Control of neoplastic proliferation reflects in part monocyte/macrophage destruction of target cells--destruction that evidently requires cell-cell interaction. We herein show it to involve the natural plasma opsonin, fibronectin. With two cultured human tumor lines--Malme melanoma and CAK-I renal carcinoma cells--addition of fibronectin, purified to homogeneity, enhances macrophage-mediated cytotoxicity 2--4-fold (p less than 0.01). Both fresh human monocytes or the U-937-cultured macrophage line become more lethal to tumor cells with added fibronectin. The fibronectin-enhanced monocyte and U-937 tumoricidal activity occurred in a dose-dependent fashion. Specificity of fibronectin's action was validated by use of affinity-purified rabbit antifibronectin antibody, which completely abated its enhancement of tumoricidal activity. Enhancement of tumoricidal activity did not occur when monocytes or U-937 were exposed to fibronectin-coated plates. However, the addition of soluble fibronectin to fibronectin-coated plates was then capable of enhancing cytocidal activity. These studies demonstrate that human fibronectin is capable of increasing both fresh and cultured human monocyte tumor-directed cytotoxicity. Fibronectin appears to be a potentially important circulating molecule that may favorably influence human monocyte tumor cell cytotoxicity.

Recent investigations have emphasized the role of activated granulocytes in mediating vascular endothelial injury in the pathogenesis of shock lung. In vitro studies have indicated that tight adherence of the neutrophil to the endothelium is crucial for the development of cellular injury. Fibronectin is critical to cell-to- substratum and cell-to-cell interactions. Since fibronectin resides in plasma, on endothelial cell surfaces and is secreted into cell matrices, the adhesive properties of fibronectin must be modulated, lest universal cell agglomeration occur, yet be enhanced when cell attachment is appropriate. In these studies, treatment of fibronectin- coated surfaces with neutrophil release products increased the adhesion of activated neutrophils. Similarly, endothelial cells treated with neutrophil release products become a more adherent substrate for neutrophils. This enhanced adherence generated by treatment of fibronectin with neutrophil supernatants is inhibitable by heat and the lysosomal proteinase inhibitor, pepstatin-A. Neutrophil release products cause proteolytic fragmentation of fibronectin and enhanced fibronectin immunofluorescence on endothelial cells. In addition, neutrophils are more injurious to endothelial cells that have been pretreated with neutrophil release products. Neutrophils may enhance their own adherence to endothelial cells by altering fibronectin, and this altered, or “inflamed,” fibronectin may serve as an amplifier of inflammation.