| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Advances in Brief |
B Signaling Inhibits Angiogenesis and Tumorigenicity of Human Ovarian Cancer Cells by Suppressing Expression of Vascular Endothelial Growth Factor and Interleukin 81
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
 |
ABSTRACT |
|---|
 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
B/relA activity
in human ovarian cancer cells can suppress angiogenesis and growth in
an orthotopic nude mouse model. The human ovarian cancer cells
SKOV3ip.1 and HEY-A8 were transfected with a mutated IB
(IBM), i.e., resistant to phosphorylation and
degradation, and hence blocks NF-B activity. NF-B signaling
blockade significantly inhibited in vitro and in
vivo expression of two major proangiogenic
molecules, vascular endothelial growth factor and
interleukin 8, in cultured cells and in cells implanted into the
peritoneal cavity of nude mice. The decreased expression of vascular
endothelial growth factor and interleukin 8 directly correlated with
decreased tumorigenicity, decreased vascularization of lesions,
decreased formation of malignant ascites, and prolonged survival of
mice. These findings suggest that inhibition of NF-B/relA activity
in ovarian cancer cells can suppress angiogenesis and progressive
growth. |
Introduction |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
50%, making it the leading cause of death
from gynecological cancer (1
, 2)
. In most patients,
metastasis occurs within the peritoneum by the time of diagnosis. The
most common route of spread is by direct extension, and metastatic
lesions may develop on any peritoneal surface, including the omentum
(2, 3, 4)
. The lesions can give rise to malignant ascites,
which inversely correlate with survival (1, 2, 3, 4)
. Efforts to reduce the growth and spread of neoplasms such as ovarian cancer have focused recently on angiogenesis because they are dependent in part on the formation of adequate vascular support (5 , 6) . Early studies have demonstrated a complex molecular interplay underlying angiogenesis (5, 6, 7, 8, 9, 10) . VEGF3 , also known as VPF, has been shown to induce the proliferation of endothelial cells, increase vascular permeability, induce the production of plasminogen activator by these cells, and prolong their survival (7 , 8) . IL-8, a chemoattractant cytokine, has been shown to attract and activate neutrophils in inflammatory regions and to be angiogenic (9 , 10) . As is true for other solid malignancies (5) , the extent of angiogenesis correlates inversely with prognosis in patients with ovarian cancer (11) . Moreover, from studies in our laboratory, we concluded that the expression level of VEGF/VPF and IL-8 by human ovarian cancer cells directly correlates with aggressive disease subsequent to i.p. implantation (12) .
The finer details of this interaction are just now becoming understood.
Recent studies have demonstrated that the pleiotropic transcription
factor NF-B plays an important role in the control of cell
proliferation and apoptosis and hence oncogenesis
(13, 14, 15, 16)
. Different neoplasms have been shown to express
high levels of NF-B/relA (17, 18, 19)
. NF-B/relA has
also been shown to regulate the expression of proangiogenic molecules,
such as IL-8 (9)
; however, its role in tumor angiogenesis
remains unclear. NF-B is an inducible dimeric transcription factor
that belongs to the Rel/NF-B family of transcription factors, the
prototype of which in most nonlymphoid cells is a heterodimer composed
of the RelA (p65) and NF-B1 (p50) subunits (16)
.
NF-B complexes are typically retained in the cytoplasm by inhibitory
IB proteins, including IB (16)
. Upon stimulation,
IB is rapidly phosphorylated and degraded via the
ubiquitin-proteasome pathway, permitting activation and nuclear import
of NF-B. Dominant-negative mutant forms of IB have been
engineered that cannot be phosphorylated and degraded and thus prevent
the activation of NF-B (14, 15, 16)
.
In this study, we set out to determine whether the expression of
NF-B/relA correlates with the degree of neoplastic angiogenesis and
with disease progression of human ovarian cancer cells implanted into
the peritoneal cavity of nude mice. We show that transfection of
malignant ovarian cancer cells with IBM, a mutated form of
IB, decreased the expression of VEGF and IL-8 and, hence,
angiogenesis and tumorigenicity.
|
Materials and Methods |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
Animals.
Female athymic BALB/c nude mice were purchased from the Animal
Production Area of the National Cancer Institute, Frederick Cancer
Research Facility (Frederick, MD). The mice were housed in laminar flow
cabinets under specific pathogen-free conditions and used at 8 weeks of
age. Animals were maintained according to institutional regulations in
facilities approved by the American Association for Accreditation of
Laboratory Animal Care in accordance with current regulations and
standards of the United States Department of Agriculture, Department of
Health and Human Services, and NIH.
ELISA for Human IL-8 and VEGF Expression.
The level of IL-8 protein in culture supernatants was determined by
using a quantitative immunometric sandwich enzyme immunoassay (ELISA)
kit (Quantikine IL-8 and VEGF ELISA kits; R&D Systems, Minneapolis,
MN). The absorbance of the samples was compared with the standard curve
(12)
.
Northern Blot Analysis.
