Expression of tissue factor (TF) in the endothelium has been observed only rarely in human disease and has been thought to be elaborated on the surface of vascular endothelial cells (VECs) in vitro as an artifact of tissue culture. Using monoclonal antibodies and a novel probe for functional TF, we have localized TF to the VECs (and tumor cells) within the tumors of seven patients with invasive breast cancer but not in the VECs (or tumor cells) of benign tumors from ten patients with fibrocystic disease of the breast. The potent procoagulant TF was shown to be a marker of the initiation of angiogenesis in human breast cancer. Further evidence that the TF was the demonstration of a similar distribution of cross-linked fibrin only in the VECs of the malignant tumors. We interpret these data as further support for the concept that tumor cells can activate nearby VECs and regulate blood vessel growth in vivo. Large clinical pathologic studies will be necessary to determine whether TF is a useful marker for the "switch" to the angiogenic phenotype" in human breast disease and/or correlates with the thromboembolic complications of breast cancer.

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ABSTRACT. Immunomodulating agents are being inves-elements that defend against bacterial invasion. Thus, therapeutic tigated for treatment of infection in newborn infants where strategies that augment host defenses in the neonate such as morbidity and mortality remain high despite the continued transfusion of PMN or i.v. Ig have begun to be examined (10-development of new antibiotics. We studied the effect of 18). The development of immunomodulating drugs that directly the methylxanthine pentoxifylline on polymorphonuclear stimulate PMN function is an alternative approach that may leukocyte (PMN) chemotaxis, F-actin content, and phag-offer advantages over PMN or i.v. Ig transfusion in regard to ocytic activity as measured by nitroblue tetrazolium reduc-specificity of effect, ease of administration, availability, and side tion and Hz02 production in neonates and adults to deter-effects (10). A number of agents that enhance PMN function mine whether pentoxifylline might be useful in augmenting have been investigated but none are in routine clinical use and PMN function. The drug was found to have a dose-depend-only a few, such as pentoxifylline, have been studied in newborn ent effect on both neonatal and adult PMN function with infants (8,(19)(20)(21)(22). enhancement at lower concentrations and suppression at Pentoxifylline is a methylxanthine that was introduced in 1984 higher concentrations. PMN chemotaxis increased 42% ( p for treatment of peripheral vasoocclusive disease. Sheetz, Wang, < 0.01) in neonates and 16% ( p < 0.05) in adults at 100 and Kreutzer were the first to demonstrate that pentoxifylline pg/mL of pentoxifylline and it decreased 4 and 25%, re-could enhance adult PMN motility in vitro (23). Subsequently, spectively, at 4000 wg/mL. PMN nitroblue tetrazolium we found that pentoxifylline decreased the morbidity and morreduction increased by 34% in neonates and 23% ( p < tality from experimentally induced Staphylococcus aureus infec-0.05) in adults at 100 wg/mL of pentoxifylline and de-tion in neonatal mice, due in part to enhancement of PMN creased by 52 (p < 0.01) and 74% ( p < 0.01), respectively, motility (19, 21). To begin to investigate the potential utility of at 2000 wg/mL. Similar dose-dependent responses were pentoxifylline in human neonates, Hill et al. (8) and Krause et noted with F-actin content and H202 production. These al. (22) evaluated the in vitro effects of this drug on neonatal and other observations support the hypothesis that pentox-PMN chemotaxis and noted enhancement of PMN motility. Our ifylline has a broad range of effects on PMN but that a study was designed to confirm and extend these findings to primary effect is alteration of PMN deformability. Pentox-include pentoxifylline effect on other PMN responses and to ifylline has potential clinical use as an immunomodulator further investigate the mechanism of action of pentoxifylline on in augmenting impaired PMN function in neonates and PMN function. The results indicate that pentoxifylline can enother immunocompromised ...