This proposal seeks to determine the relationship between low dose (i.e., non-lethal) radiation and enhanced tumor metastatic potential. Our working hypothesis is that low dose radiation triggers a cascade of biochemical responses giving rise to highly metastatic tumor cells. This cascade can be summarized as: 1) low dose radiation stimulates tumor cell biosynthesis of the arachidonic acid metabolite 12-HETE; 2) 12-HETE activates quiescent protein kinase C (PKC), possibly by inducing its translocation from the cytosol to the plasma membrane; 3) the activated PKC enhances plasma membrane surface expression of integrin receptors (e.g., glycoprotein llb/llla complex); 4) radiation enhanced expression of llb/llla complex on the tumor cell plasma membrane results in a highly metastatic phenotype, characterized by increased tumor cell adhesion to biologically relevant substrata and increased tumor cell induced platelet aggregation. We shall determine the effects of low dose radiation on the expression of the integrin receptor llb/llla. We previously reported that surface expression of llb/llla receptors regulates tumor cell adhesion to extracellular matrix and other biological substrata and regulates tumor cell metastasis. Expression of llb/llla receptors will be measured employing flow cytometric analysis and adhesion assays. Specifically we shall determine the effects of low dose radiation on tumor cell 12-HETE synthesis and reincorporation, whether the enhanced synthesis of 12-HETE is the result of non-specific activation of the tumor cell arachidonic acid pathway or a specific activation of the cyclooxygenase (COX) or lipoxygenase (LOX) pathways and whether specific COX and LOX inhibitors are able to block this phenomenon. Subsequently, we shall investigate the effects of low dose radiation on the activation of tumor cell PKC and we will determine whether the """"""""up-regulation"""""""" of (tumor cell plasma membrane) llb/llla receptors in response to low dose radiation is inducible in all tumor cells under investigation or induced only in (their) discrete tumor cell subpopulations. Finally, we shall determine whether radiation induced up-regulation of the llb/llla complex promotes tumor cell induced platelet aggregation in vitro and the formation of experimental metastasis in vivo. Studies assessing the effects of radiation on the host microvasculature (""""""""tumor bed effect"""""""") have generally used high dose radiation (1,000-10,000 rads) and typically examined the effects of irradiation at 48 hrs to > 400 days post treatment. Our preliminary studies indicate that enhanced expression of the llb/llla integrin receptor complex on the surface of tumor cells can be observed within 15 minutes post irradiation (50 rads), demonstrating a level of tumor cell response to irradiation which has not been critically examined. We believed that achieving our stated goals will provide important insight into the basic metabolism of tumor cells, and elucidate those factors which mediate the causal relationship between radiation and tumor metastatic potential. This may result in the development of more effective radiotherapeutic modalities, or at the very least, radiotherapeutic protocols based on an awareness of a possible paradoxical effect of radiation (i.e., enhancing metastatic potential) on surviving tumor cells.
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| Onoda, J M; Kantak, S S; Piechocki, M P et al. (1997) Low dose radiation induces endothelial cell eicosanoid metabolism and cytoskeletal rearrangement. Adv Exp Med Biol 400B:879-87 |
| Onoda, J M; Piechocki, M P; Honn, K V (1992) Radiation-induced increase in expression of the alpha IIb beta 3 integrin in melanoma cells: effects on metastatic potential. Radiat Res 130:281-8 |
