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Correlation of Expression of Cyclooxygenase-2, Vascular Endothelial Growth Factor, and Peroxisome Proliferator–Activated Receptor  With Head and Neck Squamous Cell Carcinoma
Elise C. Jaeckel, MD;
Shefali Raja, BS;
Jian Tan, MD;
Sanjoy K. Das, PhD;
Sudhansu K. Dey, PhD;
Douglas A. Girod, MD;
Terrance T. Tsue, MD;
Thomas R. Sanford, MD
Arch Otolaryngol Head Neck Surg. 2001;127:1253-1259.
ABSTRACT
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Cyclooxygenase (COX) is the rate-limiting enzyme in the formation of
prostaglandins from arachidonic acid. COX exists in 2 isoforms, COX-1 and
COX-2. These isoforms are encoded by separate genes and demonstrate cell-specific
expression and regulation. Peroxisome proliferator–activated receptor 
(PPAR) is a nuclear transcription factor that is activated by prostacyclin.
Vascular endothelial growth factor (VEGF) is a proangiogenic factor that is
up-regulated in various tumors. Vascular endothelial growth factor has been
shown to interact with COX-derived prostaglandins in angiogenesis. To better
understand the roles of these genes in head and neck squamous cell carcinoma
(HNSCCA), we examined the differential expression of the COX1, COX2, VEGF,
and PPAR genes in these tumors. Tissue samples
from patients with HNSCCA were analyzed for COX-1, COX-2, VEGF, and PPAR
messenger RNAs (mRNAs) by in situ hybridization. COX-1 and COX-2 mRNAs were
also evaluated with Northern blot hybridization. Immunohistochemistry was
used to analyze for COX-2 and PPAR proteins. Results showed focal areas
of accumulation for COX-2, VEGF, and PPAR but not COX-1 in human HNSCCA.
Northern blot hybridization showed higher levels of COX-2 mRNA in HNSCCA than
in normal tissue. This suggests a supportive role of COX-2 in development
and/or progression of HNSCCA. In addition, PPAR may be a receptor for
COX-2–produced prostaglandins in HNSCCA. There is a potential role for
selective COX-2 inhibitors in the treatment of these lesions.
INTRODUCTION
Prostaglandins (PGs), a family of lipid-derived autocrine and paracrine
mediators, can favor tumorigenesis by altering cell proliferation, differentiation,
and adhesion and by modulating vascular responses and immune surveillance.
Levels of PGs are higher in various tumors, including those of the breast,
lung, colon, and head and neck. There is emerging evidence that inhibition
of PG formation can protect against these forms of cancer in animals and humans.1-10
Prostaglandins are derived from arachidonic acid by cyclooxygenase (COX).
COX is the rate-limiting enzyme in the conversion of arachidonic acid to PGH2, the substrate for the synthesis of other PGs. COX exists in 2 isoforms,
COX-1 and COX-2. These isoforms are encoded by separate genes and exhibit
cell-specific expression and regulation. COX-1 is a constitutive enzyme that
produces PGs required for normal physiological functions. COX-2 is an inducible
enzyme that is not detected in most tissues under normal conditions. However,
it is induced in a variety of tissues by growth factors, oncogenes, inflammatory
stimuli, and tumor promoters.11-13
The increased levels of PGs in tumors correlate with increased COX-2 expression.12-15
COX-1 and COX-2 are expressed in both the endoplasmic reticular membrane
and the nuclear envelope, suggesting that PGs function via 2 different classes
of receptors.12 Prostaglandins generated in
the endoplasmic reticulum can exit the cell and function via G protein–coupled
cell surface receptors that are linked to intracellular signaling pathways.
