Download “Molecular” pathogenesis of normal tissue responses to therapeutic

“MOLECULAR” PATHOGENESIS OF NORMAL TISSUE RESPONSES TO
THERAPEUTIC RADIATION EXPOSURE
Wolfgang Dörr
Dept. Radiation Oncology & CD Lab for Med. Radiation Research for Radiation
Oncology, CCC, MedUniv/AKH Vienna, Austria
[email protected]
Normal tissue reactions after exposure to significant (therapeutic) doses of ionizing
radiation are classified as early or late, according to their first diagnosis either within
or after the first 90 days after the onset of the radiotherapy protocol, respectively.
Early reactions are typically seen in proliferating “turnover” tissues. In these tissues, a
continuous physiological cell loss is compensated in a precisely balanced equilibrium
by the permanent cell production in the proliferative tissue compartments. Here, the
dominating pathogenetic process of the response to irradiation is the progressive cell
depletion as a consequence of radiation-induced impairment of (stem cell)
proliferation. Late radiation effects, in contrast, are observed in essentially all tissues
and organs. With regard to late radiation sequelae, but also in early responding
tissues, changes in the cellular function of vascular and connective tissue components,
in addition to the radiation effects in tissue-specific parenchymal cells, significantly
contribute to their radiopathogenesis. Moreover, local immune reactions
(macrophages), either modulated by the radiation exposure per se or by postirradiation changes in the tissue micromilieu, contribute to the tissue radiation
sequelae.
In all cell populations involved, i.e. predominantly parenchymal, endothelial and
immune cells and fibroblasts, the oxidative stress induced by radiation exposure
results in the activation of several transcription factors (e.g., NF-B, AP-1). This, in
consequence, modifies the activity of various intra- as well as inter-cellular signaling
cascades. The latter include growth factor-mediated signal chains as well as
inflammatory signaling pathways. A whole panel of functional cellular/tissue
responses to these signaling changes is observed, including cell death or premature
differentiation (fibroblasts, epithelial and other parenchymal cells), stimulated
proliferation (epithelial cells) or apoptosis of endothelial cells. The interactive
response of all these cell populations eventually results in clinically manifest early as
well as late tissue reactions to radiation exposure.
Perspectively, ongoing studies into the “molecular” pathogenesis of normal tissue
radiation effects will allow for the identification of biomarkers for the individual
radiosensitivity of patients with regard to specific morbidity endpoints, and will also
lead to biology-based strategies for the prophylaxis and/or mitigation of adverse
events in radiation oncology.