Cytokine and Growth Factor Reviews 12 (2001) 375– 391

www.elsevier.com/locate/cytogfr

Survey

Interleukin-8 and human cancer biology

Keping Xie *
Department of Gastrointestinal Medical Oncology and Cancer Biology, M.D. Anderson Cancer Center, The Uni6ersity of Texas, Box 78,
1515 Holcombe Boule6ard, Houston, TX 77030, USA

Abstract

The aggressive nature of metastatic human cancer has been shown to be related to numerous abnormalities in growth factors
and their receptors. These perturbations confer a tremendous growth advantage to the malignant cells. Interleukin-8 (IL-8),
originally discovered as a chemotactic factor for leukocytes, has recently been shown to contribute to human cancer progression
through its potential functions as a mitogenic, angiogenic, and motogenic factor. While it is constitutively detected in human
cancer tissues and established cell lines, IL-8 expression is regulated by various tumor microenvironment factors, such as hypoxia,
acidosis, nitric oxide, and cell density. Understanding the mechanisms of both inducible and constitutive IL-8 expression will be
helpful in designing potential therapeutic strategies of targeting IL-8 to control tumor growth and metastasis. In this review, the
role and regulation of IL-8 expression in the growth and metastasis of human cancer with a focus on human pancreatic
adenocarcinoma will be discussed. © 2001 Elsevier Science Ltd. All rights reserved.

Keywords: Interleukin-8; Pancreatic adenocarcinoma; Leukocytes

Contents

1. IL-8 expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

2. Regulation of IL-8 expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

2.1. Constitutive expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
2.2. Nitric oxide (NO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
2.3. Hypoxia and anoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
2.4. Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
2.5. Other stress factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

3. IL-8 expression and cancer progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

3.1. Clinical observation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
3.2. Xenograft mouse models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
3.3. IL-8 gene transfection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382

4. IL-8 and mitogenic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

5. IL-8 and angiogenic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

6. IL-8 and motogenic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

* Tel.: +1-713-792-2013; fax: + 1-713-745-1163.

E-mail address: kepxie@mail.mdanderson.org (K. Xie).