In contrast, PGs produced via nuclear COX can exert their effects directly
on the nucleus through peroxisome proliferator–activated receptors (PPARs),
which belong to the nuclear hormone receptor superfamily and consist of PPAR ,
PPAR, and PPAR . These isoforms exhibit different expression
patterns and ligand dependency. The PPARs modulate transcription by binding
to DNA in a heterodimeric complex with retinoid X receptors. Peroxisome proliferator–activated
receptor is highly expressed in hepatocytes and implicated in lipid
homeostasis. Peroxisome proliferator–activated receptor is mainly
expressed in adipose tissue and the immune system.16
The activation of PPAR also terminally differentiates tumor cells,
suggesting a role in cell cycle regulation.17
Recent work has shown that COX-2–derived PGI2 is involved
in uterine cell proliferation and differentiation during the process of deciduation
via activation PPAR. This was the first noted function of PPAR.18 Since deciduation is considered a pseudomalignant
process, PPAR may play a role in the accelerated cellular proliferation
noted after malignant transformation. Recent findings have shown that PPAR
is involved in colorectal cancer.19
Increased vascular permeability and angiogenesis, the formation of new
blood vessels from existing ones, are the hallmarks of tumorigenesis. Vascular
endothelial growth factor (VEGF), also known as vascular permeability factor,
is a prime regulator of both processes. Vascular endothelial growth factor
(40-45 kd) is a heparin-binding homodimeric glycoprotein, and its effects
are mediated by tyrosine kinase receptors. The VEGF system has been shown
to be up-regulated in various types of tumors, and there is evidence of interactions
between this system and COX-2–derived PGs.19-25
The present investigation examined the cell-specific expression of the COX1, COX2, VEGF, and PPAR genes in head and neck
squamous cell carcinoma (HNSCCA) and in metastatic lymph nodes. The results
demonstrate that increased expression of COX-2, VEGF, and PPAR, but
not COX-1, is associated with tumor formation.
MATERIALS AND METHODS
TISSUE SAMPLES AND PROCESSING
Human samples included 14 patients with primary HNSCCA. Collection of
human samples was approved through the University of Kansas Human Subjects
Committee. From each subject, samples of tumor and normal buccal mucosa were
obtained. Metastatic lymph nodes were present in 7 of 14 patients and were
also collected immediately on surgical resection. Tissue was flash frozen
in liquid nitrogen and stored at -70° for in situ and Northern blot
hybridization. Additional samples were fixed in Bouin solution for immunohistochemical
staining.
NORTHERN BLOT HYBRIDIZATION
Total RNA was isolated from tumor, lymph node, and normal samples by
a sodium dodecyl sulfate–phenochloroform procedure.26
For Northern hybridization, antisense complementary RNA (cRNA) probes labeled
with phosphate 32 for mouse COX-1, human COX-2, and human  -actin were
generated. Total RNA was denatured, separated by formaldehyde–agarose
gel electrophoresis, transferred to nylon membranes, and UV cross-linked.
Northern blots were prehybridized, hybridized, and washed as previously described.27-28 The blot was stripped and reused
for each probe to ensure RNA integrity. Quantitation of radioactivity in hybridized
bands was achieved by densitometric scanning (Personal Densitometer SI; Molecular
Dynamics, Sunnyvale, Calif).
IN SITU HYBRIDIZATION
In situ hybridization was performed as previously described.27-29 Sense and antisense
cRNA probes labeled with sulfur 35 were generated using appropriate polymerases
from mouse-specific complementary DNA (cDNA) to COX-1– and human-specific
cDNA to COX-2, VEGF, and PPAR. Autoradiographic signals were detected
using liquid emulsion (Kodak NTB-2; Eastman Kodak Company, Rochester, NY).
The slides were poststained with hematoxylin-eosin. Sections hybridized with
the sense probes did not exhibit any positive autoradiographic signals and
served as negative controls.
IMMUNOHISTOCHEMICAL ANALYSIS
Rabbit antipeptide antibodies were used for immunolocalization of COX-2
and PPAR. Immunostaining was performed in Bouin-fixed paraffin sections
using a staining kit (Zymed-Histostain-SP kit; Zymed, San Francisco, Calif)
as previously described.18, 28
RESULTS
Tissues from 14 patients with primary HNSCCA were evaluated for the
induction of COX-1 and COX-2 mRNA, VEGF, and PPAR expression.
ANALYSIS OF NORTHERN HYBRIDIZATION OF COX-1 AND COX-2 mRNAs
Northern hybridization was performed using total RNA from 4 tumor samples,
1 metastatic lymph node sample, and 1 normal mucosa sample. A 4.7-kb transcript
for COX-2 and a 2.8-kb transcript for COX-1 were detected. The levels of COX-1
or COX-2 mRNA were compared with those of -actin (a housekeeping gene).
In 3 of 4 tumor samples, the levels of COX-2 mRNA were approximately 2- to
5-fold higher than that of the normal control. In contrast, only 1 of 4 tumor
samples showed COX-1 mRNA expression, and no COX-1 mRNA was detected in the
normal buccal tissue or the metastatic lymph node (Figure 1). These results correlated with those of in situ hybridization.
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Figure 1. Northern blot analysis of cyclooxygenase-1
(COX-1), cyclooxygenase-2 (COX-2), and -actin messenger RNAs. Total
RNA (6 µg per lane) was hybridized with specific complementary RNA probes.
