responsive genes (21)
. Although the majority of
hypoxia-regulated genes are dependent on HIF-1, other transcription
factors such as nuclear factor 
B (22
, 23)
, AP-1
(24
, 25)
, and c/EBPß (26
, 27)
as well as
Egr-1 (28)
are also activated by hypoxia.
We sought to characterize global transcriptional changes in tumor cells after exposure to hypoxic stress with the goal of determining how hypoxia influences the regulation of defined sets of genes involved in metabolic regulation, cell-cycle control, angiogenesis, and tissue invasion. We used cDNA array membranes containing 588 genes and compared gene expression under normoxic and hypoxic conditions in a squamous cell carcinoma-derived cell line. These studies resulted in the identification of nine hypoxia inducible genes that were subsequently confirmed by Northern blot analysis to be hypoxia-inducible.
To demonstrate the potential clinical applicability of hypoxic gene expression, we analyzed PAI-1 in the serum of patients with squamous cell carcinomas. Previous reports have suggested that PAI-1 plays a role in tissue invasion/remodeling and its up-regulation may contribute to the development of a more malignant tumor phenotype (29, 30, 31) . Furthermore, increased expression of PAI-1 in some human tumors has been correlated with poor prognosis (32 , 33) . Most importantly, because it is a secreted protein, serum levels are readily detectable and may be useful as a molecular marker of hypoxia. We obtained serum samples from head and neck carcinoma patients and investigated whether PAI-1 levels correlated with the degree of tumor hypoxia. The use of larger gene arrays may yield other secreted proteins and provide additional serum markers that reflect tumor hypoxia.
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Materials and Methods |
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Clontech Atlas cDNA Expression Array Membranes.
Hybridizations were carried out according to the manufacturer’s
specifications. The membranes were prehybridized at 68°C for 30 min
in ExpressHyb solution. Message RNA was purified by binding to a
poly(A) column and probe that was generated by reverse
transcription in the presence of [-32P]dATP.
The membranes were then hybridized overnight with 0.5 x 106 cpm/ml probe at 68°C with continuous
agitation. Membranes were washed twice with 2x SSC/1% SDS and
twice with 0.1x SSC/0.5% SDS. All of the washes were carried out for
30 min at 68°C. The membranes were then visualized by
phosphorimaging, and quantitation was performed with ImageQuant
software. Counts were normalized to
Mr 23,000 highly basic protein
(Accession Number P40429) for loading controls.
Northern Blot Analysis.
Total RNA was isolated with Trizol according to the manufacturer’s
protocol. RNA samples (10 µg) were denatured in glyoxal for 1 h
at 50°C and separated by agarose gel electrophoresis. The gel was
then transferred by capillary action overnight to Nytran membrane and
cross-linked by exposure to UV light. Probes were generated by reverse
trasnscription PCR using the manufacturer’s primers (Clontech),
gel-purified, and labeled with 32P by random
priming. Hybridization to 32P-labeled probes was
carried out at 65°C using ExpressHyb solution (Clontech) according to
the manufacturer’s protocol and washed for 2 h to a stringency of
0.2x SSC/1% SDS. Equal loading and transfer between lanes was
demonstrated by methylene blue staining of 28S and 18S ribosomal bands
before probing. All of the membranes were exposed by phosphorimaging
and quantitated with ImageQuant software.
Hypoxic Treatment.
FaDu and Siha cells were routinely cultured in DMEM + 10%
FCS. Fresh media was exchanged 3–5 h before treating for varying
amounts of time in a 37°C hypoxic incubator (Sheldon Manufacturing
Inc.), which maintained an environment of less than 0.05% oxygen. The
normoxic cells were maintained in a 37°C-incubator with 21%
O2. All of the experiments were performed at
70–80% cell confluency and the pH of the media remained between
7.0–7.4 for the duration of the experiment.
Immunohistochemical Staining of Tissues for EF-5 Binding;
Photography and Analysis of Binding.
The techniques used here were previously described (34
, 35)
. For each patient, at least two tumor regions and two levels
within each region (separated by 0.5 mm) were examined for regions of
in situ EF-5 binding. The regions were imaged using a x10
microscope objective (field size set electronically at 1.05 x 0.7 mm2), and typically nine fields were
examined for each section. To provide multiple pixels per cell while
improving camera sensitivity, each image field consisted of
600 x 400 pixels each of which was a 2 x 2-bin of the actual camera chip pixels, with 12-bit gray-scale
resolution.