Cellular mRNA was extracted from ovarian cancer cells by using the
FastTrack mRNA isolation kit (Invitrogen Co., San Diego, CA). The mRNA
(2 µg) was separated electrophoretically on 1% denaturing
formaldehyde agarose gel, transferred to a GeneScreen nylon membrane
(DuPont Co., Boston, MA) in 20x SSC, and cross-linked with a
UV-Stratalinker 1800 (Stratagene, La Jolla, CA). The cDNA probe used in
the analysis was a 0.5-kb EcoRI cDNA fragment corresponding
to human IL-8 and a 0.204-kb BamHI/EcoRI cDNA
fragment corresponding to human VEGF/VPF (from Dr. B. Berse, Harvard
Medical School, Boston, MA). The cDNA probes were labeled with
[32P]deoxycytidine triphosphate using a random
labeling kit (Roche, Indianapolis, IN). The equivalence of mRNA sample
loading was monitored by hybridizing the same membrane filter with a
glyceraldehyde-3-phosphate dehydrogenase cDNA probe (20)
.
Promoter Reporters and Dual Luciferase Assays.
Luciferase reporters driven by either two-copy wild-type (2x
NF-B-Luc) or mutant (2x NF-B-mt-Luc) NF-B-responsive elements
(16)
were used in this study. The pGL2-IL8 is a pGL2-basic
reporter containing a full-length firefly luciferase gene under the
control of an IL-8 promoter flanking from +44 to -1481 from pxp2-IL8
(9)
. The pGL2-VEGF is a pGL2-basic reporter containing a
full-length firefly luciferase gene under the control of both VEGF
5'-flanking region from +50 to -2274 and 3'-untranslated region from 1
to 1921 (21)
. Ovarian cancer cells (1 x 105/well) growing in six-well tissue culture
plates were transfected with 2 µg of the indicated reporter plasmids
using the Lipofectin reagent (Life Technologies, Inc., Gaithersburg,
MD). Normalization of transfection efficiency was done by
cotransfection with 0.05 µg of pB-Actin-RL reporter containing a
full-length Renilla luciferase gene (Promega Corp., Madison,
WI) under the control of the human ß-actin promoter
(21)
. Forty-eight h after transfection, the cells were
harvested in passive lysis buffer (Promega Corp.). As reported
previously, the activities of firefly luciferase and Renilla
luciferase were quantified using the dual luciferase assay system
(Promega). Fold increase of luciferase activity was calculated by
comparing test samples to luciferase activity of pGL2-basic in
SKOV3ip.1 cells assigned the value of 1 (21)
.
Stable Transfection of Ovarian Cancer Cells with IBM and
Control Vector.
SKOV3ip.1 and Hey-A8 cells (1 x 106) were transfected using 15 µl of lipofectin
reagent (Life Technologies, Inc.) and 4 µg of pLXSN-IBM
expression vector containing IB cDNA with mutations at S32 and
S36 of the NH2 terminus and a COOH-terminal PEST
sequence mutation (19)
or control pLXSN vector according
to the manufacturer’s instructions. Cells were selected with standard
medium containing 500 and 800 µg/ml G418, respectively. Fourteen days
later, Neo-resistant colonies were isolated by trypsinization and
established as subcultures. The expression of exogenous IBM was
verified by Western blot analysis.
Western Blot Analysis.
Cytosolic protein was isolated from control and transfected ovarian
cancer cells. The soluble protein was separated on 10% SDS-PAGE by
electrophoresis and electrophoretically transferred onto Immobilon-P
transfer membrane (Millipore, Bedford, MA). The endogenous and mutant
IB were probed with a polyclonal rabbit antihuman and antimouse
IB (C-21; Santa Cruz Biotechnology, Santa Cruz, CA). The probe
proteins were detected with the Amersham ECL system (Arlington Heights,
IL) according to the manufacturer’s instructions.
EMSA.
Nuclear protein extracts were prepared as described previously
(20)
. The sequence of the NF-B oligonucleotide probe
was 5'-AGTTGAGGGACTTTCCCAGGC-3'. EMSA was performed as described
previously (20)
with minor modifications. Five µg of
nuclear extract protein and 30,000 cpm of end-labeled double-stranded
DNA probe were added to the mixture. The binding reaction was allowed
to proceed for 25 min at 22°C. For supershift reactions, extracts
were preincubated with anti-p65 or anti-p50 antibody (Calbiochem, San
Diego, CA) for 20 min on ice.
In Vivo Tumor Growth.
Cultured cells were harvested by a brief treatment with 0.25% trypsin
and 0.02% EDTA. A single-cell suspension of 1 x 106 cells with a viability of >95% (trypan blue
exclusion) was injected into the peritoneal cavity of female nude mice.
The mice were monitored daily for evidence of disease (abdominal
swelling, hunched posture, and listlessness) and killed when moribund
or 90 days after the i.p. injection. All mice were necropsied, and the
pattern (discrete solid lesions, ascites) and extent of abdominal
disease (size and number of lesions, volume of ascites) were recorded.
Immunohistochemistry and Quantitation of Microvessel
Density.
Peritoneal tumors harvested at autopsy were processed for
immunostaining using rabbit polyclonal anti-IL-8 (Biosource
International, Camarillo, CA), anti-VEGF (Santa Cruz Biotechnology),
and anti-CD31/PECAM-1 (PharMingen, San Diego, CA) antibodies and
appropriate peroxidase-conjugated antirabbit IgG second antibody. The
slides were examined in a bright-field microscope. A positive reaction
was indicated by a reddish-brown precipitate in the cytoplasm. Negative
controls were done using nonspecific IgG. The number of blood vessels
was counted in each field of each sample (12)
.
