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anti-cancer drug for certain blood and
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iting the p68-β-catenin pathway and
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in preventing metastasis of other can-
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Studies in many different areas of
cancer research including epidemio-
logical studies have established the
connection between inflammation and
cancer (Balkwill et al., 2005; Balkwill
and Mantovani, 2001; Coussens and
Werb, 2002). For example, inflamma-
tory bowel disease is a risk factor for
the development of colorectal cancer.
Moreover, the usage of nonsteroid
anti-inflammatory agents is associ-
ated with protection against various
tumors, and these drugs have been
investigated as possible anticancer
agents. Even tumors where a firm con-
nection to inflammation has not been
established, such as breast cancer,
exhibit an inflammatory microenviron-
ment at the site of the tumor. Indeed,
an inflammatory component is present
in the microenvironment of most neo-
plastic tissues. In this context, Chien
et al. (2006) now identify a signaling
pathway mediated by the RalB GTPase
that regulates both tumor survival and
the inflammatory response.
Many of the inflammatory factors
that promote tumorigenesis are gen-
erated by cells in the tumor microen-
viroment, and not by the cancer cells
themselves (called the “extrinsic”
pathway in Figure 1) (Balkwill et al.,
2005; Balkwill and Mantovani, 2001;
Coussens and Werb, 2002). Inflam-
mation associated with tumors is char-
acterized by the infiltration of white
RalB signaling: A Bridge between
Inflammation and cancer
Alberto Mantovani1 and Frances Balkwill1,2,*
1Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano and University of Milan, Italy
2Centre for Translational Oncology, Barts and The London Queen Mary’s Medical School, London EC1M 6BQ, UK
A connection between the genetic events that lead to tumor formation and the signaling
pathways of the innate immune response has been established. In this issue, Chien et al.
(2006) show that the RalB GTPase regulates the IKK family member TBK1, providing an
unexpected link between the signaling pathways that promote inflammation and cancer.
In tumor cells the RalB/TBK1 pathway inhibits apoptosis and in nontumorigenic cells it
stimulates an innate immune response.
Cell 127, October 6, 2006 ©2006 Elsevier Inc. 43
blood cells including tumor-associ-
ated macrophages (TAM), mast cells,
eosinophils, and polymorphonuclear
leukocytes (PMN). These cells create
an inflammatory microenvironment by
secreting cytokines and chemokines
that contribute to tissue remodeling
and angiogenesis (Balkwill et al., 2005;
Balkwill and Mantovani, 2001). The
molecular pathways of inflammation
leading to tumor promotion have been
dissected in mutant mice. Such stud-
ies have revealed the role of particular
elements of the inflammatory process
in different steps of tumor progression
in diverse tissues (such as skin, liver,
mammary gland, and intestine). The
factors identified so far include tumor
necrosis factor, interleukin-1, the mac-
rophage growth and attractant factor
CSF-1, the prostaglandin-producing
enzyme cyclooxygenase 2, the master
inflammatory transcription factor NF-
κB, and enzymes involved in tissue
remodeling (Balkwill et al. 2005; Cous-
sens and Werb, 2002; Karin, 2006).
Additionally, a number of reports,
including the study by Chien et al.
(2006), indicate that there are also
pathways intrinsic to cancer cells
(Figure 1) that contribute to inflamma-
tion and tumorigenesis. Chien et al.
(2006) studied signaling by the RalB
GTPase, a member of the Ras GTPase
superfamily, which blocks apoptosis
in tumor cell lines. In the new work,
these authors sought to determine
which of the RalB effectors promotes
cell survival in human epithelial tumor
cells. Among the many RalB effectors
tested, Chien et al. found that Sec5
is needed to mediate the prosur-
vival function of RalB in cancer cells.
Although Sec5 is best known for its
involvement in the trafficking of secre-
tory vesicles as part of the exocyst
complex, its role in cell survival may
be separate from this function.
Surprisingly, subsequent purification
of the exocyst complex revealed the
presence of TBK1/NAK (Tank binding
kinase 1/NF-κB activating kinase), a
core component of the innate immune
response that acts downstream of
Toll-like receptors (TLRs). Chien et al.
next provided evidence that RalB acti-
vates TBK1 by promoting the associa-
tion of TBK1 with Sec5. They showed
that mouse embryonic fibroblasts that
lack TBK1 were resistant to transfor-
mation stimulated by oncogenic K-
ras. In contrast, if kinase-dead TBK1
is expressed in mouse embryonic
fibroblasts also expressing oncogenic
K-ras, the cells undergo apoptosis.
