The organ-specific chronic
inflammation-
carcinoma sequence was summarized and proposed. As a typical model, the
ulcerative colitis (UC)--UC-associated
carcinoma sequence was selected, and the mechanism of development of UC and UC-associated
carcinoma was reviewed, referring mainly to our data. Intestinal commensal bacteria, including Fusobacterium varium, obtained from the colonic mucosa of UC patients, can enter colonic epithelia and induce secretion of inflammatory
cytokines, resulting in early inflammatory lesions consisting of cryptitis and crypt
abscess. Inflammatory oxidative stress causes epithelial cell DNA-damage followed by p53 dependent G1 checkpoint activation and overloading, which causes p53 mutation. In long-standing UC, mucosal remodeling, including possible loss of crosstalk between epithelium and stroma may be critical for the development of UC-associated
carcinoma, as well as accumulation of early p53 mutation at the crypt level and increase of other stem cell mutated crypts, telomere shortening, and
genomic instability of epithelial and stromal cells, including subepithelial myofibroblasts (corresponding to colonic stellate cells or Ito cells) and interstitial cells. Thus, the stochastic (probabilistic) pathway to
tumor development over time gains commonalty through chronic
inflammation stimulation. For the prevention of
cancer development, appropriate anti-inflammatory
therapy is important with an accurate assessment of the
inflammation status in the colorectum.