Nagy J A, Meyers M S, Masse E M, Herzberg K T, Dvorak H F
Department of Pathology, Beth Israel Hospital, Boston, Massachusetts 02215.
Cancer Res. 1995 Jan 15;55(2):369-75.
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.
在前一篇论文中，我们证明了为患有两种可移植腹水癌之一的小鼠的腹膜衬里组织供血的微血管对循环中的大分子具有高通透性。实体瘤已被证明表现出类似程度的微血管高通透性，导致血浆蛋白外渗，包括纤维蛋白原，其在渗出时凝结形成血管外纤维蛋白凝胶。为了确定腹水肿瘤中是否发生类似的血浆纤维蛋白原外渗和凝结，我们使用125I标记的纤维蛋白原（125I-F）作为示踪剂，来测量纤维蛋白原流入同基因TA3/St或MOT腹水肿瘤小鼠的腹腔，以及纤维蛋白原/纤维蛋白在腹膜衬里组织（腹膜壁、肠系膜和膈肌）中的流入和积累情况。在患有任何一种腹水肿瘤的小鼠中，渗入腹腔的循环125I-F的百分比增加了10至50倍。腹水肿瘤小鼠腹膜壁的流入量是对照小鼠的3至7倍，在第8天（TA3/St）和第15天（MOT）达到最大值。在患有这些腹水肿瘤的小鼠中，腹水液和腹膜衬里组织中125I-F的积累也显著增加，在第7至8天（TA3/St）和第19至29天（MOT）达到最大值，其水平比对照水平高2至3倍（腹膜壁）和33至148倍（腹水液）。在患有腹水肿瘤的动物的腹膜衬里组织中积累的大量125I-F不溶于3M尿素，这与125I-F凝结成交联纤维蛋白一致。对两种腹水肿瘤的腹膜衬里组织提取物进行SDS-PAGE凝胶放射自显影片显示了交联纤维蛋白的特征性条带，即γ-γ二聚体和α-聚合物。通过免疫组织化学也在两种腹水肿瘤的腹膜衬里组织中鉴定出了纤维蛋白。综上所述，这些数据表明，纤维蛋白原与其他循环大分子一样，会外渗到患有腹水肿瘤的小鼠的腹腔和腹膜衬里组织中，并且其动力学与我们研究过的其他大分子示踪剂相似。此外，外渗到腹膜衬里组织中的一部分纤维蛋白原凝结形成交联纤维蛋白网络，该网络捕获肿瘤细胞并促进它们附着于腹膜表面。与实体瘤类似，这种纤维蛋白沉积也可能在启动血管生成和成熟肿瘤基质的形成中起作用。
