26 - World Journal of Gastroenterology

localization, the risk was 4.5 (95% CI, 1.3-14.9) while the
risk in patients with ileal disease was not significantly increased.
Interestingly, when comparing Crohn’s colitis with
UC of similar extent, the relative risk of developing CRC
is similar between the two groups.
Several risk factors concur to determine the probability
of developing CRC in single patients. The observation that
the cumulative risk increases over the years indicates that
disease duration does play a role [1,3] . In addition, the extension
of the disease has been shown to increase the risk of
CAC; this being 1.7 in patients with ulcerative proctitis,
2.8 in those with left-sided colitis and 14.8 in patients with
extensive colitis [3] . Also, the severity of inflammation independently
correlates with the risk of developing CAC [5] .
The same independent risk factors have been linked to the
risk of developing CRC in CD. In addition, in CD patients,
perianal disease, bypasses and strictures might be sites of
increased risk of neoplastic transformation [6-8] .
Overall, these data indicate that chronic inflammation
of the colon such as that observed during either UC or
CD increases the risk of developing CRC. However, the
mechanisms involved in this process are still poorly understood.
The current opinion regarding the pathogenesis
of IBD is that, in genetically susceptible individuals, there
is an overreaction of the immune system toward antigens
of the gut microbiota leading to chronic inflammation
[9] . UC and CD are characterized by different immune
responses. While UC is caused by an atypical T helper
(Th)2-mediated immune response characterized by high
levels of IL-5 (but not IL-4) and IL-13, in CD there is a
prevalent activation of Th1 cells with high expression of
TNF-α and IFN-γ [10-13] . More recently, a new subset of
IL-17-producing T helper cells, the Th17 cells, has been
shown to play a role in the pathogenesis of CD [14,15] . Finally,
in addition to CD4+ T cells, CD8+ T cells, natural
killer, natural killer T cells and regulatory T cells have also
been implicated in the pathogenesis of IBD [16-18] .
Given the role played by these cell subsets and by the
cytokines they express in the induction and maintenance
of gut inflammation, their role has also been investigated
in the pathogenesis of CAC. Here we review some of the
recent data that implicate immune cells and inflammatory
cytokines in the pathogenesis of CAC.
INFLAMMATION AND TUMOR
INITIATION: A DOUBLE-EDGED SWORD
Chronic inflammation is thought to induce dysplasia by inducing
DNA modifications in intestinal epithelial cells. Indeed,
chronic accumulation of activated immune cells such
as neutrophils, macrophages and dendritic cells is accompanied
by the release of oxygen and nitrogen reactive species,
which are known to induce genomic mutations [19,20] .
Moreover, chronic inflammation is associated with DNA
methylation and histone modification [21-23] . All these processes
have been associated with the altered expression of
genes involved in carcinogenesis such as p53, APC, K-ras
and Bcl-2 [24] . Once initiated, dysplastic cells are subjected
WJG|www.wjgnet.com
Rizzo A et al . Immune system activation and colorectal cancer
to the effect of cell-derived growth factors and cytokines
which contribute to tumor growth. However, lines of evidence
have also indicated that, under certain conditions,
immune cell subsets and cytokines fight to maintain dysplastic
cells in check thus preventing tumor progression. A
change in the immune response and/or an adaptation to
the selective pressure of the immune system, referred to as
immune-editing, at a certain point will select dysplastic cell
clones able to grow sustained by the presence of growth
factors and proinflammatory cytokines released in the surrounding
microenvironment, thus changing the role of
the immune system from a negative regulator of tumor
growth to cancer promoter [25] . Although most of the data
sustaining this mechanism derive from models of sporadic
cancer, it is possible that a similar alteration of the balance
between immune system and dysplastic cells might also occur
during long-standing intestinal inflammation.
CD4+ T cells and colitis-associated carcinogenesis
Whether T cells are required for the development of
colitis-associated CRC is an open question. In the azoxymethane/dextran
sulphate sodium (AOM/DSS) experimental
model of CAC, RAG1-deficient mice that do not
have B and T cells did not develop tumors even in the
presence of colitis [26] . These results indicate that lymphocytes
are required to promote tumor growth in the
context of colitis. However, it is worth considering that
an enhanced activity of natural killer (NK) cells, which
are still present in RAG1-/- mice, might be responsible
for tumor protection in these mice. Indeed, depletion
of suppressive subsets of T cells (i.e. regulatory T cells)
has been shown to increase NK cell activity and tumor
rejection [27-29] . Experiments with RAG1-/-//γ-chain-/-
double knockout mice which lack B, T and NK cells
would help to address this issue.
With regard to T helper cell subsets, the role of Th1
and Th2 cells in CAC has been shown by Osawa et al [30] .
The authors compared CAC development in IL4-/- and
IFN-γ-/- deficient mice which have a biased Th2 and Th1
immune response, respectively. Interestingly, Th1-biased
IFN-γ-/- mice developed more tumors than wild type.
Since in these mice there was high expression of IL-4 and
IL-5, the authors concluded that Th2-derived cytokines
promote tumor growth. Indeed, a Th2 response has been
correlated with progression of experimental and human
sporadic CRC [31,32] while a Th1 response has been associated
with a better prognosis [33] . Moreover, the Th2-related
cytokines IL-4 and IL-13 have been shown to induce the
upregulation of activation-induced cytidine deaminase
(AID), an enzyme involved in DNA mutation in epithelial
cells in vitro [34] . Accordingly, AID levels are highly
expressed in tumor samples from UC patients. The higher
susceptibility to develop CAC shown by IFN-γ-/- mice
might be related to a decreased immunosurveillance [34] . Indeed,
IFN-γ has been shown to be involved in the activation
of cytotoxic T cells and NK cells which play a central
role in the antitumor immune response [35,36] .
The initial observation that UC patients have a higher
risk of CAC in comparison to CD fits well with the con-
3093 July 14, 2011|Volume 17|Issue 26|