Statistics.
The significance of the in vitro results was determined by
the Student’s t test (two-tailed), and the significance of
the in vivo data were determined by the Mann-Whitney
U test.
|
Results |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
B expression vector (IBM). The expression
of both endogenous and mutant IB was verified by Western blot
analysis. As shown in Fig. 1
A, endogenous IB was detected in the parental (ip.1),
control pLXSN-transfected (Neo), and IBM-transfected cells (IM1
and IM2). Exogenous mutant IB was detected only in
IBM-transfected IM1 and IM2 cells.
|
B/relA binding activity in the
SKOV3ip.1 cells and the effect of IBM transfection on
NF-B/relA activity, nuclear protein was extracted from SKOV3 (SK3)
cells, SKOV3ip.1 (ip.1) cells, SKOV3ip.1 cells transfected with the
control pLXSN vector (Neo), and the SKOV3ip.1 cells transfected with
the IBM-expression vector (IM1 and IM2). As shown in Fig. 1
B, low and high constitutive NF-B binding activity was
detected by EMSA in SKOV3 cells and SKOV3ip.1 cells, respectively. The
expression of IBM significantly inhibited the NF-B activity in
IM1 and IM2 cells as compared with control transfected cells. The
specificity of the observed bandshift, checked by supershift
experiments with anti-p65 and anti-p50 antibodies, indicated that
NF-B complexes contained both p50 and p65 components (data not
shown).
Next, the suppressive effect of IBM transfection on constitutive
levels of NF-B/relA activity was next confirmed by NF-B reporter
activity assay. A 2x NF-B-Luc reporter or a 2x NF-B-mut-luc
reporter (16)
was transiently transfected into the SKOV3
variant cells. As shown in Fig. 1
C, constitutive NF-B
reporter activity was lower in SKOV3 cells as compared with SKOV3ip.1
cells. Moreover, the NF-B reporter activity was significantly
decreased in the IBM-transfected IM1 and IM2 cells, which was
consistent with the EMSA results (Fig. 1B)
, implying that
the SKOV3ip.1 cells constitutively expressed NF-B/relA activity that
could be inhibited by transfection of IBM expression vector.
To provide direct evidence for the contribution of NF-B/relA to the
regulation of proangiogenic molecules and hence angiogenesis and growth
of human ovarian cancer, we determined the promoter activities of
VEGF and IL-8 genes in the
IBM-transfected and control ovarian cancer cells. The level of
NF-B promoter activity directly correlated with VEGF and IL-8
promoter activity (Fig. 2, A and B)
, suggesting that NF-B activity
regulates VEGF and IL-8 expression at the transcriptional level. The
exact NF-B-responsive elements on the VEGF regulatory regions,
however, remain unknown.
|
BM-transfected cells
was determined at both the mRNA and protein levels. Cellular mRNA was
extracted from cultured ovarian cancer cells, and Northern blot
analysis was performed. As shown in Fig. 2
C, there was a
3–5-fold decrease in VEGF and IL-8 mRNA expression in the
IBM-transfected IM1 and IM2 cells as compared with control
SKOV3ip.1 and SKOV3ip.1-Neo cells. Consistently, IBM-transfected
cells secreted significantly decreased levels of VEGF and IL-8 into the
culture supernatant, as determined by quantitative IL-8 and VEGF ELISA
(Fig. 2D)
. These data show for the first time that NF-B
activity regulates both IL-8 and VEGF constitutive expression in human
ovarian cancer cells.
In the next set of in vivo experiments, we determined
the effect of decreased constitutive NF-B/relA activity on
angiogenesis, tumor growth, and formation of malignant ascites by human
ovarian cancer cells. SKOV3ip.1, SKOV3ip.1-Neo, SKOV3ip.1-IM1, and
SKOV3ip.1-IM2 cells were injected into the peritoneal cavity of groups
of nude mice (n = 10). IBM transfection
inhibited tumor growth and formation of ascites (Table 1)
. The smaller tumors and low levels of ascites in mice injected with
IBM-transfected IM1 and IM2 cells correlated with prolonged
survival (Table 1)
. In parallel studies, we also transfected the human
ovarian carcinoma cell line HEY-A8 with the IBM expression
vector, which also inhibited NF-B/relA activity and VEGF and IL-8
expression (data not shown). The IBM-transfected cells had a
significant reduction in tumorigenicity, which in turn correlated with
prolonged survival (Table 1)
.
|
B/relA activity and the
subsequent decrease in VEGF and IL-8 production by human ovarian cancer
cells were associated with suppression of angiogenesis. Tumors produced
by control and IBM-transfected SKOV3ip.1 or HEY-A8 cells were
resected and processed for immunohistochemical analyses of vascular
formation using anti-CD31 antibodies. As shown in Table 1
and Fig. 3
, tumors produced by control cells were highly vascularized, whereas
tumors produced by IBM-transfected cells had a significant
decrease in microvessel density. Consistent with the alteration of
microvessel density, higher levels of VEGF and IL-8 expression were
found in tumor lesions produced by control tumor cells than in tumors
produced by IBM-transfected SKOV3ip.1 cells (Fig. 3)
.
