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 microvasculature supplying peritoneal lining tissues of mice bearing either of two transplantable ascites carcinomas was hyperpermeable to circulating macromolecules. Solid tumors have been shown to exhibit similar levels of microvascular hyperpermeability, leading to extravasation of plasma proteins, including fibrinogen which clots on extravasation to form an extravascular fibrin gel. To determine whether similar extravasation and clotting of plasma fibrinogen occurred in ascites tumors, we used 125I-labeled fibrinogen (125I-F) as a tracer to measure inflow of fibrinogen into the peritoneal cavities, and influx and accumulation of fibrinogen/fibrin in the peritoneal lining tissues (peritoneal wall, mesentery, and diaphragm) of mice bearing syngeneic TA3/St or MOT ascites tumors. The percentage of circulating 125I-F that extravasated into the peritoneal cavity was increased from 10- to 50-fold in mice bearing either ascites tumor. Influx into the peritoneal walls of ascites tumor-bearing mice was 3-7 times that of control mice and became maximal on day 8 (TA3/St) and day 15 (MOT). Accumulation of 125I-F in ascites fluid and peritoneal lining tissues was also increased substantially 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. Significant amounts of the 125I-F that accumulated in the peritoneal lining tissues of ascites tumor-bearing animals were insoluble in 3 M urea, consistent with clotting of 125I-F to cross-linked fibrin. Autoradiographs of SDS-PAGE gels performed on extracts of peritoneal lining tissues of both ascites tumors revealed the characteristic signature of cross-linked fibrin, i.e., gamma-gamma dimers and alpha-polymers. Fibrin was also identified in peritoneal lining tissues of both ascites tumors by immunohistochemistry. Taken together, these data indicate that fibrinogen, like other circulating macromolecules, extravasates into the peritoneal cavity and peritoneal lining tissues of ascites tumor-bearing mice and does so with kinetics similar to those of other macromolecular tracers we have studied. Moreover, a portion of the fibrinogen that extravasated into peritoneal lining tissues clotted to form a cross-linked fibrin meshwork which trapped tumor cells and favored their attachment to the peritoneal surface. By analogy with solid tumors, such fibrin deposits may also be expected to have a role in initiating angiogenesis and the generation of mature tumor stroma.
Nagy
J A
JA
Department of Pathology, Beth Israel Hospital, Boston, Massachusetts 02215.
Meyers
M S
MS
Masse
E M
EM
Herzberg
K T
KT
Dvorak
H F
HF
D000818:Animals; D001201:Ascites / Q000209:etiology* / Q000378:metabolism; D002199:Capillary Permeability; D005260:Female; D005337:Fibrin / Q000032:analysis; D005340:Fibrinogen / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018482:Muscle, Skeletal / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism; D010529:Peritoneal Cavity / Q000098:blood supply*; D010537:Peritoneum / Q000098:blood supply* / Q000737:chemistry / Q000378:metabolism
D007457:Iodine Radioisotopes; D005337:Fibrin; D005340:Fibrinogen