Eppendorf pO2 Histography and PAI-1
Determination.
Eppendorf electrode measurements were taken through three tracks of
neck nodes of patients with squamous cell carcinoma of the head and
neck. Each pass with the probe recorded 50–100 measurements of oxygen
concentration along the track. Measurements were also taken through one
track of s.c. tissue of an uninvolved area in the neck to serve as a
control. Serum levels of PAI-1 protein were measured using ELISA kits
from biopool International (Ventura, CA) according to the
instructions of the manufacturer. The PAI-1 ELISA has a detection limit
of 0.5 ng/ml and measures latent (inactive) PAI-1, active PAI-1, and
PAI-1 complexed with tPA/PAI and uPA/PAI. Using this
assay and the manufacturer’s protocol, the range of PAI-1 values found
in individuals without pathophysiological conditions or in the third
trimester of pregnancy is 4–43 ng/ml All of the human serum samples
were obtained with the subjects’ informed consent and were used for
research purposes only. Total tumor burden (primary tumor and nodes) as
assessed from computed tomography and magnetic resonance imaging
scans indicated that there was no relationship between tumor burden and
PAI-1 levels. Tumor burden ranged from 12.7 cm2
to 60 cm2. However, a relationship between median
pO2 values and PAI-1 levels in the serum was
found. The graph represents data from eight patients with
pathologically verified squamous cell carcinoma of the head and neck
before any form of treatment.
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Results |
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shows a series of multiple gene array membranes that illustrate gene
expression changes induced by hypoxia in a squamous cell carcinoma cell
line (FaDu) originally derived from a pharyngeal wall tumor. These
membranes were arrayed with 588 known genes categorized into six
groups: (a) regulators of cell cycle; (b)
apoptosis/tumor suppressors/oncogenes; (c) DNA
damage/development; (d) cell adhesion/angiogenesis;
(e) regulators of invasion/cell-cell interaction; and
(f) growth factors/cytokines. Cells were exposed to 6 or
18 h of hypoxia prior to mRNA isolation, and gene expression was
then compared with cells cultured under normoxia. Quantitative analysis
of these membranes was performed with ImageQuant software.
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that exhibited a greater than 3-fold induction under hypoxic
conditions. Interestingly, the level of mRNA induction as determined by
gene array analysis did not always correlate with the level of
induction as determined by Northern blot analysis (Table 1)
. However,
all of the genes that we initially identified based on their hypoxic
inducibility when compared with VEGF were indeed found to be induced by
hypoxia as assessed by Northern blotting (Table 1)
.
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is a composite of Northern blots that demonstrates the increase in mRNA
expression of the seven most-hypoxia-inducible genes derived from
membrane analysis. In this figure, we compared the induction of each
gene in two different squamous cell carcinoma-derived cells. The
kinetics of induction of each gene after exposure to 6 and 18 h of
hypoxia was similar between FaDu cells and Siha cells (a cell line
derived from a squamous cell carcinoma of the uterine cervix). In each
Northern blot, a lane representing the effects of a 6-h treatment of
cells with 100 µM DFO (an iron-chelating, hypoxia-mimetic
agent) is also included for comparison (36)
. The
consistency between the patterns of induction by hypoxia and DFO in
these two different cell lines suggests that the regulation of these
genes may be similar in squamous cell carcinomas, at least in
vitro.
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shows an extended time course of PAI-1 induction in FaDu cells. Minimal
PAI-1 mRNA is present under aerobic conditions, and an increase is seen
2 h after exposure of FaDu cells to hypoxia. These levels continue
to increase for at least 24 h of hypoxia and return to near
baseline levels after 6 h of reoxygenation. The changes in
PAI-1 gene expression were normalized to changes in
28S ribosome gene expression which varied less than 10% in
this experiment (data not shown). The sensitivity of PAI-1
gene expression to levels of hypoxia makes it an ideal marker of
in vivo hypoxia. In addition, because it is a secreted
protein, serum levels can be monitored in a relatively noninvasive
manner to determine the response to treatment and to detect early
subclinical recurrence.