Thus, the authors conclude that RalB/
TBK1 controls a cell-autonomous host
defense signaling pathway that inhib-
its tumor cell apoptosis. In contrast to
cancer cell lines, Chien et al. find that
the RalB/Sec5/TBK1 pathway does
not affect the survival of nontumori-
genic epithelial cells.
In the innate immune pathway,
TBK1 activates the transcription fac-
tors p65Rel and interferon regulatory
factor 3 (IRF-3), which translocate to
the nucleus and promote the expres-
sion of cytokines including interferon
β. Chien et al. provide evidence that
RalB helps trigger this response
in nontumorigenic human epithe-
lial cells following stimulation with
dsRNA or Sendai virus, which acti-
vate TLRs. Thus, Chien et al. make
two surprising and interlinked dis-
coveries—that the RelB/TBK1 path-
way has critical roles both in tumor
cell survival and in innate immunity.
Other pathways intrinsic to cancer
cells that are involved in neoplastic
transformation result in activation of
innate immunity and inflammation.
Expression of activated Ras in HeLa
cells (a cervical carcinoma cell line)
induces production of the chemok-
ine CXCL8, also known as IL-8, which
promotes angiogenesis and tumor
progression. In addition, the chem-
okine receptor CXCR4, which is impli-
cated in cell survival and metastasis,
is frequently expressed on the surface
of malignant cells. The expression
of CXCR4 is upregulated by muta-
tions in von Hippel Lindau factor, as
is the expression of the inflammatory
cytokine TNF-α (reviewed in Balkwill
et al., 2005). Mutation of the tumor
suppressor gene PTEN in non-small
cell lung cancer also results in upregu-
figure 1. The Interplay between Inflammation and cancer
An inflammatory microenvironment surrounding a tumor is characterized by infiltrating white
blood cells such as tumor-associated macrophages (TAM), polymorphonuclear leukocytes
(PMN), eosinophils, and mast cells. Cytokines and chemokines produced by these cells (as part
of the extrinsic pathway) contribute to tissue remodeling, angiogenesis, and tumor metastasis.
Signaling pathways in tumor cells (the intrinsic pathway) also contribute to the inflammatory
response and tumor cell survival. These pathways include the von Hippel Lindau (vHL)/hypoxia-
inducible factor (HIF) pathway, Toll-like receptor signaling (TLR), and the Ras and BRAF signaling
pathways. Chien et al. (2006) now show that the GTPase RalB promotes tumor cell survival by
enhancing the activity of the atypical IκB kinase (IKK) family member TBK1 (TANK binding ki-
nase). This work also reveals a role for RalB in the innate immune response.
44 Cell 127, October 6, 2006 ©2006 Elsevier Inc.
lation of the activity of HIF-1 and in
HIF-1-dependent transcription of the
CXCR4 gene (Phillips et al., 2005).
Another example of an intrinsic path-
way is provided by gene rearrange-
ments involving a tyrosine kinase (Ret-
PTC) that results in papillary thyroid
carcinoma. This gene rearrangement
activates an inflammatory program
that includes production of inflamma-
tory chemokines and expression of
CXCR4 in primary human thyroid cells
(Borrello et al., 2005). Also, the onco-
gene BRAF, which is frequently acti-
vated in malignant melanoma, induces
cytokine production contributing to a
tumor-promoting milieu (Sumimoto et
al., 2006). Another important factor is
α-catenin. Its ablation results in NF-κB
activation, induction of genes involved
in inflammation, cell proliferation, and
ultimately squamous cell carcinoma
(Kobielak and Fuchs, 2006).
Although Chien et al. report elevated
TBK1 activity in some established
human carcinoma lines, the relevance
of the RalB pathway to human neopla-
sia remains to be established. However,
it is interesting that human malignant
plasmacytomas (B cell tumors) have
been shown to overexpress members
of the TLR family that activate the TBK/
IRF pathway (Bohnhorst et al., 2006).
Chien et al. emphasize the impor-
tance of the RalB/TBK1 pathway for
cell-autonomous survival, although
we surmise that the same innate
immunity pathway might activate the
production of inflammatory media-
tors contributing to a tumor-promot-
ing inflammatory microenvironment
(the extrinsic pathway in Figure 1).
This may help to explain why many
cell lines derived from advanced
malignancies generate an autocrine
cytokine network. Regardless of
whether or not TBK1 acts intrinsically
in cancer cells to promote cell survival
or contributes to a proinflammatory
environment, the work of Chien et al.
(2006) suggests that targeting TBK1
may be therapeutically beneficial for
the treatment of certain tumors.
A.M. is supported by the Italian Association
for Cancer Research, Cariplo Foundation,
European Commission, and Italian Ministry
of University and Health. F.B. is supported by
Cancer Research UK and Queen Mary, Uni-
versity of London, UK.
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