Development of ulcerative colitis and its associated colorectal neoplasia as a model of the organ‐specific chronic inflammation‐carcinoma sequence

Abstract

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.

Activation of Intestinal Human Pregnane X Receptor Protects against Azoxymethane/Dextran Sulfate Sodium–Induced Colon Cancer

“…These results suggest that rifaximin prevents AOM/DSS-induced colon carcinogenesis in a human PXR-dependent manner. Furthermore, this study showed that the expression of cytokines significantly increased in response to DSS/AOM treatment; these are involved in the "inflammation-carcinoma sequence" (Okayasu, 2012). Treatment with rifaximin decreased cytokine expression, which was in line with data showing that oral feeding with rifaximin modulates and attenuates the colonic inflammation in experimental animal colitis (Cheng et al, 2010).…”

Porcine β-Defensin 2 Attenuates Inflammation and Mucosal Lesions in Dextran Sodium Sulfate–Induced Colitis

“…The major causative factors in the initiation of human colitis include enhanced vasopermeability and upregulation of inflammatory mediators and some cytokines. Prolonged neutrophil infiltration is also involved in this animal model of colitis (44,45). Initiation and progression of intestinal inflammation, including IBD, requires the presence of bacterial pathogens (46,47).…”

Characterization of Fusobacterium isolates from the respiratory tract of white-tailed deer (Odocoileus virginianus)

“…19 Under certain conditions, some commensal organisms such as F. varium may be capable of invading epithelial cells and activating early host inflammatory responses. 19 Few studies on antimicrobial susceptibility of F. varium have been reported, although the susceptibility of other Fusobacterium species has been investigated. The results of the current study suggest that susceptibility to antimicrobials is markedly different among the Fusobacterium species evaluated, and are consistent with previous studies.…”

“…18,19 Butyric acid has been demonstrated to induce apoptosis of colonic epithelium and to induce secretion of inflammatory cytokines. 19 Under certain conditions, some commensal organisms such as F. varium may be capable of invading epithelial cells and activating early host inflammatory responses. 19 Few studies on antimicrobial susceptibility of F. varium have been reported, although the susceptibility of other Fusobacterium species has been investigated.…”

“…3,21 Although less extensively investigated, Fusobacterium varium has been associated with ulcerative colitis, colonic neoplasia, decubitus ulcers, and respiratory tract infections in human beings, and with suppurative or ulcerative lesions of the gastrointestinal tract or oral cavity in animals. 4,11,19 Various Fusobacterium spp. have been isolated from wild ruminants affected by necrobacillosis, a common disease of farmraised deer characterized by purulent necrotic lesions most commonly affecting the mouth, pharynx, lung, liver, or feet.…”