Lanes 1 through 4, head and neck squamous cell carcinoma; lane 5, metastatic
lymph node; and lane 6, normal tissue; kb indicates kilobase.
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ANALYSIS OF IN SITU HYBRIDIZATION OF COX-1, COX-2, AND VEGF mRNAs IN
NORMAL MUCOSA
Whole tissue samples are heterogeneous in cell type. Therefore, when
total RNA is derived from these samples and assessed by Northern hybridization,
it is not likely to provide specific information about gene expression from
any one cell type because of dilution effects. In situ hybridization was performed
to examine gene expression in a cell type–specific manner. Figure 2 depicts serial sections from a sample
of normal buccal mucosa. A representative section stained with hematoxylin-eosin
(A) is presented for morphologic orientation followed by sections showing
expression of COX-1 (B), COX-2 (C), and VEGF (D) mRNAs. The expression of
COX-1 mRNA was low in the epithelial layer, and no significant autoradiographic
signals were observed in the stroma of these samples. In contrast, COX-2 mRNA
was low to undetectable in most normal samples. However, when a modest accumulation
in the normal tissue was noted, as in Figure
2C, it was in the basal epithelium and subepithelial stroma with
a patchy expression pattern. The VEGF mRNA expression was more homogeneous
throughout the normal squamous epithelium, albeit at modest levels.
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Figure 2. In situ hybridization of cyclooxygenase-1
(COX-1), cyclooxygenase-2 (COX-2), and vascular endothelial growth factor
(VEGF) messenger RNAs (mRNAs) in serial sections of normal buccal mucosa.
Bright-field (A) and dark-field photomicrographs of COX-1 (B), COX-2 (C),
and VEGF (D) mRNAs are shown (original magnification x40). Reddish brown
grains indicate positive autoradiographic signals.
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ANALYSIS OF IN SITU HYBRIDIZATION OF COX-1 AND COX-2 mRNAs IN TUMOR
TISSUE
Although some normal tissues showed a small amounts of COX-2 mRNA accumulation
along the basement membrane, the tumor tissues evaluated produced distinctly
elevated COX-2 mRNA expression and in patterns that were different from normal
buccal mucosa. Figure 3 depicts
low-power (A-B) and high-power (C-D) views from a representative tumor sample,
showing a heterogeneous expression pattern that was localized within specific
foci of the tumor that was invading into the normal tissues. In one tumor
sample, expression along the leading edge of the invading tumor was highly
distinct (E-F). In well-differentiated squamous cell carcinoma, tumor cells
still attempt to differentiate and produce abnormal areas of keratin accumulation
termed keratin whorls. These areas also showed distinct
accumulation of COX-2 mRNA (G-H). An interesting pattern of COX-2 expression
was noted in metastatic lymph nodes. In all of the tissues examined, distinct
accumulations were observed in the pericapsular and perivascular regions,
contrasted by areas outside the lymph node, which showed no accumulation in
perivascular regions (Figure 4A-F).
In contrast to the elevated and varying patterns of COX-2 mRNA expression,
the levels of COX-1 mRNA were low to undetectable in tumor tissue (Figure 5). These results correlated well
with those of Northern blot hybridization. Consecutive sections of the tumor
were used for COX-1 and COX-2 mRNA localization (compare Figure 5 with Figure 3A-D).
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Figure 3. In situ hybridization of cyclooxygenase-2
(COX-2) messenger RNA (mRNA) in tumor samples. Bright-field (A, C, E, and
G) and dark-field (B, D, F, and H) photomicrographs of COX-2 mRNA are shown
for 3 samples (A-D, E-F, and G-H) (A-B, original magnification x40;
C-H, original magnification x100).
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Figure 4. In situ hybridization of cyclooxygenase-2
(COX-2) messenger RNA (mRNA) in metastatic lymph node samples. Bright-field
(A, C, E) and dark-field (B, D, F) photomicrographs of COX-2 mRNA are shown
for 2 samples (A-D and E-F) (A-B, original magnification x40; C-H, original
magnification x100). Arrows indicates extracapsular vessels without
noticeable autoradiographic signals. Arrowheads indicate vessels within metastatic
tumor with positive signals.
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Figure 5. In situ hybridization of cyclooxygenase-1
(COX-1) messenger RNA (mRNA) in tumor sample. Bright-field (A, C) and dark-field
(B, D) photomicrographs of COX-1 mRNA are shown at original magnifications
of x40 (A-B) and x100 (C-D). Note absence of positive signals
(background signals).
