Molecular Pathways

Targeting Inflammatory Pathways for Prevention and Therapy of

Cancer: Short-Term Friend, Long-Term Foe
Bharat B. Aggarwal, R.V. Vijayalekshmi, and Bokyung Sung

Abstract Chronic infections, obesity, alcohol, tobacco, radiation, environmental pollutants, and high-
calorie diet have been recognized as major risk factors for the most common types of cancer.
All these risk factors are linked to cancer through inflammation. Although acute inflammation
that persists for short-term mediates host defense against infections, chronic inflammation that
lasts for long term can predispose the host to various chronic illnesses, including cancer. Linkage
between cancer and inflammation is indicated by numerous lines of evidence; first, transcription
factors nuclear factor-nB (NF-nB) and signal transducers and activators of transcription 3
(STAT3), two major pathways for inflammation, are activated by most cancer risk factors;
second, an inflammatory condition precedes most cancers; third, NF-nB and STAT3 are cons-
titutively active in most cancers; fourth, hypoxia and acidic conditions found in solid tumors
activate NF-nB; fifth, chemotherapeutic agents and g-irradiation activate NF-nB and lead to
chemoresistance and radioresistance; sixth, most gene products linked to inflammation, survival,
proliferation, invasion, angiogenesis, and metastasis are regulated by NF-nB and STAT3; seventh,
suppression of NF-nB and STAT3 inhibits the proliferation and invasion of tumors; and eighth,
most chemopreventive agents mediate their effects through inhibition of NF-nB and STAT3
activation pathways. Thus, suppression of these proinflammatory pathways may provide oppor-
tunities for both prevention and treatment of cancer.

Cancer is now generally believed to be a preventable disease.
Only 5% to 10% of all cancers are caused by inheritance of
mutated genes and somatic mutations, whereas the remain-
ing 90% to 95% has been linked to lifestyle factors and
environment (1). Almost 30% of all cancers have been
attributed to tobacco smoke,1 35% to diet (2), 14% to 20%
to obesity (3), 18% to infections (4), and 7% to radiation and
environmental pollutants (5). The underlying mechanisms by
which these risk factors induce cancer are becoming increas-
ingly evident. One process that seems to be common to all
these risk factors is inflammation.
The great German pathologist Rudolph Virchow (1821-
1902) once remarked: ‘‘that chronic irritation which is mani-
fested by a chronic inflammation is a key promoter of cancer.’’
Inflammation (derived from Latin word ‘‘inflammatio,’’ to set
on fire), a complex biological response to harmful stimuli, was
characterized by the first century Roman physician Cornelius
Authors’ Affiliation: Cytokine Research Laboratory, Department of Experimental
Therapeutics,The University ofTexas M. D. Anderson Cancer Center, Houston,Texas
Received 1/18/08; revised 8/4/08; accepted 8/11/08.
Grant support: B.B. Aggarwal is the Ransom Horne, Jr. Professor of Cancer
Research. This work was supported by a grant from the Clayton Foundation for
Research (B.B. Aggarwal).
Requests for reprints: Bharat B. Aggarwal, Cytokine Research Laboratory,
Department of Experimental Therapeutics, The University of Texas M. D. Anderson
Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-
1817; Fax: 713-745-6339; E-mail: aggarwal@ mdanderson.org.
F 2009 American Association for Cancer Research.
doi:10.1158/1078-0432.CCR-08-0149
Celsus as that which consists of heat (calor), redness (rubor),
pain (dolor), and swelling (tumor). There are two stages of
inflammation, acute and chronic. Acute inflammation is an
initial stage of inflammation (innate immunity) mediated
through activation of the immune system; it helps the body
ward off infections, it lasts for short period and generally is
regarded as therapeutic inflammation. If the inflammation
persists for a long period of time, however, the second stage of
inflammation, i.e., chronic inflammation sets in (6). Although
this chronic inflammation has been now linked with most
chronic illnesses, including cancer, cardiovascular diseases,
diabetes, obesity, pulmonary diseases, and neurologic diseases
(7), the current review focuses on the role of inflammatory
pathways in tumorigenesis. Nuclear factor-nB (NF-nB) and
signal transducers and activators of transcription 3 (STAT3) are
two most important transcription factors in inflammatory
pathways that play major roles in tumorigenesis and thus
can be considered targets for prevention and therapy of cancer
(6, 8).
NF-nB was discovered in 1986 as a nuclear factor that binds
to the enhancer region of the nB chain of immunoglobulin in B
cells. It has been shown since, however, to be a ubiquitous
transcription factor present in all cell types. In its resting stage,
this factor resides in the cytoplasm as a heterotrimer consisting
of p50, p65, and InBa (Fig. 1). On activation, the InBa protein,
an inhibitor of NF-nB, undergoes phosphorylation, ubiquiti-
nation, and degradation. p50 and p65 are then released to be
1
http://www.dietandcancerreport.org/?p=ER

