?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 117 Number 5 May 2007
A cytokine-mediated link between innate
immunity, inflammation, and cancer
Wan-Wan Lin1 and Michael Karin2
1Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Republic of China. 2Laboratory of Gene Regulation and
Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, UCSD, La Jolla, California, USA.
Mechanisms that link inflammation and cancer
Cancer is a hyperproliferative disorder that involves morphological
cellular transformation, dysregulation of apoptosis, uncontrolled
cellular proliferation, invasion, angiogenesis, and metastasis (1).
Clinical and epidemiologic studies have suggested a strong associ-
ation between chronic infection, inflammation, and cancer (2–6).
For example, there are strong associations between alcohol abuse,
which leads to inflammation of the liver and pancreas, and cancers
of these organs. Cigarette smoking, asbestos exposure, and silica
exposure are each associated with inflammation of the lung and
lung carcinoma; inflammatory bowel disease (IBD) is associated
with colon cancer; infection with Helicobacter pylori is associated
with gastric carcinoma; chronic viral hepatitis is associated with
liver cancer; infection with Schistosoma spp. is associated with blad-
der and colon carcinoma; infection with some strains of HPV is
associated with cervical cancer; and infection with EBV is associ-
ated with Burkitt lymphoma and nasopharyngeal carcinoma. Such
observations suggest that chronic inflammation is involved in
tumor initiation (the process by which normal cells are genetically
altered so that they become malignant), promotion (the process
by which small clusters of malignant cells are stimulated to grow),
and progression (the process by which the growing tumor becomes
more aggressive) (2–7). Recent data from mouse models of human
cancer have established that inflammation, which orchestrates the
tumor microenvironment, is a critical component of both tumor
promotion and tumor progression (8–10).
The inflammatory milieu is occupied by cells such as resident
and recruited macrophages, DCs, T cells, and NK cells (11).
Among these, tumor-associated macrophages (TAMs) and T
cells are frequently the prominent leukocytes present in a tumor
(12, 13). The infiltrated immune cells can exert rather paradoxical
effects during cancer development (Figure 1) (7). Most current
data support the notion that acute inflammation triggered by
tumor-infiltrating host leukocytes does not exert normal immu-
noprotective mechanisms that lead to eradication of the evolving
cancer (antitumor immunity). Instead, excessively and chronically
produced proinflammatory mediators are thought to contribute
to tumor promotion and progression (2, 8, 14, 15).?In the tumor
microenvironment, there is a delicate balance between antitumor
immunity and?tumor-originated proinflammatory activity, which
weakens antitumor immunity (14, 16). These activities?depend on
different mediators that are released by host inflammatory cells,
cancer cells, and other types of tumor-associated host cells (such
as fibroblasts and endothelial cells). When host-mediated anti-
tumor activity is weaker than tumor-mediated immunosuppres-
sive activity, tumor cells undergo immune escape and grow rap-
idly (17). By contrast, when host-mediated antitumor immunity
is stronger than tumor-mediated immunosuppressive activity,
tumor cells are eliminated (17). The net outcome of a persistent
inflammatory microenvironment is enhanced tumor promotion,
accelerated tumor progression, invasion of the surrounding tis-
sues, angiogenesis, and often metastasis (2, 6, 9, 10).
A key molecular link between inflammation and tumor promo-
tion and progression is provided by the inhibitor of NF-kB kinase/
NF-kB (IKK/NF-kB) signaling pathway, which is activated by
many proinflammatory cytokines (9, 10). NF-kB is a transcription
factor that regulates the expression of many genes whose products
can suppress tumor cell death; stimulate tumor cell cycle progres-
sion; enhance epithelial-to-mesenchymal transition, which has an
important role in tumor invasiveness; and provide newly emerging
tumors with an inflammatory microenvironment that supports
their progression, invasion of surrounding tissues, angiogenesis,
and metastasis (6, 10, 18–20).
Infection, innate immunity, and tumorigenesis
Chronic inflammation caused by persistent infection with a
parasite, bacterium, or virus is a major driving force in tumor
development (2, 9) (Figure 1). It was noted that bacterial infec-
tion?following the surgical removal of primary tumors can pro-
mote rapid growth of metastases in mice (21) and humans (22).
Infectious organisms trigger inflammation through activation of
receptors that recognize pathogen-associated molecular patterns
Nonstandard?abbreviations?used: CAC, colitis-associated colon cancer; HCC,
hepatocellular carcinoma; IBD, inflammatory bowel disease; IKK, inhibitor of NF-kB
kinase; MM, multiple myeloma; NOD, nucleotide-binding oligomerization domain;
NSCLC; non–small cell lung carcinoma; PAMP, pathogen-associated molecular pat-
tern; PRR, pattern recognition receptor; TAM, tumor-associated macrophage; TRAIL,
TNF-related apoptosis-inducing ligand.