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is a comparison of PAI-1 protein levels and tumor hypoxia in serum from
patients with squamous cell carcinomas. The patients are divided into
two groups according to the degree of hypoxia found in their tumors.
Hypoxia was determined either by immunohistochemical staining of EF-5
adducts, a nitroimidazole that is given by i.v. infusion in which it
selectively and irreversibly binds to hypoxic cells (34
, 35)
or by intratumor Eppendorf pO2
histography (37)
. In patients who received EF-5, PAI-1
levels were substantially greater in tumors that had EF-5 staining in
more than 10% of the staining of the specimen (data not shown).
However, because Eppendorf measurements are the most widely accepted
method of estimating tumor oxygenation, we compared the levels of PAI-1
in the serum of oxic tumors with hypoxic tumors. PAI-1 values were
plotted as a function of median pO2 values (<4
mm Hg or >4 mm Hg) derived from Eppendorf readings. When compared with
normal controls, there is a substantial increase in serum PAI-1 levels
in both the low and high hypoxia groups and a trend toward higher PAI-1
levels in patients with more hypoxic tumors. This preliminary data on a
small group of patients supports the initiative for a more extensive
clinical analysis to investigate the relationship between PAI-1, tumor
hypoxia, and outcome.
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Discussion |
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With the use of a multiple gene array membrane, we screened 588 genes
that had previously been identified to play a role in oncogenesis, for
their response to changes in oxygenation. Because hypoxia had been
previously shown to be a potent transcriptional activator of VEGF, we
chose to use it as a cutoff point for identifying additional
hypoxia-regulated genes. Using this criteria, we found nine genes that
demonstrated greater hypoxic induction than VEGF as determined by
ImageQuant analysis. The level of hypoxic induction when analyzed by
Northern blot did not always correlate with the level of induction by
array analysis because of differences in both the quantitative and
qualitative aspects of probe and target gene hybridization. Such
differences have been previously reported for p53-regulated genes
(41)
. Furthermore, although the gene array screening was
performed in FaDu cells, a similar level of induction was found by
Northern blot analysis in Siha cells. It is noteworthy that Table 1
is not an exhaustive list of hypoxia-induced genes because the
squamous carcinoma cells do not express or express at varying levels
the genes on the array membrane. The gene array represents only a small
fraction of expressed genes, and we analyzed only genes that were
more-hypoxia-inducible than VEGF.
Table 1
is a ranked list of hypoxia-inducible genes that compares their
induction by gene array analysis and Northern blot analysis. These
genes can be broadly categorized into two groups: those involved in
apoptosis (BIK and IGFBP-3) and those involved in
local tissue/tumor response (MIF, PAI-1,
Endo-2, MMP-13, FGF-3,
LRP, and VEGF).
BIK and IGFBP-3 are both proapoptotic genes (42 , 43) that are transcriptionally up-regulated during hypoxia. Apoptosis is a complex process that reflects a shift in the delicate balance between pro- and antiapoptotic genes. During the time in which these genes are induced, we did not see any significant increase in apoptosis, which makes the function of these genes during hypoxia unclear. Perhaps other antiapoptotic pathways have become activated during hypoxia, which then negates the effects of these pro-apoptotic genes, or these genes may play other roles in growth regulation under hypoxic conditions.
The second and larger category of genes that we have identified by gene array analysis are involved in tissue remodeling and invasion. Young et al. have demonstrated that when tumor cells are exposed to hypoxia and reoxygenation, it results in an increased rate of metastasis as determined by lung colony formation of metastatic foci (39) . Studies presented here and elsewhere suggest that many of the genes involved in the breakdown of the basement membrane and the eventual establishment of metastatic tumor foci are hypoxia-inducible (10 , 44) . Thus, the induction of tissue-remodeling genes by hypoxia undoubtedly contributes to the development of a more malignant phenotype.