www.aacrjournals.org 425 Clin Cancer Res 2009;15(2) January 15, 2009

Molecular Pathways

Fig. 1. Association of NF-nB signaling pathway with tumorigenesis. 5-LOX, 5-lipooxygenase; bFGF, basic fibroblast growth factor; cFLIP, cellular caspase-8 (FLICE)-like
inhibitory protein; cIAP1, inhibitor of apoptosis protein; COX-2, cyclooxygenase-2; CXCR4, CXC chemokine receptor-4; EGFR, EGF receptor; ELAM-1, endothelial cell
leukocyte adhesion molecule-1; H. pylori, Helicobacter pylori ; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HGF, hepatocyte growth factor; ICAM-1, intercellular adhesion
molecule-1; IjBa, inhibitor of nBa; IKK, InB kinase; MMP-9, matrix metalloproteinase-9; PDGF, platelet-derived growth factors; PTK, protein tyrosine kinase; RANKL, receptor
activator for nuclear factor nB ligand; S. typhi, Salmonella typhi ; TAK1, TGF-activated kinase-1; TNFR, TNF receptor; uPA, urokinase-type plasminogen activator; VCAM-1,
vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor; XIAP, X-linked Inhibitor of apoptosis protein.

translocated to the nucleus, bind specific DNA sequences
present in the promoters of various genes, and initiate
transcription. The kinase that causes the phosphorylation of
InBa is called InBa kinase or IKK. Whereas IKKh mediates
the classic/canonical NF-nB activation pathway, IKKa mediates
the noncanonical pathway. What causes the activation of IKK
is not well-understood. More than a dozen different kinases
have been described that can activate IKK including AKT,
mitogen-activated protein/extracellular signal-regulated kinase
kinase kinase 1 (MEKK1), MEKK3, transforming growth
factor – activating kinase 1, NF-nB – activating kinase, NF-nB –
inducing kinase, protein kinase C, and the double-stranded
RNA-dependent protein kinase PKR. Various gene products
that have been shown to mediate inflammation, cell survival,

