PATHOGENESIS OF ASCITES TUMOR-GROWTH - ANGIOGENESIS, VASCULAR REMODELING, AND STROMA FORMATION IN THE PERITONEAL LINING

In the accompanying papers, we demonstrated that tao murine ascites tu mors (MOT and TA3/St) induced peritoneal lining blood vessels to becom e hyperpermeable to plasma proteins, leading to extravasation of fibri nogen and its clotting to cross-linked fibrin in peritoneal lining tis sues (peritoneal wall, mesentery, and diaphragm). In solid tumors, vas cular hyperpermeability and fibrin deposition lead to the generation o f vascularized connective tissue. In order to determine whether fibrin had similar consequences in ascites tumors, the vasculature and strom a of peritoneal lining tissues were analyzed at successive intervals a fter i.p. tumor cell injection. In both MOT and TA3/St ascites tumors, the size and number of peritoneal lining microvessels increased signi ficantly by 5-8 days. Subsequently, peritoneal lining vessels increase d in cross-sectional area by as much as 15-fold and peritoneal vascula r frequency increased by up to 11-fold. Incorporation of [H-3]thymidin e by mesenteric blood vessels was negligible in control animals but ca me to involve 20 and 40% of endothelial cells lining mesenteric vessel s in MOT and TA3/St ascites tumor-bearing mice, respectively. After an early dramatic increase in cross-sectional area, peritoneal lining mi crovessels subsequently underwent a novel form of remodeling to smalle r average size as the result of transvascular bridging by endothelial cell cytoplasmic processes. Thus, both of the ascites tumors studied h ere induced angiogenesis and stroma similar to that elicited when thes e same tumors were grown in solid form. However, stroma developed more slowly in ascites than in solid tumors and was entirely confined to a compartment (peritoneal lining tissues) that was distinct from that ( peritoneal cavity) containing the majority of tumor cells and ascites fluid. These findings are consistent with the hypothesis that vascular hyperpermeability, induced in both solid and ascites tumors by tumor cell-secreted vascular permeability factor, is a common early step in tumor angiogenesis, resulting in fibrinogen extravasation, fibrin depo sition, and likely other alterations of the extracellular matrix that together stimulate new vessel and fibroblast ingrowth.