A more detailed analysis of PAI-1 revealed that its regulation is exquisitely sensitive to hypoxia. Under normoxic conditions, there are undetectable levels of PAI-1 and between 2–24 h of hypoxia there is a gradual increase in PAI-1 mRNA. Reoxygenation of 2–6 h under normoxic conditions results in a marked decrease in PAI-1 expression to near-normoxic levels. Several groups have reported that PAI-1 is hypoxia-inducible in cell lines in vitro [ (45 , 46) . Furthermore, analysis of the 5' genomic sequence from the transcriptional start site of the PAI-1 gene reveals a putative hypoxia responsive element (HRE) that provides a possible mechanism for PAI-1 regulation by hypoxia.4
As discussed above, increased PAI-1 staining of tumor sections has been correlated with a worse prognosis. However, the link between PAI-1, tumor hypoxia, and outcome has yet to be made. Because PAI-1 is a secreted protein, its serum levels can be easily measured and may serve as a surrogate marker of tumor hypoxia. Although we found a relationship between serum PAI-1 levels in head and neck cancer patients and the extent of hypoxia found in the tumors of these patients, a more thorough study is warranted to investigate whether other genes involved in plasminogen metabolism are also associated with tumor aggressiveness. It is also important to note that other pathophysiological conditions may elevate serum PAI-1 including pregnancy, cardiac ischemia, and blood clotting disorders, making a thorough clinical examination a necessity. In summary, PAI-1 represents but one hypoxia-regulated secreted protein that may eventually aid in cancer diagnosis, prognosis, and surveillance.
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FOOTNOTES |
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1 Supported by Grant PO1C67166 from National
Cancer Institute and a grant from Varian Biosynergy. 
2 To whom requests for reprints should be
addressed, at Stanford University Medical Center, Department of
Radiation Oncology, Cancer Biology Research Laboratory, Stanford, CA
94305-5468. E-mail: giaccia{at}leland.stanford.edu
3 The abbreviations used are: HIF-1,
hypoxia-induced factor-1; EF-5,
[2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)
acetamide; PAI-1, plasminogen activator inhibitor-1; MIF,
migration-inhibitory factor; BIK, BCL2 interacting killer;
pO2, partial pressure of oxygen; VEGF, vascular endothelial
growth factor; DFO, desferroximine; IGFB-3, insulin-like growth
factor-binding protein 3; Endo-2, endothelin-2; MMP-13, matrix
metalloproteinase 13; LRP, low-density lipoprotein receptor-related
protein; FGF-3, fibroblast growth factor 3.
4 L. Swiersz et al., unpublished
data.
Received 10/ 4/99. Accepted 1/ 4/00.
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V. Wang, D. A. Davis, M. Haque, L. E. Huang, and R. Yarchoan Differential Gene Up-Regulation by Hypoxia-Inducible Factor-1{alpha} and Hypoxia-Inducible Factor-2{alpha} in HEK293T Cells Cancer Res., April 15, 2005; 65(8): 3299 - 3306. [Abstract] [Full Text] [PDF]
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S. M. Evans, K. D. Judy, I. Dunphy, W. T. Jenkins, W.-T. Hwang, P. T. Nelson, R. A. Lustig, K. Jenkins, D. P. Magarelli, S. M. Hahn, et al. Hypoxia Is Important in the Biology and Aggression of Human Glial Brain Tumors Clin. Cancer Res., December 15, 2004; 10(24): 8177 - 8184. [Abstract] [Full Text] [PDF]
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P. Vaupel The Role of Hypoxia-Induced Factors in Tumor Progression Oncologist, November 1, 2004; 9(suppl_5): 10 - 17. [Abstract] [Full Text] [PDF]
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L. Harrison and K. Blackwell Hypoxia and Anemia: Factors in Decreased Sensitivity to Radiation Therapy and Chemotherapy? Oncologist, November 1, 2004; 9(suppl_5): 31 - 40. [Abstract] [Full Text] [PDF]