1359-6101/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S 1 3 5 9 - 6 1 0 1 ( 0 1 ) 0 0 0 1 6 - 8
376 K. Xie / Cytokine & Growth Factor Re6iews 12 (2001) 375–391
7. Targeting IL-8 expression for cancer treatment . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pancreatic adenocarcinoma is currently the fifth lead-
ing cause of cancer-related deaths with about 27000 new
cases and 25000 deaths occurring each year in the US
[1 – 4]. The incidence appears to be increasing, especially
in women. Also, about 10% of pancreatic cancer patients
are able to undergo a curative resection. The average
survival duration from diagnosis of this disease to death
is about 5 months, and the overall 5 year survival-rate
is less than 5%. Pancreatic adenocarcinoma is usually
refractory to conventional adjuvant therapies, and many
experimental therapies for advanced disease have been
investigated with disappointing results. The major cause
of death in pancreatic adenocarcinoma cases is metasta-
sis. In fact, at the time of diagnosis, patients usually have
locally advanced disease or metastasis involving the
lymph nodes, liver, lungs, or peritoneum [1 – 4]. Consid-
ering the very limited treatment options for pancreatic
cancer patients, the development of new treatment strate-
gies is of major importance to reverse the metastatic
biology of this disease. An understanding of the biology
and pathogenesis of pancreatic cancer is crucial to
improving the treatment of this disease.
Earlier studies have established that human pancreatic
cancer overexpresses many growth factors and their
receptors, including the epidermal growth factor family
[2], vascular endothelial growth factor (VEGF) [5–7],
fibroblast growth factor [8,9], and numerous cytokines,
such as transforming growth factor-b (TGF-b) [10,11],
interleukin-1 (IL-1) [12], interleukin-6 (IL-6) [13,14],
tumor necrosis factor-a (TNF-a) [15], and most recently
interleukin-8 (IL-8) [16 – 19]. The relevance of these
factors to tumor growth and metastasis has been evalu-
ated [1–3]. In this review, IL-8 expression and regulation
and its role and mechanisms in human cancer progres-
sion, with a focus on human pancreatic adenocarcinoma,
are discussed.
1. IL-8 expression
IL-8 was originally identified as a neutrophil chemo-
tactic factor in the supernatants of activated human
monocytes. As a member of the CXC chemokine fam-
ily, IL-8 plays an important role as an activator and
chemoattractant for neutrophils. The initial observation
of IL-8 expression was done in human melanocytes and
385
385
386
386
malignant melanoma cell lines stimulated with either
TNF-a or IL-1a, the IL-8 mRNA signal corresponded
well with the amount of secreted IL-8 protein [20]. It
was predicted that IL-8 would play a role in the regula-
tion of melanoma growth and metastasis. IL-8 expres-
sion has since been found in various human cancers,
including acute myelogenous leukemia [21], B-cell
chronic lymphocytic leukemia [22], brain tumors [23],
breast cancer [24,25], colon cancer [26 –29], cervical
cancer [30], gastric cancer [31 –33], Hodgkin’s disease
[34,35], lung cancer [36 –42], melanoma [43 –48],
mesothelioma [49], ovarian cancer [50 –62], pituitary
adenomas [63], prostate cancer [64 –70], renal cell car-
cinoma [71], and thyroid tumors [72,73]. There have
also been a few studies involving IL-8 expression in
human pancreatic cancers. Wigmore et al. [74] first
mentioned that MiaPaCa-2 human pancreatic cancer
cells secrete bioactive IL-8 into culture supernatants.
Later, a high level of IL-8 secretion was also found in
a newly established YAPC human pancreatic cancer
cell line [75]. The IL-8 production in a HuP-T4 human
pancreatic cancer cell line can be suppressed by treat-
ment with IL-8 antisense oligonucleotides, which is
associated with cell growth inhibition in vitro, suggest-
ing that IL-8 produced by human pancreatic cancer
cells may act as an autocrine growth factor [76]. Our
systematic investigation has revealed that IL-8 is over-
expressed in most human pancreatic cancer tissues and
established cell lines. Additionally, the expression levels
appear to correlate with their tumorigenic and
metastatic potential in an orthotopic xenograft model
[16 –19].
2. Regulation of IL-8 expression
It is now known that IL-8 is produced by various
normal and tumorigenic human cells. While the pro-
duction of IL-8 can be induced by various stimuli, such
as lipopolysaccharide, phorbol 12-myristate 13-acetate
(PMA), IL-1, and TNF (Fig. 1) [77 –81], many tumor
cells apparently express IL-8 constitutively. Further-
more, we have found that several stress factors, such as
hypoxia, acidosis, nitric oxide (NO), and cell density,
significantly influence the expression of IL-8 in human
pancreatic cancer cells.
 K. Xie / Cytokine & Growth Factor Re6iews 12 (2001) 375–391
2.1. Constituti6e expression
Constitutive IL-8 expression has been observed in
many human cancer cell lines, including pancreatic
adenocarcinoma [16– 19,74 – 76]. We systematically de-
termined the IL-8 expression in 15 human pancreatic
cancer cell lines under in vitro culture conditions.
About 80% of the cell lines constitutively expressed
high levels of IL-8 in vitro as measured using enzyme-
linked immunosorbent assays and northern blot analy-
sis [19]. In addition, IL-8 protein secretion directly
correlates with the steady-state level of IL-8 mRNA.
Since this steady-state level can be dynamically regu-
lated by many factors at both transcriptional and post-
transcriptional levels [77– 81], we measured the
transcript degradation rate (mRNA stability) of the
IL-8 gene. We found that the IL-8 mRNA half-life was
not consistently correlated with the level of IL-8 expres-
sion, indicating that the stability of IL-8 mRNA was
not a major deciding factor in the differential IL-8
expression. In contrast, the rate of IL-8 gene transcrip-
tion was correlated with the level of IL-8 expression,
suggesting that a constitutive level of IL-8 gene tran-
scription was a major contributing factor in differential
IL-8 expression in human pancreatic cancer cells [19].
To characterize the DNA sequences involved in con-
stitutive IL-8 gene activation, luciferase reporter plas-
mids are used in which IL-8 5%-flanking sequences are
fused to the firefly luciferase coding sequences. A series
of deletion and point mutants is then generated [79],
and constitutive IL-8 promoter activity is measured.
We have found that the sequence between − 133 and
− 85 is apparently the minimal region essential for
constitutive IL-8 promoter activity. This region has
been shown to contain the binding sides for AP-1-,
Fig. 1. Transcriptional regulation of IL-8 expression. The arrow downstream of the TATA box indicates the start site of transcription ( + 1). The
AP-1, NF-kB, and NF-IL-6 indicated by the sequences are major binding sites within the IL-8 promoter. IL-1b, TNF-a, PMA, and LPS induce
AP-1, NF-kB, and NF-IL-6. These transcription factors cooperate differentially to activate IL-8 transcription in different cell types. In pancreatic
cancer cells, hypoxia and acidosis activate both AP-1 and NF-kB.
377
NF-kB-, and NF-IL-6- like factors [79]. Mutations in
the NF-kB and AP-1 sites abolish the constitutive
promoter activity, whereas mutations in the NF-IL-6
binding site preserve some promoter activity. Further-
more, high levels of NF-kB and AP-1 binding activity
as determined using electrophoretic mobility-shift assay
(EMSA) have been detected in cells expressing high
levels of IL-8, whereas low levels of NF-kB and AP-1
binding activity have been detected in cells expressing
low levels of IL-8. In addition, transfection of Mia-
PaCa-2 human pancreatic cancer cells expressing high
levels of IL-8 with a dominant-negative IkB (IkBaM)
expression vector decreases the constitutive level of
NF-kB binding activity and promoter activity. The
constitutive level of IL-8 expression at both the mRNA
and protein level is significantly decreased in these cells.
These results indicate that AP-1- and NF-kB-like fac-
tor-binding elements are mainly responsible for the
constitutive expression of the IL-8 gene in human pan-
creatic cancer cells. Also, maximal constitutive IL-8
expression appears to require the presence and coopera-
tion of the NF-kB and AP-1 binding sites.
2.2. Nitric oxide (NO)
NO is a potent biological molecule that mediates a
diverse array of activities, including vasodilatation, neu-
rotransmission, iron metabolism, and immune defense
[82–87]. Recent studies have suggested that tumor-as-
sociated NO, which is presumably produced by tumor
cells and/or host cells (e.g. macrophages) that infiltrate
tumors, has a pleiotropic effect on carcinogenesis, tu-
mor growth, and metastasis. Also, the outcome appar-
ently depends on the source and level of NO
production, which are dictated by the isoforms of NO
378 K. Xie / Cytokine & Growth Factor Re6iews 12 (2001) 375–391

Fig. 2. Expression and function of IL-8 in tumor growth. The imbalance between uncontrolled tumor growth and blood vessel formation leads
to a decrease in tumor perfusion. The resulting tumor hypoxia and acidosis activate NOS II. The production of NO may promote angiogenesis
and vessel dilatation and then increase tumor perfusion. NO, as well as hypoxia and acidosis also activate the IL-8 gene. The elevated IL-8
secretion may not only directly or indirectly stimulate tumor cell proliferation but may also support tumor mass expansion via direct or indirect
induction of tumor vessel formation.

