Although UC represents the prototypical example of the link existing between chronic inflammation and risk of developing colorectal cancer, the mechanisms underlying this process remain to be elucidated. This is likely due to limitations posed by existing experimental models, which make it difficult to recapitulate the effects of chronic inflammation on colorectal tumorigenesis. In this study, we showed that colitogenic bacteria are necessary for the development of chronic intestinal inflammation leading to tumorigenesis. Using AOM as a tumor initiator and the microbiota to trigger chronic colitis in genetically susceptible Il10−/−
mice, we show that inflammation directly correlates with colorectal tumor multiplicity and enhances tumor progression. These events were not observed in Il10−/−
mice housed under germ-free conditions and were strongly attenuated in mice associated with B. vulgatus
, a weak inducer of intestinal inflammation. Furthermore, disruption of MyD88 signaling, a key integrator of multiple TLRs prevented the development of colorectal tumors in Il10−/−
mice. These findings strongly establish the microbiota as key in triggering intestinal inflammation and neoplastic changes in a susceptible host. The role of TLR signaling in the development of colorectal cancer has been the subject of recent intense investigation. Rakoff-Nahoum and co-workers showed that MyD88 signaling contributes to tumor progression in the ApcMin
model of human familial adenomatous polyposis, suggesting a role for intestinal microorganisms in the process of tumorigensis 
. However, because cytokines such as IL1 and IL18 also utilize MyD88 to activate downstream target genes 
the involvement of the intestinal microbiota in this model is unclear. Moreover, the involvement of MyD88 signaling in the development of CAC was not addressed in this study. A better picture of the role of TLR signaling in CAC has begun to emerge from studies using the AOM/DSS model. For example, Fukata and coworkers demonstrated that colorectal tumorigenesis is strongly decreased in Tlr4−/−
mice, suggesting that this innate receptor is important for the development of CAC 
. However, this strong reduction in neoplasia was not accompanied by a concomitant reduction in inflammation. Consequently, there is an apparent disconnect between intestinal inflammation and tumorigenesis in the AOM/DSS model. This phenomenon is not specific to TLR signaling since a recent report showed that tumorigenesis is dramatically reduced in Il6−/−
mice, despite significantly higher inflammatory scores in these mice 
. In contrast, using the AOM/Il10−/−
model, we observed a strong correlation between inflammation score and tumor multiplicity. This suggests that severe inflammation more aptly supports the survival of early transformation events. Additionally our data indicates that the presence of inflammation irrespective of severity influences tumor progression. It is possible that the tumor microenvironment present in the AOM/DSS model differs from that in the AOM/Il10−/−
model, which could account for decreased tumorigenesis despite the high inflammatory state in the former model.
Recent reports have provided insight into the role of colitis as a promoter of colorectal tumorigenesis in the AOM/DSS model 
. However, one important question that remains unanswered is whether these tumor-promoting effects are elicited by the wound-healing response inherently caused by DSS treatment or by the inflammation that accompanies it. For example, Grivennikov and co-workers demonstrate that Il6−/−
mice exhibit decreased tumor multiplicity and load compared to WT mice after AOM/DSS treatment yet these mice displayed more severe intestinal inflammation than WT mice. Consequently, reduced tumorigenesis in this model is the result of impaired IL6/STAT3 signaling in intestinal epithelial cells (IEC) and not necessarily of intestinal inflammation. We demonstrate here that the AOM/Il10−/−
model of CAC can be used to investigate specifically, the impact of colitis on colorectal tumorigenesis. Whether IL6/STAT3 signaling is important in the development of CAC in AOM/Il10−/−
mice remains to be investigated. Additionally, we show that CAC occurs in the context of activated NFκB pathway signaling as shown by the presence of NFκB positive immune cells suggesting that this inflammatory signaling pathway is important in the development and/or promotion of neoplasia. Additional studies will be required to more specifically define a role for NFκB-mediated inflammatory signaling in CAC.
In summary, we show that the gut microbiota is essential to the development of CAC and that chronic colitis promotes the oncogenic potential of colorectal tumors resulting in progression to advanced stages. These events are dependent on microbial recognition by the TLR/MyD88 system. Modulation of this important innate sensing system could represent a novel means by which to prevent/attenuate development of CAC.