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Y. Chen, G. Shi, W. Xia, C. Kong, S. Zhao, A. F. Gaw, E. Y. Chen, G. P. Yang, A. J. Giaccia, Q.-T. Le, et al. Identification of Hypoxia-Regulated Proteins in Head and Neck Cancer by Proteomic and Tissue Array Profiling Cancer Res., October 15, 2004; 64(20): 7302 - 7310. [Abstract] [Full Text] [PDF]
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C. Murdoch, A. Giannoudis, and C. E. Lewis Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues Blood, October 15, 2004; 104(8): 2224 - 2234. [Abstract] [Full Text] [PDF]
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 J. D. Blais, V. Filipenko, M. Bi, H. P. Harding, D. Ron, C. Koumenis, B. G. Wouters, and J. C. Bell Activating Transcription Factor 4 Is Translationally Regulated by Hypoxic Stress Mol. Cell. Biol., September 1, 2004; 24(17): 7469 - 7482. [Abstract] [Full Text] [PDF]
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Q.-T. Le, J. McCoy, S. Williamson, J. Ryu, L. E. Gaspar, M. J. Edelman, S. R. Dakhil, S. D. Sides, J. J. Crowley, and D. R. Gandara Phase I Study of Tirapazamine Plus Cisplatin/Etoposide and Concurrent Thoracic Radiotherapy in Limited-Stage Small Cell Lung Cancer (S0004): A Southwest Oncology Group Study Clin. Cancer Res., August 15, 2004; 10(16): 5418 - 5424. [Abstract] [Full Text] [PDF]
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 J. C. Murray, P. Symonds, W. Ward, M. Huggins, A. Tiga, K. Rice, Y. M. Heng, I. Todd, and R. A. Robins Colorectal Cancer Cells Induce Lymphocyte Apoptosis by an Endothelial Monocyte-Activating Polypeptide-II-Dependent Mechanism J. Immunol., January 1, 2004; 172(1): 274 - 281. [Abstract] [Full Text] [PDF]
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G. H. Mahabeleshwar and G. C. Kundu Tyrosine Kinase p56lck Regulates Cell Motility and Nuclear Factor {kappa}B-mediated Secretion of Urokinase Type Plasminogen Activator through Tyrosine Phosphorylation of I{kappa}B{alpha} following Hypoxia/Reoxygenation J. Biol. Chem., December 26, 2003; 278(52): 52598 - 52612. [Abstract] [Full Text] [PDF]
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S. S. HUANG, T.-Y. LING, W.-F. TSENG, Y.-H. HUANG, F.-M. TANG, S. M. LEAL, and J. S. HUANG Cellular growth inhibition by IGFBP-3 and TGF-{beta}1 requires LRP-1 FASEB J, November 1, 2003; 17(14): 2068 - 2081. [Abstract] [Full Text] [PDF]
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P. N. Lara Jr., D. I. Quinn, K. Margolin, F. J. Meyers, J. Longmate, P. Frankel, P. C. Mack, C. Turrell, P. Valk, J. Rao, et al. SU5416 Plus Interferon {alpha} in Advanced Renal Cell Carcinoma: A Phase II California Cancer Consortium Study with Biological and Imaging Correlates of Angiogenesis Inhibition Clin. Cancer Res., October 15, 2003; 9(13): 4772 - 4781. [Abstract] [Full Text] [PDF]
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 B. Burke, A. Giannoudis, K. P. Corke, D. Gill, M. Wells, L. Ziegler-Heitbrock, and C. E. Lewis Hypoxia-Induced Gene Expression in Human Macrophages: Implications for Ischemic Tissues and Hypoxia-Regulated Gene Therapy Am. J. Pathol., October 1, 2003; 163(4): 1233 - 1243. [Abstract] [Full Text] [PDF]
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P. N. Lara Jr., P. Frankel, P. C. Mack, P. H. Gumerlock, I. Galvin, C. L. Martel, J. Longmate, J. H. Doroshow, H. J. Lenz, D. H. M. Lau, et al. Tirapazamine Plus Carboplatin and Paclitaxel in Advanced Malignant Solid Tumors: A California Cancer Consortium Phase I and Molecular Correlative Study Clin. Cancer Res., October 1, 2003; 9(12): 4356 - 4362. [Abstract] [Full Text] [PDF]
