26 - World Journal of Gastroenterology

The role of chemokines in CAC is further supported
by recent studies on chemokine decoy receptor D6. D6,
like all decoy receptors, does not induce a conventional
intracellular signal but mediates high-affinity ligand binding
and efficient ligand degradation. D6 expression is
increased in patients with IBD and with CAC compared
with healthy subjects. In the AOM/DSS model of CAC,
D6-deficient mice showed increased expression of chemokines
and higher accumulation of inflammatory cells in
comparison to the wild type, resulting in the development
of more severe colitis and higher incidence of CAC [101] .
CONCLUSION
Clinical and experimental data indicate that chronic inflammation
increases the risk of developing CAC, acting
at different stages of the carcinogenesis process. The
constant release of free radicals is known to be genotoxic
leading to the dysregulation of important oncogenes
and onco-suppressors. Moreover, it is also known that
the release of cytokines such as IL-6 and TNF-α during
chronic colitis can promote tumor growth and that
low expression of immunosuppressive cytokines such as
TGF-b and IL-10 can exacerbate this process. However,
it is also clear that what we call macroscopically chronic
inflammation may be the result of very different kinds of
immune responses and their impact on CAC development
is still unclear.
Many lines of evidence indicate that IFN-γ expressed
by Th1 cells protects from tumorigenesis in different experimental
models. Indeed, IFN-γ is critical in the activation
of cytotoxic cells and antitumor activity. Moreover,
IFN-γ renders dysplastic cells more susceptible to cellmediated
cytotoxicity. In contrast, Th2- and Th17-mediated
immune responses in the gut seem to promote CAC
development. Therefore, it is tempting to speculate that
different Th-driven “chronic inflammations” of the gut
could be associated with different risk of CAC (Figure 2).
If this concept will turn out to be true, not only generic
immunosuppressive therapy but also modulation of the
ongoing intestinal immune response could be considered
as an approach in the prevention of CAC in IBD patients.
In clinical practice, many anti-inflammatory drugs and
immune-modulators are routinely used in the therapy of
IBD. Their efficacy is based on the capacity to reduce clinical
manifestations related to disease and to reduce the in
situ macroscopic/microscopic inflammation. However, in
most of the cases little is known about their impact on the
immune response at a molecular level and the consequent
effect on colon carcinogenesis. An exception is represented
by 5-ASA. Clinical data indicate that the long term use
of 5-ASA might prevent CAC in UC patients, acting as an
anti-inflammatory agent and interfering with cancer cell
growth [102] . However, whether 5-ASA might act in part by
modulating the activity of the immune system, sustaining
immunosurveillance, has not yet been investigated. The
impact of other anti-inflammatory drugs and immunemodulators
on UC-related colon carcinogenesis, and their
WJG|www.wjgnet.com
Rizzo A et al . Immune system activation and colorectal cancer
Immune system
activation
Colitis
CAC
capacity to improve or dampen the immunosurveillance
against dysplastic cells, are still unknown. The long term
evaluation of patients undergoing different therapeutic
regimens will help address this issue.
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Th2 Th1 Th17
Ulcerative colitis Crohn's disease
No CAC
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3097 July 14, 2011|Volume 17|Issue 26|
Th1
Figure 2 Hypothetical relationship between inflammatory bowel disease
and colitis associated colorectal cancer. The T helper (Th)2 immune response
characterizing ulcerative colitis determines an elevated risk of developing
colitis associated colorectal cancer (CAC). In Crohn's disease, while a
Th17-mediated immune response could cause inflammation and enhance CAC
risk, the shift towards a Th1-mediated colitis could lower the incidence of CAC.