synthases (NOSs), i.e. NOS I, NOS II, and NOS III. A
low level of NO production, mostly from elevated
expression of NOS I and NOS III (constitutive NOS),
most likely benefits tumor growth [83– 85]. The expres-
sion of NOS II (inducible NOS), however, can have the
opposite effect. Besides its capacity to mediate cytotox-
icity, NO is also potentially a key molecule that regu-
lates expression of genes important to tumor growth
and metastasis.
Several studies using NOS inhibitors and NO donors
have indicated that NO serves as an intracellular sec-
ond messenger to regulate IL-8 gene expression [88].
For example, in a study using a G361 human
melanoma cell line, three NO donors— 3-morpholi-
nosydnonimine hydrochloride, S-nitroso-N-acetylpeni-
cillamine, and S-nitroso-L-glutathione — all caused an
increase in both IL-8 protein secretion and promoter
activity. Truncation of the promoter showed that 101
bp of the 5%-flanking region proximal to the transcrip-
tion start site are sufficient for the response to NO.
Also, mutation of the NF-kB and NF-IL-6 binding
sites led to a significant decrease in NO-stimulated
promoter activity. Furthermore, TNF-a-stimulated IL-
8 promoter activity, was inhibited by the NOS inhibitor
N G-amino-L-homoarginine (NAHA). The NAHA-me-
diated inhibition could be partially reversed by the
addition of excess L-arginine but not D-arginine. These
results suggested that NO is an endogenous regulator of
IL-8 production in G361 melanoma cells [89]. More
recent experiments showed that IL-1b stimulation is
necessary for IL-8 induction by NO in human kerati-
nocytes [90]. Conversely, NO can suppress IL-8 expres-
sion. Fowler et al. [91] found that exogenously supplied
NO down regulated the secretion of IL-8 in activated
endothelium. This process also required the NF-kB site
in the promotor region to be intact. Additionally, Oda
et al. [92] using a T98G human glioblastoma cell line
cocultured with a RAW 264.7 murine macrophage cell
line, demonstrated that excessive production of NO
during the interaction of glioma cells with macrophages
suppresses the production of IL-8. The apparent dis-
crepancy may be due to the use of different cell lines
and NO sources. Finally, it is known that the NO
concentration is an important determinant of its impact
on cell functions, including gene expression [85]. The
biological relevance of NO-mediated IL-8 regulation in
tumor progression remains to be determined.
2.3. Hypoxia and anoxia
Like with many other solid tumors, growth and
metastasis of human pancreatic cancer depend on the
development of adequate vasculature [93–97]. Despite
undergoing extensive angiogenesis, solid tumors have
an overall vasculature that is poorly organized and
marginally functional due to structural abnormalities
(Fig. 2). Consequently, regional and temporal varia-
tions in tumor blood flow as well as tissue oxygen
tension and diffusion limitations produce hypoxic re-
gions within solid tumors [94–97]. A local decrease in
 K. Xie / Cytokine & Growth Factor Re6iews 12 (2001) 375–391
oxygen tension has been considered a major cause of
the induction of many angiogenic factors, such as
VEGF [93 –97]. Such factors profoundly influence
many aspects of tumor cell function including
metabolism, proliferation, metastasis, and therapeutic
response. Our studies and others have indicated that
IL-8 is predominantly expressed in the tumor cells
surrounding necrotic areas of human cancer lesions,
suggesting that hypoxia may contribute to the overex-
pression of IL-8 [16,98– 100]. A similar finding was
observed in human melanoma as determined using in
situ hybridization of IL-8 mRNA in primary
melanoma lesions and metastases. High levels of
melanoma cell-associated IL-8-specific transcripts were
exclusively detected in close vicinity of necrotic/hy-
poxic areas of melanoma metastases, whereas IL-8 ex-
pression was low or absent in both primary
melanomas and in non-necrotic metastases [100].
The induction of IL-8 by hypoxia was first demon-
strated in human endothelial cells [101]. Specifically,
incubation of human endothelial cells under hypoxic
conditions (pO2 of approximately 14– 18 Torr) leads
to a time-dependent release of bioactive IL-8 into the
culture medium. Production of IL-8 by hypoxic hu-
man endothelial cells occurs concomitantly with both
increased levels of IL-8 mRNA and transcription. The
induction of IL-8 by hypoxia in tumor cells was first
demonstrated in human glioblastoma cells [98]. Hy-
poxic/anoxic insults on glioblastoma cells in vitro us-
ing anaerobic chamber systems or within spheroids
developing central necrosis induced an increase in IL-
8 mRNA and protein expression, which is associated
with increased protein binding to the AP-1 site on the
IL-8 promoter [99]. Interestingly, in human melanoma
cell lines, anoxia induces IL-8 mRNA and protein
expression in the highly aggressive/metastatic cell lines
but not in the poorly aggressive cell lines [100].
In human pancreatic cancer, hypoxia-mediated IL-8
upregulation involves transcriptional regulation and
posttranscriptional mRNA stabilization because hy-
poxia increases the transcription rate of the IL-8 gene
and stability of the IL-8 transcript [18]. IL-8 pro-
moter reporter analyses have revealed that the activa-
tion of the IL-8 promoter by hypoxia requires a
similar minimal region that has been shown to confer
responsiveness to IL-1, TNF-a, and PMA in many
human cancer cell lines, including fibrosarcoma, gas-
tric carcinoma, and ovarian cancer cell line, T cells
and monocyte cell lines [77– 80]. This region contains
a putative AP-1 binding site (− 126 to −120 bp), an
NF-kB-like binding site (− 80 to −71 bp), and the
C/EBP-like factor NF-IL-6 binding site (− 94 to −
81 bp) (Fig. 1). Mutation of either the AP-1 or NF-
kB binding site abolishes transcriptional activation of
the IL-8 promoter during hypoxia, suggesting that
both AP-1 and NF-kB are indispensable for IL-8
379
gene expression during hypoxia. This is further sup-
ported by our experiments showing that hypoxia acti-
vated both AP-1 and NF-kB binding activity as
determined using EMSA [18]. Therefore, hypoxia in-
duces IL-8 expression via activation and cooperation
of NF-kB and AP-1 and contributes to the progres-
sion and metastasis of human pancreatic cancer.
2.4. Acidosis
Functional and structural abnormalities of vascula-
ture lead to the development of hypoxic regions
within solid tumors [93–97]. Hypoxia increases anaer-
obic metabolism of tumor cells and leads to elevated
production of acidic metabolites. Reduced blood flow
hinders the removal of these metabolites. Conse-
quently, hydrogen ions accumulate and cause a de-
crease in extracellular pH (Fig. 2). In addition,
induction of IL-8 by hypoxia appears to require pro-
longed hypoxic or anoxic exposure under normal cul-
ture medium in vitro, whereas significant and rapid
induction can occur under HCO− 3 -deficient culture
medium [18]. These data suggest that prolonged expo-
sure to hypoxia or anoxia induces IL-8 expression via
a decrease in the pH of the culture medium and/or
the intracellular pH because the cellular capacity to
maintain intracellular alkaline pH is impaired in an
HCO− 3 -deficient, hypoxic environment. Therefore, it is
highly possible that hypoxic tumor cells are also un-
dergoing acidic stress, which may contribute to the
elevation of IL-8 expression in these cells as well [16–
19]. This hypothesis was tested in COLO357 human
pancreatic cancer cells, which were incubated in
medium having different pH levels. The expression of
IL-8 was inversely correlated with the pH of the cul-
ture medium. Also, the extent of IL-8 induction de-
pended on the level of pH and the incubation time
[16]. Low extracellular pH also induced IL-8 expres-
sion in other human cell lines, including SW620 hu-
man colon cancer cells and PC-3 prostate cancer cells
[16,17]. Therefore, like platelet-derived endothelial cell
growth factor/thymidine phosphorylase and inducible
NOS [102,103]. IL-8 can be upregulated by low tu-
mor pH, suggesting that tumor pH regulates angio-
genesis-related molecules and contributes to tumor
progression.
Further investigation has indicated that the rate of
IL-8 transcription increases only with mild acidosis,
e.g. pH 6.9 for short time as compared with that at
pH 7.4. However, more extensive acidosis, e.g. pH
levels at or lower than 6.7 or prolonged incubation at
pH 6.9, significantly inhibits IL-8 transcription. These
data demonstrate that only transient exposure to low
extracellular pH that is near the neutral level acti-
vates IL-8 gene transcription, whereas persistent expo-
sure to low pH does the opposite [17]. This effect
380 K. Xie / Cytokine & Growth Factor Re6iews 12 (2001) 375–391
may be due to the cytotoxic effects of low pH in tissue
culture and in vivo as earlier reported [94,96]. Interest-
ingly, the stability of IL-8 mRNA was significantly
increased in the tumor cells incubated in a medium
having a low pH (7.1– 6.7). Therefore, pH regulates
IL-8 expression at both the transcriptional and post-
transcriptional level. The increased IL-8 mRNA stabil-
ity is consistent with reports showing that there are
stability-sensitive elements in the 3%-UTR of the IL-8
transcript [77–80]. However, it remains to be deter-
mined whether extracellular pH acts on these elements
through the same factors. Therefore, transient exposure
to low extracellular pH (6.7–7.1) induces an increased
steady-state level of IL-8 mRNA, which correlates with
prolonged IL-8 mRNA stability and to a lesser extent,
transactivation of the IL-8 gene. Also, mild acidosis
activates AP-1 and NF-kB activity, whereas extensive
acidosis (pH 6.7 or lower) inhibits both AP-1 and
NF-kB activities. The presence and cooperation of
these factors appear to be necessary for maximal IL-8
gene transactivation by mild acidosis. Since most solid
tumors contain regions of pH lower than that in their
corresponding normal tissues in a given time, we expect
that temporal and spatial heterogeneous tumor pH may
lead to similar patterns of IL-8 expression and con-
tribute to tumor progression [16,18].
2.5. Other stress factors
Ultraviolet light at wavelengths of 280– 320 nm can
stimulate synthesis of IL-8 in keratinocytes [104], A431
cells [105], and human cutaneous melanoma cells [106].
In addition, the expression of IL-8 in human melanoma
cells can be upregulated by inflammatory cytokines,
however, IFN-a and IFN-b can counterregulate this
stimulation [107]. The up-regulation of IL-8 expression
in melanoma cells is regulated at the transcriptional
level and is rapidly and specifically inhibited by IFN-a
or IFN-b, independent of de novo protein synthesis,
perhaps due to a transient modification of a pre-exist-
ing factor or factors [108]. In a study of paclitaxel-in-
duced secretion of IL-8 in a series of cell lines, including
human ovarian cancer, induction was dependent on
transcriptional activation [56,57,59,109]. Additionally,
treatment with all-trans retinoic acid enhances IL-8
protein release in HOC-7 human epithelial ovarian
cancer cell line at the transcriptional level [110]. Also,
our recent data indicate that the cell density directly
influences IL-8 expression under in vitro culture condi-
tions. Although dense culture upregulates many genes,
e.g. VEGF, IL-8 expression drastically decreases in
pancreatic cancer cells under confluent culture condi-
tions. We are currently investigating the molecular
mechanism of the downregulation of IL-8 expression
due to a high cell density in human pancreatic cancer
cells.
3. IL-8 expression and cancer progression
As a potential prognostic factor, IL-8 expression has
been investigated in clinical studies using patient tumor
tissue specimens and preclinical animal models using
established cell lines. In human pancreatic cancer, IL-8
is overexpressed in tumor tissue as compared with
normal tissue. To determine the role of IL-8 expression
in tumor growth and metastasis, we used an orthotopic
xenograft model to evaluate the tumorigenic and
metastatic potential of COLO357, FG, SG, and L3.3
cells, which were derived from a parental COLO357
human pancreatic adenocarcinoma cell line. The consti-
tutive IL-8 expression in vitro directly correlated with
the extent of local growth and production of sponta-
neous liver metastasis following implantation of these
cancer cells into the pancreas of nude mice. Further-
more, the sequence spanning nucleotides 1– 298 of the
human IL-8 gene was amplified by polymerase chain
reaction (PCR). The PCR product of the IL-8 fragment
was subcloned into the pcDNA3.1 expression vector
downstream of the cytomegalovirus promoter in an
antisense orientation. Also, the FG human pancreatic
adenocarcinoma cells were stably transfected with an
IL-8 antisense oligonucleotide expression vector. The
transfection blocked IL-8 mRNA expression, decreased
IL-8 protein secretion, and suppressed tumor growth
and metastasis in vivo. Our data clearly indicate that
IL-8 plays a significant role in both local growth and
metastasis in this pancreatic cancer model [16]. It re-
mains to be determined whether the expression of IL-8
can serve as a prognostic factor for pancreatic cancer.
3.1. Clinical obser6ation
Diverse results have been generated in clinical studies
of IL-8 expression as a prognostic factor, reflecting the
use of different approaches and different tumor types
(Table 1). For example, several recent reports indicate
that expression of IL-8 correlates with disease progres-
sion in human melanoma [111–113]. In ovarian cancer,
ascites and/or plasma of patients with ovarian cancer
showed significantly higher levels of IL-8 and other
cytokines as compared with that of patients with benign
gynecological disorders [53,55,116]. In addition, IL-8
mRNA was up-regulated in the peripheral blood leuko-
cytes of patients with metastatic prostate cancer com-
pared with that in similar cells obtained from healthy
individuals. The IL-8 serum concentrations correlated
with increasing prostate cancer stage and also differen-
tiated benign prostatic hyperplasia from clinical cancer
[117]. Immunohistochemical studies of prostate tissue
showed that prostate cancer cells stained positively for
IL-8, while benign prostatic hyperplasia and normal
prostate cells displayed little staining. Other results
indicated that significant levels of IL-8 are present in
 K. Xie / Cytokine & Growth Factor Re6iews 12 (2001) 375–391 381