|
|
Discussion |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
B/relA
by human ovarian carcinoma cells with disease progression in the
peritoneal cavity of nude mice and with angiogenesis. SKOV3 cells
produce slow-growing tumors with a low volume of malignant ascites,
whereas the SKOV3ip.1 variant (isolated from the SKOV3 parental line)
produces rapidly progressing peritoneal disease and a high volume
of malignant ascites (12)
. In agreement with the in
vivo behavior, the SKOV3ip.1 cells expressed higher levels of IL-8
and VEGF/VPF than did SKOV3 cells (12)
. Our present data
demonstrate that SKOV3ip.1 cells (high expression level of VEGF/VPF and
IL-8) expressed significantly higher levels of NF-B/relA activity
than the SKOV3 cells (low expression level of VEGF/VPF and IL-8),
suggesting that this transcription factor may play a role in the
progression of human ovarian cancers. Expression of VEGF/VPF and IL-8 by tumor cells directly correlates with angiogenesis (7 , 8 , 10) , which contributes to the progressive growth of neoplasms, including human ovarian cancer (11 , 12 , 22, 23, 24) . Specifically, the expression of VEGF/VPF by ovarian cancer cells directly correlates with production of malignant ascites (12 , 22) . Indeed, the administration of anti-VEGF antibodies to mice injected with human ovarian cancer cells has been shown to inhibit growth of solid peritoneal lesions and formation of ascites (23) . The expression level of IL-8 by many human ovarian cancer cells directly correlates with aggressive peritoneal disease (12 , 24) . However, overexpression of IL-8 achieved by transfection has been shown to retard growth of the transfected cells subsequent to s.c. implantation because of massive infiltration with neutrophils (25) . In an orthotopic nude mouse model, however, the constitutive expression of IL-8 by five different human ovarian cancer cell lines directly correlated with disease progression (12) , probably by inducing angiogenesis associated with IL-8 interaction with IL-8 receptors on endothelial cells in the peritoneum (10) .
The regulation of both VEGF and IL-8 expression during tumor
progression may involve diverse mechanisms. Although it is well
established that the transcription factor NF-B is essential for both
inducible and constitutive IL-8 expression (9)
, it is not
known whether NF-B regulates VEGF expression. In this study, we
sought to determine whether NF-B also regulates VEGF expression.
IBM transfection, which blocks NF-B activation
(19)
, suppressed the production of both IL-8 and VEGF
under in vitro and in vivo conditions. The
significant decrease in VEGF promoter activity found in the
IBM-transfected cells suggested that the regulation of VEGF by
NF-B probably occurred at the transcriptional level. Studies are
under way to define the NF-B binding site(s) in 5'- and/or
3'-regulatory region(s) of the VEGF gene.
NF-B activation can protect tumor cells from apoptosis; thus,
suppression of tumor growth by blocking NF-B activity could have
been attributable to increased apoptosis (14
, 15)
.
However, consistent with previous reports showing that stable
inhibition of NF-B in cancer cells by stable transfection of
IBM does not inhibit cell growth in vitro (15
, 26
, 27)
, the in vitro growth of the
IBM-transfected SKOV3ip.1 cells was similar to that of control
SKOV3ip.1 cells. Thus, the inhibition of tumorigenicity by suppression
of NF-B activity had to occur by other mechanisms, such as
inhibition of cell adhesion (28)
, inhibition of
proinflammatory cytokine production (15)
, or inhibition of
plasminogen activator and matrix metalloproteinase (29
, 30)
, which contribute to neoplastic angiogenesis, growth, and
metastasis. NF-B has also been shown to play a role in retinal
neovascularization (31)
because of its activation by VEGF
(32)
and in oxidative stress-induced tubular morphogenesis
of endothelial cells (33)
. Our data showing that the
NF-B expression level directly correlates with expression of
VEGF/VPF and IL-8 support the role that NF-B may play in
angiogenesis, an essential feature of progressive tumor growth.
In summary, we show that human ovarian cancer cells with high malignant
potential express high levels of constitutive NF-B/relA activity.
Suppression of NF-B/relA activity through expression of a
phosphorylation mutant IB decreased angiogenesis, retarded tumor
growth, and reduced formation of malignant ascites, in part through
down-regulation of the angiogenic molecules VEGF and IL-8. These data
provide the first direct evidence for the essential role of
NF-B/relA in angiogenesis, tumor growth, and formation of malignant
ascites by human ovarian cancer. Targeting NF-B may therefore be a
potential approach to controlling angiogenesis and growth of human
ovarian cancer.
|
ACKNOWLEDGMENTS |
|---|
BM, Dr. B. Su (Department of Immunology) for 2x NF-B
reporter constructs, Dr. K. Xie (Department of Gastrointestinal Medical
Oncology) for pGL2-VEGF reporter, and Drs. N. Mukaida and K. Matsushima
(Kanazowa University, Kanazawa, Japan) for pxp2-IL8–1481 promoter. We
are grateful to Walter Pagel for his critical editorial comments and to
Lola López for expert assistance in the preparation of the
manuscript. |
FOOTNOTES |
|---|
1 This work was supported in part by Cancer Center
Support Core Grant CA16672 and Grant R35-CA42107 (to I. J. F.) from
the National Cancer Institute, NIH. 
