The role of platelet activating factor in tumour progression and neurodegeneration.

Abstract

Tumourigenesis is the result of increased cell number. Progressive neurodegenerative disorders are characterized by decreased cell number. These illnesses emphasize the life-threatening consequences of disrupting the delicate balance between cell growth, cell differentiation, and cell death. Exposure to chronic inflammation is a recognized risk factor for a variety of human cancers and progressive neurodegenerative diseases. This thesis represents an attempt to determine whether one endogenous proinflammatory agent, platelet activating factor (PAF), may participate in tumourigenesis and/or neurodegeneration. Data are presented to indicate that PAF is capable of inducing sustained alterations in both the rate of cell growth and the rate of cell death in non-inflammatory cells. This ability can be characterized as follows: (1) Brief stimulation (<1 hr) of rodent and human fibroblasts and epithelial cells cultured in vitro induced PAF receptor activation, PKC activity, phosphorylation of proteins on tyrosine residues, oxyradical production, and de novo gene expression of the proto-oncogene c-fos and the active cell death (ACD)-related gene clusterin. (2) Transient stimulation (1-6 hr) elicited long-term growth enhancement (60-80 days) characterized by increased focus formation, saturation density, autonomous cell growth, and AI growth in the absence of further ligand exposure. Cell proliferation was, apparently, mediated by increases in intracellular PAF concentrations triggering the synthesis and release of mitogenic factors. Growth enhancement was accompanied by induction of clusterin and urokinase plasminogen activator gene expression. (3) Prolonged exposure (72 hr) to PAF induced ACD when cells were cultured in the absence of excess growth factors. ACD was determined by changes in nuclear and cytoplasmic morphology and by DNA analysis. (4) The kinetics of these responses to PAF could be altered by introduction of an activated ras oncogene into cells. Transient exposure to PAF under suboptimal growth conditions was sufficient to elicit a defined period of cell loss in ras-transformed fibroblasts followed by growth enhancement in surviving cells. (5) Increased PAFR expression was associated with chronic neurodegenerative lesions and cell death in vivo using a kainic acid model of myoclonic epilepsy. In summary, PAF, was shown to be capable of disrupting the delicate balance between cell growth and cell death. In this manner, PAF may contribute to tumour progression and progressive neurodegenerative disorders.