5,8,11,14-Eicosatatranoic acid-induced differentiation of U937 cells

U937 cells, transformed human monocyte/macrophage precursors, incubated with 5,8,11,14 eicosatatraynoic acid (ETYA), a competitive in vitro and in vivo inhibitor of arachidonic acid, develop properties consistent with a form of cellular differentiation. In order to define the extent of this differentiation and decide whether a monocyte or macrophage-like cell developed, control cells and cells cultured for three days with 40 μm ETYA were examined by transmission electron microscopy. Control cells were characterized by oval nuclei, a high nuclear to cytoplasmic ratio, a cytoplasm with a relative paucity of mitochondria, vesicles and vacuoles, and a Golgi apparatus that was not extensively developed. Ribosomes and putative ribosome-like granules were frequently 'grouped' in the cytoplasm, rather than as single granules or in association with the endoplasmic reticulum. The plasma membrane included a discrete region of fimbriated structures that were distinct from pseudopodia. Such structures frequently are expressed in embryonic and transformed cells and may be associated with motility, metastases, with immunologic reactions or with endocytosis. After culture with 40 μm ETYA for three or more days, a morphology consistent with that of immature monocytes developed. These characteristics included lobulated nuclei, a reversal of the nuclear to cytoplasmic ratio, an increased complexity and development of the cytoplasmic components and the disappearance of the fimbriated plasma membrane structures. In addition, 'grouped' ribosomes were less evident. In vitro induction of differentiation in a human cancer cell by a competitive inhibitor of arachidonic acid, itself a physiologic metabolite, is of interest for at least four reasons: as an aid in understanding the mechanism of inhibition of stem cell replication and the induction of cellular differentiation, and because of the possibility of increased immunogenicity and of reduced invasiveness of the ETYA-differentiated cells. In vivo expression of these features could militate against the deleterious effects of such transformed cells on the host.