2 To whom requests for reprints should be
addressed, at Department of Cancer Biology, Box 173, The University of
Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston,
TX 77030. Phone: (713) 792-8577; Fax: (713) 792-8747; E-mail: ijfidler{at}mail.mdanderson.org
3 The abbreviations used are: VEGF, vascular
endothelial growth factor; VPF, vascular permeability factor; NF,
nuclear factor; IBM, mutated IB; IL, interleukin; EMSA,
electrophoretic mobility shift assay.
Received 5/24/00. Accepted 8/15/00.
|
REFERENCES |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
B transcription factor in oncogenesis. Anticancer Res., 16: 1589-1596, 1996.
B activation in Bcr-Abl-mediated transformation. Gene Dev., 12: 968-981, 1998.B of NF-B in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression and tumor growth in vivo. Cancer Res., 59: 3468-3474, 1999.B: a pivotal transcription factor in chronic inflammatory diseases (review). N. Engl. J. Med., 336: 1066-1071, 1997.B during progression of breast cancer to hormone-independent growth. Mol. Cell. Biol., 17: 3629-3639, 1997.[Abstract]
B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin. Cancer Res., 5: 119-127, 1999.-induced apoptosis by NF-B. Science (Washington DC), 274: 787-789, 1996.B in cancer cells does not increase sensitivity to cytotoxic drugs. Cancer Res., 59: 811-815, 1999.B, clonogenicity, and radiosensitivity of human cancer cells. J. Natl. Cancer Inst., 91: 1956-1960, 1999.B blocks tumorigenicity and causes tumor regression. Proc. Natl. Acad. Sci. USA, 90: 9901-9905, 1993.B. FEBS Lett., 435: 29-34, 1998.[Medline]
B-mediated interleukin-8 expression in intraocular neovascularization. Investig. Ophthalmol. Visual Sci., 39: 1097-1106, 1998.B and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells. Diabetes, 48: 1131-1137, 1999.[Abstract]
B in tubular morphogenesis of human microvascular endothelial cells by oxidative stress. Mol. Cell. Biol., 16: 4231-4239, 1996.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  M. N. Chahine and G. N. Pierce Therapeutic Targeting of Nuclear Protein Import in Pathological Cell Conditions Pharmacol. Rev., September 1, 2009; 61(3): 358 - 372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Zhu, Y. Ou, Y. Li, R. Xiao, M. Shu, Y. Zhou, J. Xie, S. He, P. Qiu, and G. Yan A Small-Molecule Triptolide Suppresses Angiogenesis and Invasion of Human Anaplastic Thyroid Carcinoma Cells via Down-Regulation of the Nuclear Factor-{kappa}B Pathway Mol. Pharmacol., April 1, 2009; 75(4): 812 - 819. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Martin, R. Galisteo, and J. S. Gutkind CXCL8/IL8 Stimulates Vascular Endothelial Growth Factor (VEGF) Expression and the Autocrine Activation of VEGFR2 in Endothelial Cells by Activating NF{kappa}B through the CBM (Carma3/Bcl10/Malt1) Complex J. Biol. Chem., March 6, 2009; 284(10): 6038 - 6042. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. B. Aggarwal, R.V. Vijayalekshmi, and B. Sung Targeting Inflammatory Pathways for Prevention and Therapy of Cancer: Short-Term Friend, Long-Term Foe Clin. Cancer Res., January 15, 2009; 15(2): 425 - 430. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Shibata, K. Nakagawa, P. Sookwong, T. Tsuduki, S. Tomita, H. Shirakawa, M. Komai, and T. Miyazawa Tocotrienol Inhibits Secretion of Angiogenic Factors from Human Colorectal Adenocarcinoma Cells by Suppressing Hypoxia-Inducible Factor-1{alpha} J. Nutr., November 1, 2008; 138(11): 2136 - 2142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Raghuwanshi, M. W. Nasser, X. Chen, R. M. Strieter, and R. M. Richardson Depletion of {beta}-Arrestin-2 Promotes Tumor Growth and Angiogenesis in a Murine Model of Lung Cancer J. Immunol., April 15, 2008; 180(8): 5699 - 5706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. N. Landen Jr, M. J. Birrer, and A. K. Sood Early Events in the Pathogenesis of Epithelial Ovarian Cancer J. Clin. Oncol., February 20, 2008; 26(6): 995 - 1005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Mizukami, Y. Kohgo, and D. C. Chung Hypoxia Inducible Factor-1 Independent Pathways in Tumor Angiogenesis Clin. Cancer Res., October 1, 2007; 13(19): 5670 - 5674. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zhang and R. P. Hill Hypoxia Enhances Metastatic Efficiency in HT1080 Fibrosarcoma Cells by Increasing Cell Survival in Lungs, Not Cell Adhesion and Invasion Cancer Res., August 15, 2007; 67(16): 7789 - 7797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Angelo and R. Kurzrock Vascular Endothelial Growth Factor and Its Relationship to Inflammatory Mediators Clin. Cancer Res., May 15, 2007; 13(10): 2825 - 2830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-W. Jang, Y. S. Kim, Y. R. Kim, H. J. Sung, and J. Ko Regulation of Human LZIP Expression by NF-{kappa}B and Its Involvement in Monocyte Cell Migration Induced by Lkn-1 J. Biol. Chem., April 13, 2007; 282(15): 11092 - 11100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kong, Y. Li, Z. Wang, S. Banerjee, and F. H. Sarkar Inhibition of Angiogenesis and Invasion by 3,3'-Diindolylmethane Is Mediated by the Nuclear Factor-{kappa}B Downstream Target Genes MMP-9 and uPA that Regulated Bioavailability of Vascular Endothelial Growth Factor in Prostate Cancer Cancer Res., April 1, 2007; 67(7): 3310 - 3319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kishida, H. Yoshikawa, and A. Myoui Parthenolide, a Natural Inhibitor of Nuclear Factor-{kappa}B, Inhibits Lung Colonization of Murine Osteosarcoma Cells Clin. Cancer Res., January 1, 2007; 13(1): 59 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. McCarty and K. I. Block Preadministration of High-Dose Salicylates, Suppressors of NF-{kappa}B Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy Integr Cancer Ther, September 1, 2006; 5(3): 252 - 268. [Abstract] [PDF]
|
|
|
|
|
|
T.-x. Xie, F.-J. Huang, K. D. Aldape, S.-H. Kang, M. Liu, J. E. Gershenwald, K. Xie, R. Sawaya, and S. Huang Activation of Stat3 in Human Melanoma Promotes Brain Metastasis. Cancer Res., March 15, 2006; 66(6): 3188 - 3196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shishodia, G. Sethi, M. Konopleva, M. Andreeff, and B. B. Aggarwal A Synthetic Triterpenoid, CDDO-Me, Inhibits I{kappa}B{alpha} Kinase and Enhances Apoptosis Induced by TNF and Chemotherapeutic Agents through Down-Regulation of Expression of Nuclear Factor {kappa}B-Regulated Gene Products in Human Leukemic Cells Clin. Cancer Res., March 15, 2006; 12(6): 1828 - 1838. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Moscova, D. J. Marsh, and R. C. Baxter Protein Chip Discovery of Secreted Proteins Regulated by the Phosphatidylinositol 3-Kinase Pathway in Ovarian Cancer Cell Lines Cancer Res., February 1, 2006; 66(3): 1376 - 1383. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. T. Stathopoulos, Z. Zhu, M. B. Everhart, I. Kalomenidis, W. E. Lawson, S. Bilaceroglu, T. E. Peterson, D. Mitchell, F. E. Yull, R. W. Light, et al. Nuclear Factor-{kappa}B Affects Tumor Progression in a Mouse Model of Malignant Pleural Effusion Am. J. Respir. Cell Mol. Biol., February 1, 2006; 34(2): 142 - 150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chigurupati, T. Kulkarni, S. Thomas, and G. Shah Calcitonin Stimulates Multiple Stages of Angiogenesis by Directly Acting on Endothelial Cells Cancer Res., September 15, 2005; 65(18): 8519 - 8529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cicek, R. Fukuyama, D. R. Welch, N. Sizemore, and G. Casey Breast Cancer Metastasis Suppressor 1 Inhibits Gene Expression by Targeting Nuclear Factor-{kappa}B Activity Cancer Res., May 1, 2005; 65(9): 3586 - 3595. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Zhu, M. A. Amin, Y. Zha, L. A. Harlow, and A. E. Koch Mechanism by which H-2g, a glucose analog of blood group H antigen, mediates angiogenesis Blood, March 15, 2005; 105(6): 2343 - 2349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Cheng, C. Cenciarelli, G. Nelkin, R. Tsan, D. Fan, C. Cheng-Mayer, and I. J. Fidler Molecular Mechanism of hTid-1, the Human Homolog of Drosophila Tumor Suppressor l(2)Tid, in the Regulation of NF-{kappa}B Activity and Suppression of Tumor Growth Mol. Cell. Biol., January 1, 2005; 25(1): 44 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Elner, V. M. Elner, A. Yoshida, R. D. Dick, and G. J. Brewer Effects of Tetrathiomolybdate in a Mouse Model of Retinal Neovascularization Invest. Ophthalmol. Vis. Sci., January 1, 2005; 46(1): 299 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shishodia and B. B. Aggarwal Guggulsterone Inhibits NF-{kappa}B and I{kappa}B{alpha} Kinase Activation, Suppresses Expression of Anti-apoptotic Gene Products, and Enhances Apoptosis J. Biol. Chem., November 5, 2004; 279(45): 47148 - 47158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fujioka, J. Niu, C. Schmidt, G. M. Sclabas, B. Peng, T. Uwagawa, Z. Li, D. B. Evans, J. L. Abbruzzese, and P. J. Chiao NF-{kappa}B and AP-1 Connection: Mechanism of NF-{kappa}B-Dependent Regulation of AP-1 Activity Mol. Cell. Biol., September 1, 2004; 24(17): 7806 - 7819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Jeong, M. Radonovich, J. N. Brady, and C. A. Pise-Masison HTLV-I Tax induces a novel interaction between p65/RelA and p53 that results in inhibition of p53 transcriptional activity Blood, September 1, 