Clin Cancer Res 2009;15(2) January 15, 2009 426 www.aacrjournals.org


cell proliferation, invasion, angiogenesis, and metastasis are
regulated by NF-nB. Similarly, most agents that promote
inflammation and proliferation activate NF-nB. These include
endotoxin, carcinogens (such as cigarette smoke), radiation,
chemotherapeutic agents, hyperglycemia, tumor promoters,
inflammatory cytokines [e.g., tumor necrosis factor (TNF) and
interleukin (IL)-1] and growth factors [e.g., epidermal growth
factor (EGF); ref. 9].
STAT3 is another transcription factor that is normally present
in the cytoplasm of most cells. In response to certain
inflammatory stimuli (e.g., IL-6) and growth factors (e.g.,
EGF), STAT3 undergoes sequential tyrosine phosphorylation,
homodimerization, nuclear translocation, DNA binding, and
gene transcription. Several protein kinases that cause specific
phosphorylation of STAT3 have been identified, including
Janus-activated kinase 1, 2, and 3. Similarly, protein phospha-
tases that cause the dephosphorylation of STAT3 also have
been identified. Gene products linked with survival (e.g., Bcl-
xL), proliferation (e.g., cyclin D1), and angiogenesis (e.g.,
vascular endothelial growth factor) are regulated by STAT3
activation (8).
Clinical-Translational Advances
Most carcinogens activate NF-kB and STAT3 pathways. Most
carcinogens, including cigarette smoke (10), polycyclic hydro-
carbons (11), asbestos (12), alcohol (13), sun light (14), and
UV light (15), have been shown to activate the proinflamma-
tory NF-nB pathway. Almost all infectious agents linked with
cancer activate NF-nB. For instance, human papillomavirus
(16), HIV (17), human herpes virus (18), EBV (19), hepatitis B
virus (20), hepatitis C virus (21), and Helicobacter pylori (22)
have been shown to activate NF-nB. The roles of human
papillomavirus in cervical cancer, human herpes virus in
lymphoma, hepatitis B virus and hepatitis C virus in hepatocel-
lular carcinoma, Helicobacter pylori in gastric cancer and HIV, and
EBV in leukemia, are well-documented. Hyperglycemia associ-
ated with diabetes and obesity, a risk factor for various cancers,
has been shown to mediate NF-nB activation (23). Moreover,
most growth factors (such as EGF) and growth factor receptors
such as EGF receptor and HER2 have been shown to mediate
NF-nB activation (24, 25). TNF, the proinflammatory cytokine
that has been linked with survival, proliferation, invasion, and
metastasis of tumors, is one of the most prominent activators of
NF-nB (26).
How all these diverse agents activate NF-nB is not fully
understood (Fig. 1). That cigarette smoke and EGF activate NF-
nB through a mechanism different from that of TNF has been
shown in our laboratory (27, 28). Whereas TNF-induced NF-nB
activation was found to be IKK dependent, for example, EGF
activated NF-nB through an IKK-independent mechanism (28).
Similarly, the mechanism of NF-nB activation by UV, the major
risk factor for melanoma, has been shown to be different from
that of TNF (29). Most solid tumors exhibit hypoxic and acidic
conditions in their core; both of these conditions can lead to
NF-nB activation (30). Proinflammatory cytokine IL-6, whose
expression is regulated by NF-nB, is a potent activator of the
STAT3 pathway (31). STAT3 is also activated by EGF and other
growth factors linked to tumorigenesis (32). Although NF-nB
and STAT3 activation by most agents is transitory, however,
www.aacrjournals.org
Role of Inflammatory Pathways in Tumorigenesis
long-term exposure is likely to make it irreversible. These lines
of evidence strongly support the hypothesis that carcinogen-
induced NF-nB activation could lead to tumorigenesis.
Inflammation precedes most cancers. The suffix ‘‘itis’’ is used
typically to denote inflammation. Bronchitis, colitis, cervicitis,
gastritis, and hepatitis, for example, reflect inflammation of the
bronchus, colon, cervix, stomach, and liver, respectively. It
seems that most cancers, especially solid tumors, are preceded
by inflammation of a given organ. For instance, people who
smoke cigarette develop bronchitis, and 15% to 20% of these
people develop lung cancer (33). Similarly, people who have
colitis are at high risk of developing colon cancer (34).
Infection with Helicobacter pylori can induce gastritis, which in
its chronic form can lead to gastric cancer (35).
Proinflammatory stimuli such as TNF, IL-1, IL-6, cyclo-
oxygenase-2, and 5-lipo-oxygenase, all regulated by the NF-nB
pathway, have been shown to be expressed in bronchitis, colitis,
cervicitis, gastritis, or hepatitis. Overexpression of cyclooxyge-
nase-2, for example, has been shown in colitis, bronchitis, and
gastritis (36). We have recently shown that TNF is overexpressed
in head and neck squamous cell carcinoma and mediates tumor
cell proliferation (37). Similarly, TNF expression and its pro-
liferative role have been shown in mantle cell lymphoma (38),
acute myeloid leukemia (39), cutaneous T-cell lymphoma (40),
