Review article: inflammation-related promotion of gastrointestinal carcinogenesis--a perigenetic pathway.
Chronic inflammation has been reported to accelerate neoplasmas in gastrointestinal tract. Certain bacteria including Helicobacter pylori directly interact with host cells, induce proinflammatory cytokines and stimulate production of free radicals. Free radicals cause mutations in target cells so that neoplastic clones are established. Accumulation of such genetic alterations may cause malignant transformation of some established clones. In addition, inflammatory alterations may promote growth, expansion and invasion of gastrointestinal epithelial cells. The latter changes caused by inflammation may occur even without further genetic mutations or epigenetic alterations, and therefore may be categorized as 'perigenetic alterations' of neoplastic cells. For an example, tumour necrosis factor alpha (TNF-alpha) plays pivotal roles not only in the reduction but also in the growth, invasion and metastases of certain neoplasmas. Our studies show that TNF-alpha increases intracellular radical production, degradates E-cadherin / beta-catenin complex and promotes dispersion and migration in epithelial cells transformed with an activated src oncogene (v-src). These data indicate that an inflammatory cytokine induces the malignant potential of src-activated neoplastic cells. Interestingly, TNF-alpha also induced these phenotypic changes in nonmutated cells whose c-Src was activated by TGF-alpha, suggesting that the invasive properties of the cell were not necessarily related to gene mutation. Furthermore, certain radical scavengers suppressed the invasive phenotype of the cells. These results indicate that perigenetic alterations are an important target of pharmacological intervention of carcinogenesis.
Tsuji
S
S
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan. tsuji@medone.med.osaka-u.ac.jp
Kawai
N
N
Tsujii
M
M
Kawano
S
S
Hori
M
M
D002450:Cell Communication; D016207:Cytokines / Q000502:physiology*; D005759:Gastroenteritis / Q000150:complications* / Q000473:pathology; D005770:Gastrointestinal Neoplasms / Q000209:etiology* / Q000473:pathology; D006801:Humans
D016207:Cytokines