PATHOGENESIS OF ASCITES TUMOR-GROWTH - FIBRINOGEN INFLUX AND FIBRIN ACCUMULATION IN TISSUES LINING THE PERITONEAL-CAVITY

In the immediately preceding paper, we demonstrated that the microvasc ulature supplying peritoneal lining tissues of mice bearing either of two transplantable ascites carcinomas was hyperpermeable to circulatin g macromolecules. Solid tumors have been shown to exhibit similar leve ls of microvascular hyperpermeability, leading to extravasation of pla sma proteins, including fibrinogen which clots on extravasation to for m an extravascular fibrin gel. To determine whether similar extravasat ion and clotting of plasma fibrinogen occurred in ascites tumors, we u sed I-125-labeled fibrinogen (I-125-F) as a tracer to measure inflow o f fibrinogen into the peritoneal cavities, and influx and accumulation of fibrinogen/fibrin in the peritoneal lining tissues (peritoneal wal l, mesentery, and diaphragm) of mice bearing syngeneic TA3/St or MOT a scites tumors. The percentage of circulating I-125-F that extravasated into the peritoneal cavity was increased from 10- to 50-fold in mice bearing either ascites tumor. Influx into the peritoneal wads of ascit es tumor-bearing mice was 3-7 times that of control mice and became ma ximal on day 8 (TA3/St) and day 15 (MOT). Accumulation of I-125-F in a scites fluid and peritoneal lining tissues was also increased substant ially in mice bearing these ascites tumors, reaching maximal values on days 7-8 (TA3/St) and 19-29 (MOT) at levels 2- to 3-fold (peritoneal wall) and 33- to 148-fold (ascites fluid) above control levels. Signif icant amounts of the I-125-F that accumulated in the peritoneal lining tissues of ascites tumor-bearing animals were insoluble in 3 M urea, consistent with dotting of I-125-F to cross-linked fibrin. Autoradiogr aphs of SDS-PAGE gels performed on extracts of peritoneal lining tissu es or both ascites tumors revealed the characteristic signature of cro ss-linked fibrin, i.e., gamma-gamma dimers and alpha-polymers. Fibrin was also identified in peritoneal lining tissues of both ascites tumor s by immunohistochemistry. Taken together, these data indicate that fi brinogen, like other circulating macromolecules, extravasates into the peritoneal cavity and peritoneal lining tissues of ascites tumor-bear ing mice and does so with kinetics similar to those of other macromole cular tracers we have studied. Moreover, a portion of the fibrinogen t hat extravasated into peritoneal lining tissues dotted to form a cross -linked fibrin meshwork which trapped tumor cells and favored their at tachment to the peritoneal surface. By analogy with solid tumors, such fibrin deposits may also be expected to have a role in initiating ang iogenesis and the generation of mature tumor stroma.