PATHOGENESIS OF ASCITES TUMOR-GROWTH - VASCULAR-PERMEABILITY FACTOR, VASCULAR HYPERPERMEABILITY, AND ASCITES-FLUID ACCUMULATION

Previous studies have shown that accumulation of tumor ascites fluid r esults in large part from increased permeability of peritoneal lining vessels (Nagy et at, Cancer Res., 49: 5449-5458, 1989; Nagy et at, Can cer Res., 53: 2631-2643, 1993). However, the specific microvessels ren dered hyperpermeable have not been identified nor has the basis of per itoneal vascular hyperpermeability been established. To address these questions, TA3/St and MOT carcinomas, web-characterized transplantable murine tumors that grow in both solid and ascites form, were studied as model systems. Ascites tumor cells of either type were injected i.p . into syngeneic A/Jax and C3Heb/FeJ mice, and ascites fluid and plasm a were collected at intervals thereafter up to 8 and 28 days, respecti vely. Beginning several days after tumor cell injection, small blood v essels located in tissues lining the peritoneal cavity (mesentery, per itoneal wall, and diaphragm) became hyperpermeable to several macromol ecular tracers (I-125-hunan serum albumin, FITC-dextran, colloidal car bon, and Monastral Blue B). Increased microvascular permeability corre lated with the appearance in ascites fluid of vascular permeability fa ctor (VPF), a tumor cell-secreted mediator that potently enhances vasc ular permeability to circulating macromolecules. VPF was measured in p eritoneal fluid by both a functional bioassay and a sensitive immunofl uorometric assay. The VPF concentration, total peritoneal VPF, ascites fluid volume, tumor cell number, and hyperpermeability of peritoneal lining microvessels were found to increase in parallel over time. The close correlation of peritoneal fluid VPF concentration with the devel opment of hyperpermeable peritoneal microvessels in these two well-def ined ascites tumors suggests that VPF secretion by tumor cells is resp onsible, in whole or in part, for initiating and maintaining the ascit es pattern of tumor growth.