prostate cancer cells but not benign prostatic hyper-
plasia or normal prostate cells in vivo [118].
However, there is still controvery regarding IL-8
expression in melanoma metastases [111,113]. A recent
report pointed out that melanoma cells express multiple
cytokines and that the role of IL-8 was not as promi-
nent as that described above [111]. Also, IL-8 expres-
sion in melanoma associates only with biologically early
malignancy, whereas other cytokines, such as TGF-b,
GM-CSF and IL-1a are highly expressed in biologically
late lesions and TNF-b is an apparent marker of
metastatic dissemination. Therefore, melanoma cells
can utilize cascades of growth factors and cytokines for
their progression [119]. In another study, constitutive
IL-8 expression was determined in melanoma cells from
20 fresh surgical specimens. Most of the melanoma cells
tested expressed IL-8 mRNA, which did not directly
correlate with the clinical stage at the time when the
bioptic specimen was obtained [120]. The serum IL-8
level was detectable in about 50% of the patients with
metastatic melanoma and correlated with tumor load
but not metastatic sites in a third study [121]. Finally,
loss of IL-8 immunoreactivity appears to be a sign of
malignant transformation of human keratinocytes
[122]. Therefore, to some extent, IL-8 expression may
serve as a prognostic factor for human cancer
progression.
3.2. Xenograft mouse models
The prognostic value of IL-8 has been tested further
in preclinical experimental xenograft models (Table 2).
In a SKOV3 human ovarian cancer system, SKOV3
cells growing in nude mice displayed constitutive ex-
pression of IL-8 [126]. The expression of IL-8 in
SKOV3 and SKOV3.ip1 cells was inversely associated
with animal survival [60,127–129]. In a PC-3 human
prostate cancer system, steady-state IL-8 mRNA ex-
pression appeared to correlate with the metastatic po-
tential of a metastatic PC-3 human prostate cancer cell
line and its metastatic variants derived from selection in
nude mice [130]. In contrast, the role of IL-8 was
negligible in an LNCaP human prostate cancer cell line
growing in mice as analyzed in LNCaP cells and two
variants derived from selection in nude mice [131]. In a
COLO 357 human pancreatic cancer system, IL-8 ex-
pression correlated with the tumorigenic and metastatic
potential [16]. Interestingly, Singh et al. [132] first corre-
lated the steady-state transcription and protein secre-
tion of IL-8 in 13 different human melanoma cell lines

