http://ar.iiarjournals.org/content/25/3B/2299.full.pdf+html?sid=c4c40b4a-1bc8-4cbc-92a7%2097789011723c
Abstract:
Nontransformed (effector) cells induce apoptosis selectively in transformed (target) cells. This process, originally described for the interaction of nontransformed and transformed fibroblasts, has been termed “intercellularinduction of apoptosis”.
Meanwhile, this concept of a potential control step during oncogenesis has been shown to be relevant for a variety of other effector and target cell systems.
For example, macrophages and granulocytes causeselective elimination of transformed cells, using the same signaling chemistry as fibroblasts. Intercellular induction of apoptosis seems to act selectively on transformed cells, as induction of the transformed state causes induction of sensitivity, whereas abrogation of the transformed state causes insensitivity to intercellular induction of apoptosis.
Intercellular induction of apoptosis is independent of direct contact between effector and target cells. Transforming growth factor type-beta triggers the onset of intercellular induction of apoptosis in the fibroblast system, but does not seem to be required by the other effector cell systems.
The selectivity, as well as efficiency, of intercellular induction of apoptosis are based on reactive oxygen and nitrogen species (ROS and RNS). Extracellular superoxide anions generated specifically by transformed target cells represent the central element in this signaling system.
In a first signaling pathway, target cell-derived superoxide anions spontaneously dismutate to hydrogen peroxide, which fosters HOCl generation by a target cell-derived peroxidase. HOCl then interacts with target cell-derived superoxide anions and generates apoptosis-inducing hydroxyl radicals.
In a second signaling pathway, target cell-derived superoxide anions interact with effector cell-derived nitric oxide and form the apoptosis-inducer peroxynitrite.
In a third signaling pathway, HOCl and nitrite form toxic nitryl chloride. Our data show that nontransformed effector cells cause selective apoptosis induction in transformed cells through specific ROS and RNS interactions. Thereby, the efficiency and the selectivity of the reaction are determined by target cellderived superoxide anions.
In addition to intercellular induction of apoptosis, transformed cells are eliminated by TGF-beta-triggered, ROS-mediated autocrine/ paracrine self-destruction. In this process, the effector molecules, peroxidase and NO, are generated by the transformed target cells themselves and cooperate with their own extracellular ROS to induce apoptosis.
Tumor formation seems to require interference with or resistance to intercellular induction of apoptosis and to apoptotic self-destruction. Understanding and subsequent abrogation of tumor cell resistance may have a therapeutic potential.
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Georg Bauer - Abteilung Virologie, Institut für MedizinischeMikrobiologie und Hygiene, Universität Freiburg, D-79104 Freiburg, Germany. e-mail: tgfb@ukl.uni-freiburg.de
http://ar.iiarjournals.org/content/25/3B/2299.full.pdf+html?sid=c4c40b4a-1bc8-4cbc-92a7%2097789011723c
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