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ANALYSIS OF IN SITU HYBRIDIZATION OF VEGF mRNA IN TUMOR TISSUE
The VEGF mRNA expression was evaluated in 5 tumor specimens. In all
of them, the expression was heterogeneous and more intense (Figure 6A-D) than in the control tissues (Figure 2D). In general, the areas of COX-2 expression correlated
with those of VEGF (compare Figure 6A-D
with Figure 3A-D), suggesting that
the same tumor cells could express both COX-2 and VEGF. Collectively, the
results suggest that although COX-2 and VEGF are each expressed in normally
proliferating cells at modest levels, the levels in areas of tumor growth
are much higher with different patterns.
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Figure 6. In situ hybridization of vascular
endothelial growth factor (VEGF) messenger RNA (mRNA) in tumor samples. Bright-field
(A, C, E) and dark-field (B, D, F) photomicrographs of VEGF mRNA are shown
for 2 samples (A-D and E-F) (A-B, original magnification x40; C-H, original
magnification x100).
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ANALYSIS OF IN SITU HYBRIDIZATION OF PPAR IN NORMAL, LYMPH NODE,
AND TUMOR TISSUES
The PPAR mRNA expression was evaluated in 5 tumor specimens.
The expression in normal tissues was homogeneous throughout the squamous epithelium,
albeit at low levels (Figure 7A-B).
In contrast, diffuse but increased expression was noted within the metastatic
lymph nodes (C-D). In all 5 tumor tissues examined, PPAR mRNA expression
was heterogeneous and more intense (E-F) than that in the controls. Serial
sections of tumor tissues were evaluated for COX-2 and PPAR mRNA expression.
Although the expression of COX-2 was heterogeneous and within specific localized
foci, the expression of PPAR was more diffuse throughout the tissue
(data not shown). These results suggest that similar tumor cells can express
both COX-2 and PPAR.
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Figure 7. In situ hybridization of peroxisome
proliferator–activated receptor (PPAR) in normal, metastatic
lymph node, and tumor tissue. Bright-field (A, C, E) and dark-field (B, D,
F) photomicrographs of normal (A-B), metastatic lymph node (C-D), and tumor
(E-F) messenger RNAs (A-B, original magnification x40; C-H, original
magnification x100).
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ANALYSIS OF IMMUNOHISTOCHEMICAL STAINING OF COX-2 AND PPAR
The cell-specific accumulation of COX-2 and PPAR proteins was
examined by immunohistochemical staining. No noticeable accumulation of either
COX-2 or PPAR was evident in normal tissues (Figure 8). In contrast, distinct accumulation of COX-2 and PPAR
proteins was observed in tumor tissues. The accumulation of COX-2, within
malignant cells, was cytoplasmic and perinuclear. The distinct nuclear immunolocalization
of PPAR was more widespread within the tumor compared with COX-2. The
accumulation of both COX-2 and PPAR proteins followed the same patterns
as those observed for their mRNA localizations.
COMMENT
The COX-2–derived PGs are involved in a variety of physiologic
and pathologic processes.12 The role of COX-2
in various forms of cancer is emerging as a major research focus. However,
the mechanism by which the COX-2–derived PGs participate in tumor promotion
is not clearly understood.
The highlight of the present investigation is that COX-2, but not COX-1,
expression is elevated in HNSCCA cells. Although the increased expression
of COX-2 in these cells has been reported,30
its site of synthesis has not been documented. Our results establish that
the COX-2 expression pattern varies, depending on the nature of the tumor,
suggesting that it may have multiple roles in tumor maintenance and progression.
For example, COX-2 mRNA expression in the invasive border suggests the involvement
of PGs in the aggressive behavior of the tumor, whereas that within the vascular
cores implicates their role in vascular permeability and angiogenesis. In
addition, well-differentiated tumors demonstrated the presence of COX-2 in
keratin whorls, suggesting a role in differentiation. The pericapsular and
perivascular expression of COX-2 in metastatic lymph nodes implies a role
in immune response regulation. This is consistent with known roles of PGs
in immunologic responses.11-12
Vascular permeability and angiogenesis are 2 major characteristics of
tumor formation. Vascular endothelial growth factor is a potent mediator of
these processes and is up-regulated in various types of tumors, including
HNSCCA.22-25
Prostaglandins are also well-known proangiogenic factors that are implicated
in vascular permeability changes and angiogenesis. For example, prostacyclin
agonists can induce VEGF in monocyte cell lines and rat lungs. Alternatively,
VEGF can stimulate prostacyclin production, which in turn can enhance vascular
permeability.19-20 These observations
suggest a close relationship between the VEGF and PGs in mediating vascular
changes. Thus, our findings of COX2 and VEGF coexpression in HNSCCA cells suggest a relationship between these
2 genes in angiogenesis and tumorigenesis.
