Get access

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

Authors

  • Isao Okayasu

    Corresponding author
    1. Department of Pathology, Kitasato University School of Medicine
    2. Department of Cellular and Histopathology, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan
    Search for more papers by this author

Isao Okayasu, MD, PhD, Department of Pathology, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan, Email: isaokaya@med.kitasato-u.ac.jp

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.

Ancillary