Various factors are known to regulate cell growth and differentiation, but less is known of agents which affect movement and positioning, particularly in epithelial-mesenchymal interactions. Cultured human embryo fibroblasts release a protein with a relative molecular mass (Mr) of approximately 50,000 (50K) that affects epithelial cells by causing a disruption of junctions, an increase in local motility and a scattering of contiguous sheets of cells. To investigate specificity, a range of cells has been examined for the ability to produce the factor and for sensitivity to its action. Most freshly isolated normal epithelia and epithelia from cell lines of normal tissue, but not epithelia from tumour cell lines or fibroblasts, were sensitive to scatter factor. In contrast, production of the factor, as identified by activity and by chromatography, was restricted to embryonic fibroblasts and certain variants of 3T3 and BHK21 cells and their transformed derivatives. We conclude that the scatter factor is a paracrine effector of epithelial-mesenchymal interaction, which affects the intercellular connections and mobility of normal epithelial cells. The factor might be involved in epithelial migration, such as occurs in embryogenesis or wound healing.

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Scatter factor is a fibroblast-derived protein that causes separation of contiguous epithelial cells and increased local mobility of unanchored cells. Highly purified scatter factor has been obtained by a combination of ionexchange and reverse-phase chromatography from serum-free medium conditioned by a ras-transformed clone (D4) of mouse NIH 3T3 fibroblasts. Under nonreducing conditions scatter factor has a pI of -9.5 and migrates in SDS/polyacrylamide gels as a single band at -62 kDa from which epithelial scatter activity can be recovered. Treatment with reducing agents destroys biological activity and is associated with the appearance of two major bands at "57 and "30 kDa. Whether both the 57-kDa and 30-kDa polypeptides are required for biological activity remains to be established. All the activities observed in crude medium conditioned by cells producing scatter factor are retained by highly purified preparations of scatter factor.These include (i) increased local movement, modulation of morphology, and inhibition of junction formation by single epithelial cells and (it) disruption of epithelial interactions and cell scattering from preformed epithelial sheets. These changes occur with picomolar concentrations of purified scatter factor and without an effect on cell growth.Cell movement is restricted by the interaction with basement and extracellular membrane proteins (1) and, in certain tissues, by cell-cell interactions that involve cell-specific adhesion molecules (2). Movement of epithelial cells is further limited by cell-cell (desmosomes, tight and gap junctions) and cell-substratum (hemidesmosomes) junctional systems. Cytokines are also involved in the regulation of cell movement, as it appears that certain growth factors, including nerve growth factor (3), platelet-derived growth factor (4), and epidermal growth factor (5, 6) may stimulate cell movement as well as cell growth.There is increasing evidence, however, for a new group of cytokines that regulate cell movement with little or no effect on cell growth. Pioneering studies by Yoshida et al. (7) indicated that certain mouse and rat hepatoma lines and mouse and human leukemias produced a protein of 70 kDa that was chemotactic for the producer cells as well as for other tumor cells but not for polymorphonuclear cells (7). More recently, another motility factor has been isolated from serum-free medium conditioned by the human melanoma line A2058. This 55-kDa protein has both chemotactic and chemokinetic activity for the producer cells (but not for polymorphonuclear cells) and has been designated autocrine motility factor (AMF) (8). ras-transformed derivatives of mouse NIH 3T3 fibroblasts also produce AMF and respond to it and, interestingly, normal NIH 3T3 firboblasts, which do not produce AMF, are able to respond to the AMF secreted by ras-tranformed cells (8). A factor similar to AMF has been isolated from serum-free medium conditioned by a highly metastatic clone (MTLn3) of rat mammary adenocarcinoma (9). This factor (53 kDa) is chemota...