Conflict?of?interest: The authors have declared that no conflict of interest exists.
Citation?for?this?article: J. Clin. Invest. 117:1175–1183 (2007). doi:10.1172/JCI31537.
1176?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 117 Number 5 May 2007
(PAMPs), such as cell wall components and nucleic acids (23). At
least four families of mammalian innate immune receptors that
recognize PAMPs have been identified; these are known as pattern
recognition receptors (PRRs) and include TLRs, nucleotide-bind-
ing oligomerization domain–like (NOD-like) receptors (NLRs),
C-type lectin receptors (CLRs), and triggering receptors expressed
on myeloid cells (TREMs) (24–27). The interaction between PAMPs
and PRRs results in the activation of inflammatory cells and ini-
tiation of host responses whose major purpose is to eliminate
and kill invading organisms (9). However, inadequate pathogen
eradication, prolonged inflammatory signaling, and defects in anti-
inflammatory mechanisms can all lead to chronic inflammation
and benefit tumor development (28).
In addition to epidemiological data linking chronic infections to
increased cancer risk (2, 3, 29), genetic links between PRRs and can-
cer also exist. Polymorphisms in a gene cluster encoding TLR6 and
TLR10 have been linked to an increased risk of prostate cancer (30),
and mutations in the NOD2 locus have been linked to an increased
risk for developing Crohn disease (31), an IBD associated with a
modestly increased risk of developing colorectal cancer (32).?These
mutations in NOD2 have been suggested to provide a gain-of-func-
tion that results in increased IL-1β production, which makes the
environment more proinflammatory (33). Interestingly, polymor-
phisms in the promoter region of the gene encoding IL-1β and the
gene encoding the IL-1 receptor antagonist (IL-1RA) have also been
linked to an increased risk of developing cancer, in particular gas-
tric cancer (34, 35). IL-1 is abundant at tumor sites, where it can
stimulate the growth and invasiveness of malignant cells (36). Inhi-
bition of IL-1 function using the naturally occurring inhibitor of
IL-1, IL-1RA, might be useful for the treatment of cancer (37).
Activation of TLR signaling can enhance tumor development
through various mechanisms. In a mouse model of transplanted
metastatic cancers, activation of TLR4 by intraperitoneal injec-
tion of bacterial LPS stimulated the growth of lung metastases
(21, 38, 39). TLR4 activation of host macrophages resulted in
the production of several different inflammatory cytokines that
influenced tumor growth. TNF-α was identified as the major
host-produced factor that enhances the growth of lung metasta-
ses in this mouse model, in part through activation of NF-kB in
the tumor cells (39). However, TLR4 signaling also induced the
production of IFNs, cytokines that have antitumor effects (39).
In this particular case, IFNs were found to stimulate production
of the TNF superfamily member TNF-related apoptosis-induc-
ing ligand (TRAIL) (39). TRAIL is a potent inducer of tumor cell
death (40), but in this mouse model of transplanted metastatic
cancer, its tumoricidal activity was evident only upon inhibition
of NF-kB activity in the tumor cells (39). These results illustrate
that activation of innate immunity results in the production of
different cytokines with opposing activities (Figure 2) — TNF-α
stimulated tumor cell growth and survival, whereas TRAIL
induced tumor cell death, leading to tumor regression. However,
only by inhibiting NF-kB activation in the tumor cells was the
balance shifted?from stimulation of tumor growth by TNF-α to
enhanced tumor cell killing by TRAIL (39).
TLR expression and function are not restricted to innate
immune cells and can directly affect the tumor cell. For example,
multiple myeloma (MM) cells frequently express multiple TLRs
and can thereby sense the presence of microorganisms (41, 42).
Indeed, ligands for both TLR7 and TLR9 have been shown to
stimulate the growth of MM cells and to protect these cells from
The diagram shows two outcomes of inter-
actions between tumor cells and infiltrating
inflammatory and/or immune cells in the
tumor microenvironment. Cytokines secret-
ed by tumor and inflammatory/immune cells
can either promote tumor development and
tumor cell survival or exert antitumor effects.
Chronic inflammation develops through the
action of various inflammatory mediators,
including TNF-α, IL-6, and IL-17, leading to
eradication of antitumor immunity and accel-
erated tumor progression. However, TRAIL,
through direct induction of tumor cell apopto-
sis, IL-10, through antiinflammatory effects,
and IL-12, through activation of CTLs and NK
cells and expression of cytotoxic mediators,
can lead to tumor suppression. The multiple
actions of TGF-β (cytotoxic in colon cancer
cells, and having both positive and negative
effects on the tumor microenvironment) and
IL-23 (see Figure 3) explain their dual roles
in tumor development.
? The?Journal?of?Clinical?Investigation http://www.jci.org Volume 117 Number 5 May 2007
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