Table 1
Expression of IL-8 in human tumor tissues

Tumor Materials and IL-8 expression and prognosis Authors

methodsa

Breast cancer ELISA serum High in progressive and recurrent disease Yokoe et al.,
1997 [114]
IHS surgical Higher in tumor tissues than normal tissues Green et al.,
specimens 1997 [24]
Colon cancer ELISA serum High in patients with poorly differentiated tumor and higher in patients with liver or Ueda et al.,
lung metastasis 1994 [115]
Gastric cancer IHC, ISH Higher in gastric carcinomas (32/39) than in corresponding normal mucosa; correlates Kitadai et al.,
surgical with vascularization 1998 [32]
specimens
Melanoma IHC surgical High in thick melanomas, but little or none in dysplastic nevi and thin or metastatic Hensley et al.,
specimens melanomas 1998 [111]
ISH surgical High in 59% (22/37) of melanomas (14/19) in superficial spreading melanomas versus Numberg et al.,
specimens 4/12 in nodular melanomas), but none in melanocytes and melanocytic nevi; IL-8 1999 [112]
expression correlates with worse prognosis
IHC surgical Highest in metastatic lesions and high in 50% vertical growth-phase (invasive) Singh et al.,
specimens melanomas but not in radial growth-phase melanomas in situ. IL-8 expression 1999 [113]
correlates with disease stage and metastatic phenotype
Ovarian cancer ELISA ascites High in patients with ovarian cancer compared with those with benign disorders Radke et al.,
and plasma 1998 [53]
ELISA serum High in malignant ovarian tumors but low in benign ovarian tumors Ivarsson et al.,
and cyst fluids 1998 [55]
Pancreatic IHC surgical Higher in tumor tissues than in normal tissues Le et al., 2000
cancer specimens [19]
Prostate cancer ELISA serum High in tumor tissues; correlates with increasing prostate cancer stage and differentiates Veltri et al.,
benign prostatic hyperplasia from stage A, B, C, or prostate cancer 1999 [117]
IHC surgical Present in prostate cancer but not benign prostatic hyperplasia or normal prostate cells Ferrer et al.,
specimens 1998 [118]