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B. Bachtiary, M. Schindl, R. Potter, B. Dreier, T. H. Knocke, J. A. Hainfellner, R. Horvat, and P. Birner Overexpression of Hypoxia-inducible Factor 1{alpha} Indicates Diminished Response to Radiotherapy and Unfavorable Prognosis in Patients Receiving Radical Radiotherapy for Cervical Cancer Clin. Cancer Res., June 1, 2003; 9(6): 2234 - 2240. [Abstract] [Full Text] [PDF]
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 R. M. Douglas and G. G. Haddad Genetic Models in Applied Physiology: Invited Review: Effect of oxygen deprivation on cell cycle activity: a profile of delay and arrest J Appl Physiol, May 1, 2003; 94(5): 2068 - 2083. [Abstract] [Full Text] [PDF]
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V. T. Mihaylova, R. S. Bindra, J. Yuan, D. Campisi, L. Narayanan, R. Jensen, F. Giordano, R. S. Johnson, S. Rockwell, and P. M. Glazer Decreased Expression of the DNA Mismatch Repair Gene Mlh1 under Hypoxic Stress in Mammalian Cells Mol. Cell. Biol., May 1, 2003; 23(9): 3265 - 3273. [Abstract] [Full Text] [PDF]
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Y. Jiang, W. Zhang, K. Kondo, J. M. Klco, T. B. St. Martin, M. R. Dufault, S. L. Madden, W. G. Kaelin Jr, and M. Nacht Gene Expression Profiling in a Renal Cell Carcinoma Cell Line: Dissecting VHL and Hypoxia-Dependent Pathways Mol. Cancer Res., April 1, 2003; 1(6): 453 - 462. [Abstract] [Full Text] [PDF]
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 L. A. Sonna, M. L. Cullivan, H. K. Sheldon, R. E. Pratt, and C. M. Lilly Effect of hypoxia on gene expression by human hepatocytes (HepG2) Physiol Genomics, February 6, 2003; 12(3): 195 - 207. [Abstract] [Full Text] [PDF]
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M. Bacher, J. Schrader, N. Thompson, K. Kuschela, D. Gemsa, G. Waeber, and J. Schlegel Up-Regulation of Macrophage Migration Inhibitory Factor Gene and Protein Expression in Glial Tumor Cells during Hypoxic and Hypoglycemic Stress Indicates a Critical Role for Angiogenesis in Glioblastoma Multiforme Am. J. Pathol., January 1, 2003; 162(1): 11 - 17. [Abstract] [Full Text] [PDF]
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T. W. Chong, L. D. Horwitz, J. W. Moore, H. M. Sowter, and A. L. Harris A Mycobacterial Iron Chelator, Desferri-Exochelin, Induces Hypoxia-inducible Factors 1 and 2, NIP3, and Vascular Endothelial Growth Factor in Cancer Cell Lines Cancer Res., December 1, 2002; 62(23): 6924 - 6927. [Abstract] [Full Text] [PDF]
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 M. J. Grimshaw, S. Naylor, and F. R. Balkwill Endothelin-2 Is a Hypoxia-induced Autocrine Survival Factor for Breast Tumor Cells Mol. Cancer Ther., December 1, 2002; 1(14): 1273 - 1281. [Abstract] [Full Text] [PDF]
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J. Fukuzawa, J. Nishihira, N. Hasebe, T. Haneda, J. Osaki, T. Saito, T. Nomura, T. Fujino, N. Wakamiya, and K. Kikuchi Contribution of Macrophage Migration Inhibitory Factor to Extracellular Signal-regulated Kinase Activation by Oxidative Stress in Cardiomyocytes J. Biol. Chem., July 5, 2002; 277(28): 24889 - 24895. [Abstract] [Full Text] [PDF]
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M. Zatyka, N. F. da Silva, S. C. Clifford, M. R. Morris, M. S. Wiesener, K.-U. Eckardt, R. S. Houlston, F. M. Richards, F. Latif, and E. R. Maher Identification of Cyclin D1 and Other Novel Targets for the von Hippel-Lindau Tumor Suppressor Gene by Expression Array Analysis and Investigation of Cyclin D1 Genotype as a Modifier in von Hippel-Lindau Disease Cancer Res., July 1, 2002; 62(13): 3803 - 3811. [Abstract] [Full Text] [PDF]
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K. J. Turner, J. W. Moore, A. Jones, C. F. Taylor, D. Cuthbert-Heavens, C. Han, R. D. Leek, K. C. Gatter, P. H. Maxwell, P. J. Ratcliffe, et al. Expression of Hypoxia-inducible Factors in Human Renal Cancer: Relationship to Angiogenesis and to the von Hippel-Lindau Gene Mutation Cancer Res., May 1, 2002; 62(10): 2957 - 2961. [Abstract] [Full Text] [PDF]
