title: Tumor promotion as a target of cancer prevention.
abstract: Tumor promotion is an essential process in multistage cancer development providing the conditions for clonal expansion and genetic instability of preneoplastic and premalignant cells. It is caused by a continuous disturbance of cellular signal transduction that results in an overstimulation of metabolic pathways along which mediators of cell proliferation and inflammation as well as genotoxic by-products are generated. Among such pathways the oxidative metabolism of arachidonic acid has turned out to be of utmost importance in tumor promotion. The aberrant overexpression of cyclooxygenase-2, an inducible enzyme of prostanoid synthesis and lipid peroxidation, is a characteristic feature of more than two-thirds of all human neoplasias, and the specific inhibition of this enzyme has been found to have a substantial chemopreventive effect in both animal models and man. The prostaglandins produced by COX-2 promote tumor development by stimulating cell proliferation and angiogenesis and by suppressing programmed cell death and immune defense. In mice, a COX-2 transgene fused with the keratin 5 promoter, which is constitutively active in the basal (proliferative) compartment of stratified and simple epithelia, causes a preneoplastic and premalignant phenotype in several organs. Among these organs, skin, mammary gland, urinary bladder, and pancreas have been investigated in more detail. Histologically and biochemically, the COX-2-dependent alterations resemble an autopromoted state that--as shown for skin and urinary bladder--strongly sensitizes the tissue for carcinogenesis. In transgenic animals COX-2 expression is not restricted to keratin 5-positive cells but is seen also in adjacent keratin 5-negative cells. This spreading of the COX-2 signal indicates a paracrine mechanism of autoamplification. While cancer chemoprevention by COX-2 inhibition is a rapidly developing field, much less is known about other pathways of unsaturated fatty acid metabolism, although some of them may play a role in carcinogenesis rivaling that of prostaglandin formation. Here an urgent demand for systematic research exists.
authors.affiliation: Deutsches Krebsforschungszentrum, Research Program Cell and Tumor Biology, Heidelberg, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Marks
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fürstenberger
authors.forename: Karin
authors.initials: K
authors.lastname: Müller-Decker
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000517:prevention & control*; D011230:Precancerous Conditions / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051546:Cyclooxygenase 2