a
Abbreviations: IHC, immunohistochemistry; ISH, in situ hybridization; ELISA, enzyme-linked immunosorbent assay.
382 K. Xie / Cytokine & Growth Factor Re6iews 12 (2001) 375–391
Table 2
Predicting the malignancy of human tumors using nude mouse xenograft models
Tumor system Animal model
Human melanoma
Thirteen human melanoma cell lines Nude
mice/subcutis
A375P, A375-C5, A375SM, and A375-C28 Nude
mice/subcutis
WM 98-1, WM 1341, UKRV-Mel-4, M7, M13, Nude
UKRV-Mel-2, and MV3 mice/subcutis
O6arian cancer
HEY-A8, SKOV3, SKOV3.ipl, OCCI, and 2776 Nude
mice/peritoneum correlation with animal survival
Pancreatic cancer
SG, FG, an dL3.3 Nude
mice/pancreas
Twelve human pancreatic cancer cell lines Nude
mice/pancreas
Prostate cancer
PC-3P, PC-3M, and PC-3MM2 cells Nude
mice/prostate
LNCaP, LNCaP-LN3, and LNCaP-ProS Nude
mice/prostate
with their ability to grow and metastasize in nude mice.
They found that highly metastatic cells expressed higher
steady state levels of IL-8 mRNA transcripts than did
lesser metastatic cells.
However, Schadendorf et al. [124] studied the
metastatic behavior of seven human melanoma cell
lines derived from two primary cutaneous melanomas
and five metastases established from the liver, skin
pleural effusions and lymph nodes. All cell lines were
analyzed for their capacity to grow in nude mice after
s.c. and i.v. injection. The diverse pattern of growth
kinetics and metastases found did not correlate with the
IL-8 expresson. In addition, we compared the IL-8
expression and tumorigenic and metastatic potential of
12 human pancreatic cancer cell lines using a nude
mouse model. These cell lines are established from
different patients and show a diverse pattern of IL-8
expression, which is not correlated with their tumori-
genic and metastatic potential in nude mice (data not
shown). It appears that there is an intrinsic relationship
between the IL-8 expression in and malignancy of a
given tumor cell line system consisting of an original
cell line (parental line) and its sublines obtained from
selection, mostly in nude mice (poorly or highly
metastatic variants). However, there is no clear-cut
relationship between IL-8 expression and metastatic
potential in cell lines representing different clinical
stages.
Relationship between IL-8 expression in vitro and Authors
malignancy in vivo [reference]
Direct correlation with angiogenic, tumorigenic, Singh RK et al.,
and metastatic potential 1994 [123]
Direct correlation with angiogenic, tumorigenic, Singh RK et al.,
and metastatic potential 1994 [123]
Diverse expression and no clear-cut correlation Schadendorf D et
with angiogenic, tumorigenic, and metastafic al., 1996 [124]
potential
Direct correlation with tumor growth and inverse Yoneda J et al.,
1998 [60]
Direct correlation with angiogenic, tumorigenic, Shi Q et al., 1999
and metastatic potential [16]
Diverse expression and no clear-cut correlation Le X et al., 2000
with angiogenic, tumorigenic, and metastatic [19]
potential
Direct correlation with angiogenic, tumorigenic, Greene GF et al.,
and metastatic potential 1997 [65]
Low IL-8 expression and no correlation with Balbay MD et
angiogenic, tumorigenic, and metastatic potential al., 1999 [125]
Since all of these studies involved the use of estab-
lished cell lines that had been subjected to multiple
rounds of in vitro and in vivo selection and the use of
nude mouse xenograft models, the experimental results
may no longer reflect the natural history of human
cancer progression. Therefore, the biological relevance
and significance of IL-8 expression in human cancer
progression remains unclear. The current data must be
interpreted with care, and the role of IL-8 in human
cancer progression needs further investigation. Like-
wise, it is necessary to re-evaluate the rationale using
nude mouse xenograft models to predict the metastatic
potential of human cancer.
3.3. IL-8 gene transfection
As a direct approach to determining the relationship
between IL-8 and tumor progression, various types of
human tumor cells have been transfected with the IL-8
gene (Table 3). IL-8-transfection leads to both tumor
inhibition and promotion depending on the cell type.
For example, in gastric and pancreatic cancer IL-8-
transfected cells produced rapidly growing, highly vas-
cular neoplasms as compared with control tumor cells
[16,33]. The most surprising finding was a report show-
ing that IL-8 transfection makes nonmetastatic human
melanoma cells metastatic [133]. In sharp contrast, Lee
et al. [62] transfected human ovarian cancer cell lines
 K. Xie / Cytokine & Growth Factor Re6iews 12 (2001) 375–391 383

with an expression vector for human IL-8 and tested
their ability to form tumors in nude mice. IL-8 expres-
sion in the transfected cells did not alter their growth
properties in vitro. In contrast, tumor growth in vivo
was significantly retarded in animals that received IL-8-
expressing cells when compared with mice injected with
control cells. In addition, ovarian cancer cell lines in
which constitutive IL-8 expression was elevated did not
form tumors. These results suggest that IL-8 produc-
tion by human ovarian tumor cells can play a role in
reducing the rate of tumor growth. This effect appears
to be mediated by the increased targeting of neutrophils
and other mononuclear cells to the tumor injection site.
Also, in a rat model of colon cancer carcinomatosis,
IL-8 produced an antitumoral effect, which was associ-
ated with the enhanced infiltration of CD4+ T
lymphocytes [137,138]. These inconsistent results may
indicate the use of different cell lines, mouse models,
and levels of IL-8 production.
4. IL-8 and mitogenic effect
Since the discovery of IL-8 production by tumor
cells, it has been predicted that IL-8 may stimulate
tumor growth [20]. Schadendorf et al. [48] first demon-
strated that endogenously produced human IL-8 can
act as an important growth factor for human
melanoma cells. They found that human melanoma cell
lines secrete significant amounts of bioactive IL-8
protein into the culture supernatant and that this secre-
tion was inducible by IL-1 and PMA. Exposure of
some human melanoma cell lines in vitro to antisense
oligonucleotides targeted against two different sites of
human IL-8 mRNA inhibited secretion of IL-8 protein
into the culture supernatant, cell proliferation, and
colony formation in soft agar in a dose-dependent
fashion. The effects were reversible by both removal of
the oligomers and addition of exogenous IL-8 protein.
A monospecific immune serum and two IL-8-specific
monoclonal antibodies were also capable of inhibiting
melanoma cell proliferation in the same manner. There-
fore, IL-8 can form an autocrine loop for IL-8-depen-
dent proliferation of melanoma and may play a role in
melanoma progression and metastasis [48]. This finding
was confirmed in human melanoma [123,139], pancre-
atic cancer [140], colon cancer [28,29], and malignant
mesothelioma [141].
In addition, identification of IL-8 receptors on tumor
cells further supports the autocrine growth factor hy-
pothesis. Specifically, Norgauer et al. [139] demon-
strated the expression of IL-8Rb protein at the cell
surface of various melanoma cell lines using flow cy-
tometry with F(ab%)2 fragments of the IL-8Rb anti-
serum. This antiserum partially blocked
serum-independent melanoma cell growth. Similar re-