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T. Fink, A. Kazlauskas, L. Poellinger, P. Ebbesen, and V. Zachar Identification of a tightly regulated hypoxia-response element in the promoter of human plasminogen activator inhibitor-1 Blood, March 15, 2002; 99(6): 2077 - 2083. [Abstract] [Full Text] [PDF]
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E. K. Rofstad, H. Rasmussen, K. Galappathi, B. Mathiesen, K. Nilsen, and B. A. Graff Hypoxia Promotes Lymph Node Metastasis in Human Melanoma Xenografts by Up-Regulating the Urokinase-Type Plasminogen Activator Receptor Cancer Res., March 1, 2002; 62(6): 1847 - 1853. [Abstract] [Full Text] [PDF]
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C. N. Coleman, J. B. Mitchell, and K. Camphausen Tumor Hypoxia: Chicken, Egg, or a Piece of the Farm? J. Clin. Oncol., February 1, 2002; 20(3): 610 - 615. [Full Text] [PDF]
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K. Koga, Y. Osuga, O. Tsutsumi, T. Yano, O. Yoshino, Y. Takai, H. Matsumi, H. Hiroi, K. Kugu, M. Momoeda, et al. Demonstration of Angiogenin in Human Endometrium and Its Enhanced Expression in Endometrial Tissues in the Secretory Phase and the Decidua J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5609 - 5614. [Abstract] [Full Text] [PDF]
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 A. Lal, H. Peters, B. St. Croix, Z. A. Haroon, M. W. Dewhirst, R. L. Strausberg, J. H. A. M. Kaanders, A. J. van der Kogel, and G. J. Riggins Transcriptional Response to Hypoxia in Human Tumors J Natl Cancer Inst, September 5, 2001; 93(17): 1337 - 1343. [Abstract] [Full Text] [PDF]
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N. J. P. Beasley, C. C. Wykoff, P. H. Watson, R. Leek, H. Turley, K. Gatter, J. Pastorek, G. J. Cox, P. Ratcliffe, and A. L. Harris Carbonic Anhydrase IX, an Endogenous Hypoxia Marker, Expression in Head and Neck Squamous Cell Carcinoma and its Relationship to Hypoxia, Necrosis, and Microvessel Density Cancer Res., July 1, 2001; 61(13): 5262 - 5267. [Abstract] [Full Text] [PDF]
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C. M. L. West, R. A. Cooper, J. A. Loncaster, D. P. Wilks, and M. Bromley Tumor Vascularity: A Histological Measure of Angiogenesis and Hypoxia Cancer Res., April 1, 2001; 61(7): 2907 - 2910. [Abstract] [Full Text]
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N. C. Denko and A. J. Giaccia Tumor Hypoxia, the Physiological Link between Trousseau's Syndrome (Carcinoma-induced Coagulopathy) and Metastasis Cancer Res., February 1, 2001; 61(3): 795 - 798. [Full Text]
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C. C. Wykoff, N. J. P. Beasley, P. H. Watson, K. J. Turner, J. Pastorek, A. Sibtain, G. D. Wilson, H. Turley, K. L. Talks, P. H. Maxwell, et al. Hypoxia-inducible Expression of Tumor-associated Carbonic Anhydrases Cancer Res., December 1, 2000; 60(24): 7075 - 7083. [Abstract] [Full Text]
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X.-H. Ning, S.-H. Chen, C.-S. Xu, L. Li, L. Y. Yao, K. Qian, J. J. Krueger, O. M. Hyyti, and M. A. Portman Molecular Biology of Thermoregulation: Selected Contribution: Hypothermic protection of the ischemic heart via alterations in apoptotic pathways as assessed by gene array analysis J Appl Physiol, May 1, 2002; 92(5): 2200 - 2207. [Abstract] [Full Text] [PDF]
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 L. P. Hale, R. D. Braun, W. M. Gwinn, P. K. Greer, and M. W. Dewhirst Hypoxia in the thymus: role of oxygen tension in thymocyte survival Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1467 - H1477. [Abstract] [Full Text] [PDF]
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