Recent work31 suggests that prostacyclin
is the major COX-2–derived PG in many tissues. We have also shown that
this PG is the major product in the uterus during implantation and activates
PPAR in this process. The implantation process involves massive stromal
cell proliferation and polyploidy at the site of the embryo, a process known
as deciduation. These cellular changes are considered a transient "pseudomalignant"
state. This led us to speculate that COX-2–derived PGs could be involved
in tumorigenesis by activation of PPAR. Our results demonstrate the
increased region-specific expression of COX-2 and PPAR within tumor
tissues. This would implicate a tumorigenic pathway. Indeed, there is developing
evidence that COX-2–PPAR signaling is associated with colorectal
cancer.32 Another important aspect of the present
study is the interaction between native normal tissue and the invading tumor
cells, which could not be evaluated under in vitro conditions. This is an
important focus, since host COX-2 recently has been shown to influence the
growth of transplanted tumor in the murine model.
The results of the present investigation point toward a relationship
between PGs, PPAR, and VEGF in tumorigenesis. Further investigation
of these molecular interactions will enhance our understanding of HNSSCA management
and prevention. Despite recent advances in the therapy for head and neck cancer,
there has been little increase in patient survival. Chemotherapeutic use of
nonsteroidal anti-inflammatory drugs, as nonspecific inhibitors of COX-1 and
COX-2, has shown beneficial effects in the prevention of certain forms of
cancer6-10,12
and may prove useful in the treatment of HNSCCA. However, the broad-scale
use of these drugs for cancer prevention is undesirable because the incidence
of adverse effects, including peptic ulcer disease and impaired renal function,
is significant. Therefore, the use of recently developed selective COX-2 inhibitors
may prove advantageous in limiting the adverse effects of the drugs while
maximizing the benefits.
CONCLUSIONS
This study has provided evidence of the potential role of COX-2 in HNSCCA.
COX-2 expression was found in discrete patterns both in primary tumors and
metastatic sites. The increase in COX-2 within HNSCCA suggests an autocrine
and paracrine signaling mechanism that participates in cellular differentiation,
angiogenesis, and/or modulation of immunologic responses. This proposal is
consistent with the concomitant elevated expression of VEGF and PPAR
within similar sites of HNSCCA. The definitive involvement of COX-2 and its
mode of action in HNSCCA will require further investigation.
AUTHOR INFORMATION
Accepted for publication June 12, 2001.
This work was supported in part by grants HD 12304 and HD 29968 (Dr
Dey) and ES 07814 (Dr Das) from National Institutes of Health (Bethesda, Md)
and a grant from the University of Kansas Medical Center Cancer Center (Kansas
City) (Dr Sanford).
Presented at the Triologic Middle Section Meeting, Cincinnati, Ohio,
February 12, 2000 (John Lindsey Resident Research award winner).
Corresponding author and reprints: Thomas R. Sanford, MD, Department
of Otolaryngology–Head and Neck Surgery, University of Kansas Medical
Center, 3901 Rainbow Blvd, Kansas City, KS 66160 (e-mail: TSanford{at}kumc.edu).
From the Departments of Otolaryngology–Head and Neck Surgery
(Drs Jaeckel, Girod, Tsue, and Sanford) and Physiology (Ms Raja and Drs Tan,
Das, and Dey), University of Kansas Medical Center, Kansas City.
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Peroxisome Proliferator-activated Receptor {beta} ({delta})-dependent Regulation of Ubiquitin C Expression Contributes to Attenuation of Skin Carcinogenesis
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NSAIDs for the Chemoprevention of Oral Cancer: Promise or Pessimism?: Commentary re J. L. Mulshine et al., Randomized, Double-Blind, Placebo-Controlled, Phase IIB Trial of the Cyclooxygenase Inhibitor Ketorolac as an Oral Rinse in Oropharyngeal Leukoplakia. Clin. Cancer Res., 10: 1565-1573, 2004.
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Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-{kappa}B activation through inhibition of I{kappa}B{alpha} kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1
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The Cyclooxygenase 2-selective Inhibitor NS398 Inhibits Proliferation of Oral Carcinoma Cell Lines by Mechanisms Dependent and Independent of Reduced Prostaglandin E2 Synthesis
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Cigarette smoke condensate activates nuclear transcription factor-{kappa}B through phosphorylation and degradation of I{kappa}B{alpha}: correlation with induction of cyclooxygenase-2
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