Table 3
Modulation of tumor growth and metastasis by IL-8 gene transfection

Tumor system Animal model Effects and mechanisms Authors

[reference]

hu-IL-8 expression 6ector

SB-2 human melanoma cells Nude mice/subcutis Increased tumor angiogenesis, growth, Luca M et al.,
and metastasis through upregulation of 1997 [133]
MMP-2
FG human pancreatic adenocarcinoma Nude mice/pancreas Increased angiogenesis Shi Q et al.,
cells 1999 [16]
TMK-1 human gastric carcinoma cells Nude mice/stomach Increased tumor angiogenesis, growth, Kitadai Y et al.,
and metastasis 1999 [33]
SK-OV-3 human ovarian cancer cells Nude mice/subcutis Decreased tumor growth through Lee LF et al.,
increased neutrophil and mononuclear 2000 [62]
cell infiltration
CT-26 murine colon carcinoma cells Syngeneic immunocompetent BALB/c Decreased tumor growth through Nakashima E et
mice/footpad increased T lymphocyte infiltration al., 1996 [134]
253J-P human transitional cell Nude mice/bladder Increased tumor angiogenesis, Inoue K et al.,
carcinoma cell line invasiveness, tumorigenicity, and 2000 [135]
metastasis via upregulation of MMP-9
hu-IL-8 antisense expression 6ector
Human glioma cells Nude mice/subcutis Inhibition of tumor growth in vitro Yamanaka Ret
al., 1995 [136]
FG human pancreatic adenocarcinoma Nude mice/pancreas Decreased angiogenesis, tumor growth, Shi Q et al.,
cells and metastasis 1999 [19]