and glioblastoma (41). IL-6, whose expression is regulated by
NF-nB, has been shown to induce proliferation of multiple
myeloma cells through activation of the STAT3 pathway (42).
Inflammatory cells that express activated NF-nB and secrete
inflammatory cytokines have been shown to contribute to
tumor initiation and progression (43). For instance, inhibition
of TNF production by nonparenchymal cells (Kupffer and
endothelial cells) prevented NF-nB activation in hepatocytes
and in early tumors; and reduced tumor multiplicity (44).
Greten et al. (45) reported that deleting IKKh in myeloid cells
caused suppression of NF-nB activation, diminished expression
of inflammatory cytokines, and thus leading to a significant
decrease in tumor size.
NF-kB and STAT3 are constitutively activated in most tumor
cells. In a majority of tumor cell lines, both solid and
hematologic tumors, NF-nB has been shown to be constitu-
tively active (46). What causes the constitutive activation of
NF-nB in these tumor cells is not fully understood. Many
different mechanisms have been described, including over-
expression of growth factor receptors, mutation of InBa such
that it cannot bind to NF-nB, constitutive activation of ras pro-
tein, high proteolytic activity directed to InBa, and autocrine
secretion of inflammatory cytokines. In most of these tumor
cells, constitutive activation of NF-nB is responsible for
proliferation, because inhibition of NF-nB leads to abrogation
of proliferation (47). Constitutive activation also has been
linked to chemoresistance and radioresistance (48). Constitu-
tive activation of STAT3 has been reported in various tumor cell
lines (8) and is known to mediate proliferation of these cells.
Constitutive activation of NF-nB and STAT3 is encountered in
samples from cancer patients (8, 48). We found that cons-
titutive activation of NF-nB and STAT3 in CD134+ cells from
patients with multiple myeloma (49). Similarly, we showed
constitutive activation of NF-nB in samples from patients with
lung cancer (50) and pancreatic cancer (51).
Organ-specific conditional knock-in and knockout of the
inflammatory intermediates promote cancer. Using mice bearing
427 Clin Cancer Res 2009;15(2) January 15, 2009
Molecular Pathways
mutations in the genes coding for the IKKh and IKKa catalytic
subunits, Karin and his colleagues (52 – 54) examined the role
of the NF-nB pathway in tumorigenesis. They found that mice
lacking IKKh only in hepatocytes or hematopoietic-derived
Kupffer cells showed a marked increase in hepatocarcinogenesis
induced by diethylnitrosamine (53). Interestingly, although
tumorigenic function of IKKh was found to be mediated via
NF-nB, the metastatic function of IKKa was found to be
independent of NF-nB (54). Moreover, they showed that
processes that occur within inflammatory cells are essential
for cancer development and progression (53).
To determine the role of NF-nB in inflammation-induced
tumor growth, Luo et al. (52) used an experimental murine
cancer metastasis model in which a colon adenocarcinoma cell
line metastasizes to the lungs when stimulated by lipopolysac-
charide. They found that endotoxin-induced metastatic growth
response depends on TNF-a production by host hematopoietic
cells, leading to NF-nB activation in tumor cells. Inhibition of
NF-nB in colon led to tumor regression. The latter depends on
TRAIL receptor induction in NF-nB – deficient cancer cells.
These findings support the role of inflammatory pathways in
tumor development.
Most genes linked with tumorigenesis are regulated by NF-kB
and STAT3. NF-nB plays a pivotal role, not only in immune
response and inflammatory reaction but also in regulating
expression of genes involved in characteristic processes leading
to tumorigenesis, such as cell survival, proliferation, invasion,
angiogenesis, and metastasis (9).
Numerous genes have been described that are regulated by
NF-nB and mediate survival of tumor cells. These include cFLIP,
(55) Bcl-xL (56), Bcl-2 (57), XIAP (58), c-IAP1 (59), cIAP-2
(59), and survivin (60), all of which negatively regulate
apoptosis. Some of the genes that are regulated by NF-nB and
are linked with proliferation of tumors include cyclin D1 (61),
c-myc (62), and cyclooxygenase-2 (63). Other genes such as
matrix metalloproteinase-9 (64), vascular endothelial growth
factor (65), CXCR4 (66), and TWIST (67), which have been
closely associated with invasion, angiogenesis, and metastasis,
also are regulated by NF-nB. STAT3 is known to regulate the
expression of Bcl-xL (68), Mcl-1 (69), survivin (70), cyclin D1
(71), vascular endothelial growth factor (72), and TWIST (73).
Most proinflammatory genes that have been linked with car-
cinogenesis also are regulated by NF-nB and STAT3, including
TNF (74), RANKL (75), IL-1 (76), IL-6 (77), IL-8 (78, 79), and
cell surface adhesion molecules such as intercellular adhesion
molecule-1, ELAM-1, and VCAM-1 (80). Thus genes regulated
by NF-nB and STAT3 are clearly implicated in tumorgenesis.