2004; 104(5): 1490 - 1497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Sweeney, L. Li, R. Shanmugam, P. Bhat-Nakshatri, V. Jayaprakasan, L. A. Baldridge, T. Gardner, M. Smith, H. Nakshatri, and L. Cheng Nuclear Factor-{kappa}B Is Constitutively Activated in Prostate Cancer In vitro and Is Overexpressed in Prostatic Intraepithelial Neoplasia and Adenocarcinoma of the Prostate Clin. Cancer Res., August 15, 2004; 10(16): 5501 - 5507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. V. Bobrovnikova-Marjon, P. L. Marjon, O. Barbash, D. L. Vander Jagt, and S. F. Abcouwer Expression of Angiogenic Factors Vascular Endothelial Growth Factor and Interleukin-8/CXCL8 Is Highly Responsive to Ambient Glutamine Availability: Role of Nuclear Factor-{kappa}B and Activating Protein-1 Cancer Res., July 15, 2004; 64(14): 4858 - 4869. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Arsham, D. R. Plas, C. B. Thompson, and M. C. Simon Akt and Hypoxia-Inducible Factor-1 Independently Enhance Tumor Growth and Angiogenesis Cancer Res., May 15, 2004; 64(10): 3500 - 3507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Fang, S. Yu, R. C. Bast, S. Liu, H.-J. Xu, S.-X. Hu, R. LaPushin, F. X. Claret, B. B. Aggarwal, Y. Lu, et al. Mechanisms for Lysophosphatidic Acid-induced Cytokine Production in Ovarian Cancer Cells J. Biol. Chem., March 5, 2004; 279(10): 9653 - 9661. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, G. Yang, J. A. Thompson-Lanza, A. Glassman, K. Hayes, A. Patterson, R. T. Marquez, N. Auersperg, Y. Yu, W. C. Hahn, et al. A Genetically Defined Model for Human Ovarian Cancer Cancer Res., March 1, 2004; 64(5): 1655 - 1663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pold, L. X. Zhu, S. Sharma, M. D. Burdick, Y. Lin, P. P. N. Lee, A. Pold, J. Luo, K. Krysan, M. Dohadwala, et al. Cyclooxygenase-2-Dependent Expression of Angiogenic CXC Chemokines ENA-78/CXC Ligand (CXCL) 5 and Interleukin-8/CXCL8 in Human Non-Small Cell Lung Cancer Cancer Res., March 1, 2004; 64(5): 1853 - 1860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Samanta, H. J. Huang, R. C. Bast Jr., and W. S.-L. Liao Overexpression of MEKK3 Confers Resistance to Apoptosis through Activation of NF{kappa}B J. Biol. Chem., February 27, 2004; 279(9): 7576 - 7583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Takada and B. B. Aggarwal Flavopiridol Inhibits NF-{kappa}B Activation Induced by Various Carcinogens and Inflammatory Agents through Inhibition of I{kappa}B{alpha} Kinase and p65 Phosphorylation: ABROGATION OF CYCLIN D1, CYCLOOXYGENASE-2, AND MATRIX METALLOPROTEASE-9 J. Biol. Chem., February 6, 2004; 279(6): 4750 - 4759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. W. Distler, C. Hagen, A. Hirth, U. Muller-Ladner, H. M. Lorenz, A. del Rosso, B. A. Michel, R. E. Gay, R. Nanagara, K. Nishioka, et al. Bucillamine Induces the Synthesis of Vascular Endothelial Growth Factor Dose-Dependently in Systemic Sclerosis Fibroblasts via Nuclear Factor-{kappa}B and Simian Virus 40 Promoter Factor 1 Pathways Mol. Pharmacol., February 1, 2004; 65(2): 389 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. H. Yang, M. H. Ma, R. A. Vescio, and J. R. Berenson Overcoming Drug Resistance in Multiple Myeloma: The Emergence of Therapeutic Approaches to Induce Apoptosis J. Clin. Oncol., November 15, 2003; 21(22): 4239 - 4247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Tabruyn, C. M. Sorlet, F. Rentier-Delrue, V. Bours, R. I. Weiner, J. A. Martial, and I. Struman The Antiangiogenic Factor 16K Human Prolactin Induces Caspase-Dependent Apoptosis by a Mechanism that Requires Activation of Nuclear Factor-{kappa}B Mol. Endocrinol., September 1, 2003; 17(9): 1815 - 1823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Pan, L. W. Bao, and S. D. Merajver Tetrathiomolybdate Inhibits Angiogenesis and Metastasis Through Suppression of the NF{kappa}B Signaling Cascade Mol. Cancer Res., August 1, 2003; 1(10): 701 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Lev, M. Ruiz, L. Mills, E. C. McGary, J. E. Price, and M. Bar-Eli Dacarbazine Causes Transcriptional Up-Regulation of Interleukin 8 and Vascular Endothelial Growth Factor in Melanoma Cells: A Possible Escape Mechanism from Chemotherapy Mol. Cancer Ther., August 1, 2003; 2(8): 753 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Mian, C. P. N. Dinney, C. E. Bermejo, P. Sweeney, C. Tellez, X. D. Yang, J. M. Gudas, D. J. McConkey, and M. Bar-Eli Fully Human Anti-Interleukin 8 Antibody Inhibits Tumor Growth in Orthotopic Bladder Cancer Xenografts via Down-Regulation of Matrix Metalloproteases and Nuclear Factor-{kappa}B Clin. Cancer Res., August 1, 2003; 9(8): 3167 - 3175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Karashima, P. Sweeney, A. Kamat, S. Huang, S. J. Kim, M. Bar-Eli, D. J. McConkey, and C. P. N. Dinney Nuclear Factor-{kappa}B Mediates Angiogenesis and Metastasis of Human Bladder Cancer through the Regulation of Interleukin-8 Clin. Cancer Res., July 1, 2003; 9(7): 2786 - 2797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-L. Hu, C. Albanese, R. G. Pestell, and R. B. Jaffe Dual Mechanisms for Lysophosphatidic Acid Stimulation of Human Ovarian Carcinoma Cells J Natl Cancer Inst, May 21, 2003; 95(10): 733 - 740. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kiriakidis, E. Andreakos, C. Monaco, B. Foxwell, M. Feldmann, and E. Paleolog VEGF expression in human macrophages is NF-{kappa}B-dependent: studies using adenoviruses expressing the endogenous NF-{kappa}B inhibitor I{kappa}B{alpha} and a kinase-defective form of the I{kappa}B kinase 2 J. Cell Sci., February 15, 2003; 116(4): 665 - 674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Bayon, M. A. Ortiz, F. J. Lopez-Hernandez, F. Gao, M. Karin, M. Pfahl, and F. J. Piedrafita Inhibition of I{kappa}B Kinase by a New Class of Retinoid-Related Anticancer Agents That Induce Apoptosis Mol. Cell. Biol., February 1, 2003; 23(3): 1061 - 1074. [Abstract] [Full Text]
|
|
|
|
|
|
I. Lavon, E. Pikarsky, E. Gutkovich, I. Goldberg, J. Bar, M. Oren, and Y. Ben-Neriah Nuclear Factor-{kappa}B Protects the Liver against Genotoxic Stress and Functions Independently of p53 Cancer Res., January 1, 2003; 63(1): 25 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fujioka, G. M. Sclabas, C. Schmidt, W. A. Frederick, Q. G. Dong, J. L. Abbruzzese, D. B. Evans, C. Baker, and P. J. Chiao Function of Nuclear Factor {kappa}B in Pancreatic Cancer Metastasis Clin. Cancer Res., January 1, 2003; 9(1): 346 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Pan, C. G. Kleer, K. L. van Golen, J. Irani, K. M. Bottema, C. Bias, M. De Carvalho, E. A. Mesri, D. M. Robins, R. D. Dick, et al. Copper Deficiency Induced by Tetrathiomolybdate Suppresses Tumor Growth and Angiogenesis Cancer Res., September 1, 2002; 62(17): 4854 - 4859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Huang, M. Van Arsdall, S. Tedjarati, M. McCarty, W. Wu, R. Langley, and I. J. Fidler Contributions of Stromal Metalloproteinase-9 to Angiogenesis and Growth of Human Ovarian Carcinoma in Mice J Natl Cancer Inst, August 7, 2002; 94(15): 1134 - 1142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Abcouwer, P. L. Marjon, R. K. Loper, and D. L. Vander Jagt Response of VEGF Expression to Amino Acid Deprivation and Inducers of Endoplasmic Reticulum Stress Invest. Ophthalmol. Vis. Sci., August 1, 2002; 43(8): 2791 - 2798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Ojo-Amaize, E. J. Nchekwube, H. B. Cottam, R. Bai, P. Verdier-Pinard, V. N. Kakkanaiah, J. A. Varner, L. Leoni, J. I. Okogun, A. A. Adesomoju, et al. Hypoestoxide, a Natural Nonmutagenic Diterpenoid with Antiangiogenic and Antitumor Activity: Possible Mechanisms of Action Cancer Res., July 15, 2002; 62(14): 4007 - 4014. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kashani-Sabet, Y. Liu, S. Fong, P.-Y. Desprez, S. Liu, G. Tu, M. Nosrati, C. Handumrongkul, D. Liggitt, A. D. Thor, et al. Identification of gene function and functional pathways by systemic plasmid-based ribozyme targeting in adult mice PNAS, March 19, 2002; 99(6): 3878 - 3883. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-M. Ko, K. H. Seo, S.-J. Han, K. Y. Ahn, I.-H. Choi, G. Y. Koh, H.-K. Lee, M. S. Ra, and S.-Y. Im Nuclear Factor {kappa}B Dependency of Platelet-activating Factor-induced Angiogenesis Cancer Res., March 1, 2002; 62(6): 1809 - 1814. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Niki, T. Kohno, S. Iba, Y. Moriya, Y. Takahashi, M. Saito, A. Maeshima, T. Yamada, Y. Matsuno, M. Fukayama, et al. Frequent Co-Localization of Cox-2 and Laminin-5 {gamma}2 Chain at the Invasive Front of Early-Stage Lung Adenocarcinomas Am. J. Pathol., March 1, 2002; 160(3): 1129 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Clay, G.-i. Atsumi, K. P. High, and F. H. Chilton Early de Novo Gene Expression Is Required for 15-Deoxy-Delta 12,14-prostaglandin J2-induced Apoptosis in Breast Cancer Cells J. Biol. Chem., December 7, 2001; 276(50): 47131 - 47135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fukumura, L. Xu, Y. Chen, T. Gohongi, B. Seed, and R. K. Jain Hypoxia and Acidosis Independently Up-Regulate Vascular Endothelial Growth Factor Transcription in Brain Tumors in Vivo Cancer Res., August 1, 2001; 61(16): 6020 - 6024. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