253J B-V human transitional cell Nude mice/bladder Decreased angiogenesis, invasiveness, Inoue K et al.,
carcinoma cell line tumorigenicity 2000 [135]
384 K. Xie / Cytokine & Growth Factor Re6iews 12 (2001) 375–391
sults were obtained in human colorectal carcinoma cells
in vitro using the specific antagonist peptide AcR-
RWWCR or with blocking anti-IL-8 antibody. All of
the colon carcinoma cell lines tested expressed mRNA
for both IL-8Ra and IL-8Rb when grown at conflu-
ence. At the protein level, all the cell linesexpressed
IL-8Ra. Expression of IL-8Rb was weak [28,29].
In earlier studies of pancreatic cancer, treatment with
IL-8 antisense oligonucleotides suppressed IL-8 produc-
tion from and cell growth of HuP-T4pancreatic cancer
cell line. These data also indicated that IL-8 produced
by human pancreatic cancer may act as an autocrine
growth factor [76]. In our recent study, we found that
the growth of FG human pancreatic cancer cells in
vitro was minimally affected by the production of IL-8.
This was based on our observation showing that a
specific IL-8-neutralizing antibody only marginally
blocks the growth of the cells in vitro. Even suppressing
of IL-8 expression by 90% after transfection with
pcDNA-8Af (the antisense oligonucleotide expression
vector) affected the in vitro growth rate by less than
10%. Therefore, the dependence on IL-8 for cell growth
in vitro varied widely among different tumor types.
Some tumor cell lines were apparently dependent on
IL-8, whereas others were not. However, in vivo, there
was greater than 90% suppression of tumorigenicity
and 100% suppression of metastasis, suggesting that the
role of IL-8 in the progression of pancreatic cancer is
more complex than that of a simple autocrine growth
stimulator [16].
5. IL-8 and angiogenic effect
The angiogenic activity of IL-8 produced by mono-
cytes and macrophages was first demonstrated by Koch
et al., [142] in 1992. They found that human recombi-
nant IL-8 was potently angiogenic when implanted in a
rat cornea and induced proliferation and chemotaxis of
human umbilical vein endothelial cells. The angiogenic
activity present in the conditioned medium of inflamed
human rheumatoid synovial tissue macrophages and
lipopolysaccharide-stimulated blood monocytes was
equally blocked by antibodies against IL-8 and TNF-a.
In addition, an IL-8 antisense oligonucleotide specifi-
cally blocked the production of monocyte-induced an-
giogenic activity. These data suggested that
macrophage-derived IL-8 has a function in angiogene-
sis-dependent disorders, such as rheumatoid arthritis
and tumor growth. The abrogation of angiogenesis
using IL-8-neutralizing antibodies has been predicted to
control these angiogenesis-dependent diseases [143].
This initial observation was immediately confirmed by
several studies using different approaches including a
rat sponge angiogenesis model [144], in vitro model of
tubular morphogenesis of vascular endothelial cells
[145], rabbit neovascularization cornea in vivo [146],
and others [147]. IL-8 is now been recognized as one of
the secretory products that influence angiogenesis in
vitro and in vivo from macrophages [147–149] and
mast cells [150]. IL-8 may also play a role in angiogen-
esis by IL-1 [151], TNF-a [146], H2O2 [152], hypoxia
[16,18], and acidosis [17].
The involvement of IL-8 in tumor angiogenesis was
first demonstrated in human bronchogenic carcinoma
[36,39]. The researchers found that increased quantities
of IL-8 were detected in tumor tissue as compared with
normal lung tissue. Additionally, immunohistochemical
staining of tumors revealed primary localization of IL-8
to individual tumor cells and demonstrated the capacity
of tumors to elaborate IL-8. Functional studies that
used tissue homogenates of tumors demonstrated the
induction of both in vitro endothelial cell chemotaxis
and in vivo corneal neovascularization. The addition of
neutralizing antisera to IL-8 in these assays resulted in
the marked, specific attenuation of these responses.
These observations definitively established IL-8 as a
primary mediator of angiogenesis in bronchogenic car-
cinoma and offered a potential target for immunothera-
pies against solid malignancies. They also predicted
that interference of the angiogenic function of CXC
chemokines, including IL-8, permits novel targeted
therapy aimed specifically at attenuating tumor growth
and metastasis [38]. This observation has been confi-
rmed in human glioma [153], mesothelioma [154],
glioblastoma [121], head and neck squamous cell car-
cinoma [155,156], none-small cell lung carcinoma
[40,157], prostate cancer [158–160], colon cancer [161],
breast cancer [162], ovarian cancer [55,128,163], gastric
carcinoma [33], uterine cervical cancer [164], melanoma
[165] and pancreatic cancer [16].
IL-8 receptor expression on endothelial cells has also
been demonstrated. For example, human microvascular
endothelial cells express the IL-8 receptor, which allows
direct interaction of IL-8 with endothelial cells [166].
IL-8 may also promote angiogenesis by inducing of
endothelial migration or chemotaxis [167].
6. IL-8 and motogenic effect
IL-8 is a physiological initiator of the chemotactic
migration of leukocytes, e.g. neutrophils and
macrophages. Overexpression of IL-8 by tumor cells
may lead to elevated infiltration of leukocytes, which
have been shown to potentially produce various growth
factors and angiogenic factors in large quantities and
rapid expansion of tumor mass. The tumor cell-initiated
and tumor infiltration cell-mediated tumor angiogenesis
may produce strong indirect tumor-stimulating effects
and underscore the importance of the direct effects of
IL-8 as a growth factor and/or angiogenic factor as well
 K. Xie / Cytokine & Growth Factor Re6iews 12 (2001) 375–391
as those of other potential growth factors and angio-
genic factors produced by tumor cells. On the other
hand, it is interesting to notice that IL-8 can also
function as a motility factor for tumor cells, which may
be relevant to tumor invasion and metastasis. This
concept was first tested in human melanoma cells [168].
Both natural and recombinant IL-8-induced migration
across polycarbonate filters of A2058 human melanoma
cells. Also anti-IL-8 antibodies blocked IL-8 induced
melanoma cell migration. Checkerboard experiments
revealed a gradient-dependent response of the
melanoma cells to IL-8. Filters that were exposed to
IL-8 and washed supported melanoma cell migration,
thus implying a chemotactic component in the
response.
The initial observation described above was repro-
duced in many other tumor cell lines, including human
colon cancer, prostate cancer, and leukemia. In the
human colon cancer model, LIM1215 cell migration
was determined in circular wounds made in the conflu-
ent monolayer culture. This migration was stimulated
in a concentration-dependent manner by IL-8 with
maximal effects of about two-fold above basal migra-
tion. The motogenic effect of IL-8 was mediated inde-
pendently of the effects on cell proliferation. In
contrast, the effect was partially dependent on gene
transcription and protein synthesis and involved the
activation of pertussis toxin-sensitive G-proteins. The
short-chain fatty acids, acetate, propionate, butyrate,
valerate, PMA, and TNF all stimulated the secretion of
IL-8. However, only the motogenic effect of TNF was
dependent on IL-8 [169]. More recently, IL-8 has been
shown to stimulate PC-3 prostate cancer cell migration
and invasion in vitro through a reconstituted basement
membrane and both long-term migration and short-
term adhesion to laminin, a major component of the
basement membrane. The stimulation of tumor cell
migration and invasion by IL-8 was achieved in part by
altering the activation states of the b1 integrins [170]. In
addition, Till et al. [171] showed that IL-8 induced the
migration of chronic lymphocytic leukemia cells within
lymphoreticular tissues. Furthermore, IL-8 may regu-
late tumor cell migration by regulating the expression
of MMP-2 and/or MMP-9 at the gene transcription
level [133,172].
7. Targeting IL-8 expression for cancer treatment
The role of IL-8 in the growth and metastasis of
some types of cancer, including human pancreatic ade-
nocarcinoma, makes IL-8 an attractive target for treat-
ment of cancer. A direct strategy may be to use an
IL-8-neutralizing antibody to interfere with the func-
tions of IL-8. Alternatively, blocking the IL-8 receptors
will also block the signal transduction pathway initiated
385
by IL-8. Additionally, there are two receptors for IL-8:
IL-8Ra, which is specific for IL-8, and IL-8Rb, which
also binds to other CXC chemokines, such as neu-
trophil-activating polypeptide-2, epithelial neutrophil
activating factor, 78 amino acids, and melanoma
growth stimulating activity (Gro-a) [173]. Several mu-
tated IL-8 antagonists of the IL-8 receptor have been
shown to compete with IL-8 [174]. For example, a
synthetic peptide inhibits GRO-a from binding to its
receptors and inhibits the growth and metastasis of
human melanoma cells in nude mice [175]. Antisense
oligonucleotides have also been shown to decrease IL-8
receptor mRNA and inhibits the proliferation of non-
small cell lung cancer cells both in vitro and in vivo
[176].
We have shown that human pancreatic cancer cells
transfected with an IL-8 antisense oligonucleotide ex-
pression vector significantly decrease the constitutive
and inducible levels of IL-8 mRNA and protein secre-
tion and suppress tumorigenic and metastatic potential.
Since NF-kB is essential for constitutive and inducible
IL-8 expression, we transfected MiaPaCa-2 pancreatic
cancer cells with a dominant-negative IkB (IkBaM)
expression vector. The expression of exogenous domi-
nant-negative IkBa significantly suppressed NF-kB
binding activity and NF-kB reporter activity, IL-8 pro-
moter activity, and IL-8 expression at both the mRNA
and protein level [19]. In fact, interference with NF-kB
signaling has been shown to inhibit tumor growth and
metastasis via blockade of angiogenesis and promotion
of apoptosis [177,178].
8. Conclusion and future directions
The development of multiple autocrine growth-sig-
naling pathways renders tumor cells a tremendous
growth advantage and imposes significant difficulties in
designing effective cancer therapy. Adding to the long
list of growth factors and cytokines, IL-8 may also play
a role in human cancer progression. The inference of
the impact of IL-8 expression on tumor growth requires
combined consideration of data obtained from cell
cultures, animal models, and clinical studies. Neverthe-
less, multiple mechanisms are apparently involved in
IL-8 action, including direct effects on tumor cell prolif-
eration, angiogenesis, and migration, and indirect ef-
fects via attracting host infiltration cells, such as
neutrophils and macrophages, which may in turn pro-
duce numerous factors that promote tumor angiogene-
sis and growth. While the upstream signaling of
inducible and constitutive IL-8 expression remains to be
determined at greater length, targeting the expression of
IL-8 may indicate new directions for the development
of antitumor strategies.
386 K. Xie / Cytokine & Growth Factor Re6iews 12 (2001) 375–391
Acknowledgements
I thank Don Norwood for editorial comments and
Judy King for assistance in the preparation of this
manuscript. This work was supported by the Research
Project Grant cRPG-00-054-01-CMS from the Ameri-
can Cancer Society, the Lustgarten Pancreatic Cancer
Research Foundation, the Multidisciplinary Pancreatic
Program Research Grant, and Cancer Center Support
Core grant CA 16672-23 form the National Institutes
of Health (to Keping Xie).
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