42 Cell 127, October 6, 2006 ©2006 Elsevier Inc.
(Rocak and Linder 2004). If ATP
hydrolysis by p68 is required for dis-
placement of β-catenin from Axin as
suggested but yet to be demonstrated
by Yang et al. (2006b), is it possible
that the Axin complex contains an
RNA that activates p68 ATPase? Or
is p68 a protein-dependent (more
ATPase as well? Tyrosine 593 of p68
is conserved in vertebrates (but not in
invertebrates) and is located in the p68
carboxyl terminus outside the globu-
lar catalytic core (Rocak and Linder
2004). Does phosphorylation at this
site regulate p68 catalytic function in
addition to providing an interaction
interface for β-catenin? Finally, as
EMT has been implicated in cancer
invasion (Thiery and Sleeman 2006),
inhibitors of the c-Abl-p68-β-catenin
pathway may be beneficial in prevent-
ing metastasis of tumor cells. In this
regard, it is worth considering whether
STI571/Gleevac—which inhibits c-Abl
(and PDGF) signaling and is a potent
anti-cancer drug for certain blood and
solid tumors—may act in part by inhib-
iting the p68-β-catenin pathway and
whether Gleevec may exhibit efficacy
in preventing metastasis of other can-
Bienz, M. (2002). Nat. Rev. Mol. Cell Biol. 3,
Brembeck, F.H., Rosario, M., and Birchmeier,
W. (2006). Curr. Opin. Genet. Dev. 16, 51–59.
Cong, F., and Varmus, H.E. (2004). Proc. Natl.
Acad. Sci. USA 101, 2882–2887.
Krieghoff, E., Behrens, J., and Mayr, B. (2006).
J. Cell Sci. 119, 1453–1463.
Liu, X., Rubin, J.S., and Kimmel, A.R. (2005).
Curr. Biol. 15, 1989–1997.
Rocak, S., and Linder, P. (2004). Nat. Rev. Mol.
Cell Biol. 5, 232–241.
Thiery, J.P., and Sleeman, J.P. (2006). Nat.
Rev. Mol. Cell Biol. 7, 131–142.
Tolwinski, N.S., and Wieschaus, E. (2001). De-
velopment 128, 2107–2117.
Yang, J., Zhang, W., Evans, P.M., Chen, X.,
He, X., and Liu, C. (2006a). J. Biol. Chem. 281,
Yang, L., Lin, C., and Liu, Z.R. (2005). Mol.
Cancer Res. 3, 355–363.
Yang, L., Lin, C., and Liu, Z.R. (2006b). Cell,
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.