Most chemotherapeutic agents and g-radiation activate NF-kB
and mediate chemoresistance and radioresistance. Several che-
motherapeutic agents have been shown to activate NF-nB,
including paclitaxel, vinblastine, vincristine, doxorubicin,
daunomycin, 5-fluorouracil, cisplatin, and tamoxifen in human
lung cancer, cervical cancer, and in T cells (81 – 83). Ionizing
radiation also has been shown to activate this transcription
factor in various tumor cells including human myeloid
leukemia cells (84). The mechanism by which chemotherapeu-
tic agents activate NF-nB, however, differs from that of
g-radiation. Activation of NF-nB by ionizing radiation induced
tyrosine phosphorylation of InBa, whereas that by chemother-
apeutic agents involves serine phosphorylation (85). Activation
of NF-nB by these agents has been linked in turn with
Clin Cancer Res 2009;15(2) January 15, 2009
chemoresistance and radioresistance (48). Thus suppression
of the NF-nB pathway provides a unique window of opportu-
nity to overcome chemoresistance and radioresistance. Activa-
tion of the NF-nB pathway by these agents is selective; none of
them activate the STAT3 pathway.
Inhibitors of proinflammatory pathways have therapeutic
potential. Because the NF-nB and STAT3 pathways play a
critical role in tumorigenesis and in induction of resistance of
tumor cells to currently available therapy, inhibitors of these
pathways have enormous potential. Several inhibitors of NF-nB
and STAT3 have been reported (8, 48). Some of these inhibitors
are ‘‘proof of principle’’ type, others are rationally designed, and
still others have been identified from natural products known
to have antiinflammatory activities. For instance, a peptide
derived from the phosphorylation domain of p65 can block
NF-nB activation and enhance the effect of chemotherapeutic
agents (86). Similarly, proteasome inhibitors that were ratio-
nally designed as a NF-nB inhibitor, when combined with
chemotherapy, can potentiate its effects in multiple myeloma
(87, 88). For instance, Velcade, a proteasome inhibitor, has
been shown to suppress the NF-nB activation of multiple
myeloma cells in culture (89). However, there is no data to
indicate that Velcade could inhibit NF-nB activation in the
patients. Similarly, thalidomide has been shown to suppress
NF-nB activation in cell culture and inhibit cell growth (90).
Such data in the patients treated with thalidomide analogues,
is lacking.
Numerous agents identified from natural sources can block
the NF-nB pathway, including curcumin, resveratrol, ursolic
acid, capsaicin, silymarin, guggulsterone, and plumbagin
(91 – 97). Several of these agents also suppress the STAT3
pathway (98 – 103), suggesting that they exhibit multiple
targets. In addition to agents from natural products, synthetic
and semisynthetic agents also inhibit the NF-nB or STAT3
pathway. For example, the semisynthetic compound flavopir-
idol has been reported its activity on NF-nB and STAT3
suppression. Pharmacologically, these agents have been shown
to be quite safe, and thus, they can be used not for just
prevention but also therapy. In human clinical trials, curcumin
has been shown to actually down-regulate both the NF-nB and
STAT3 pathways (104). To our knowledge, curcumin is the
only agent among all those tested in patients that has been
shown to down-regulate both the NF-nB and STAT3 pathways
(49, 51, 104). By this property, therefore, curcumin has been
shown to have potential in the treatment of human pancreatic
cancer (51), familial adenomatous polyposis (105), inflamma-
tory bowel disease (Crohn’s disease; ref. 106), irritable bowel
disease (107), and other proinflammatory diseases (108) in
clinical trials. Further clinical trials are needed to fully realize
the potential of the inflammatory pathways described here in
the treatment of human cancers.
Conclusion
Whether the objective is prevention or therapy of cancer, the
targets are the same. The evidence described here clearly shows
that inflammatory pathways are critical targets in both
prevention and therapy of cancer. Therefore, identification of
agents/drugs that can suppress these pathways has enormous
potential. Most drugs fail because they are monotargeted, toxic,
ineffective, and unaffordable by many. Because of cross-talk
428 www.aacrjournals.org

between the pathways, cancers are caused by dysregulation of
multiple pathways. Thus, agents that can suppress NF-nB, STAT3,
and other pathways (e.g., PI3K/AKT, HIF-1) are likely to be more
effective drugs. Because of their safety and ability to affect
multiple targets, natural products are likely to have a special
place in the preventive and therapeutic armamentarium for
cancer. Although there are plenty of preclinical data to support
such claims, only clinical studies can fully validate them.
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Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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