81 Growth and dissemination of lewis lung carcinoma in plasminogen-deficient mice

Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages

“…We chose, as a simple model system, to study the orthotopic growth of a fibrosarcoma in the intradermal space of syngeneic mice with single and combined genetic deficiencies in components of the PA system. Similar to other tumor models (Bugge et al, 1997;Sabapathy et al, 1997), wholesale ablation of the PA cascade in this model system resulted in the impairment of the intradermal growth of the sarcoma, underscoring the importance of the PA system in tumor progression. The most conspicuous histological difference associated with Plg-deficiency resided in the density of tumor-infiltrating macrophages, which was approximately doubled in Plgdeprived tumors.…”

“…Fibrin(ogen) immunostaining revealed a diffuse deposition of fibrin(ogen) around healthy tumor cells, and more prominent fibrin(ogen) deposition at the invasive front of the tumors, in areas of frank necrosis, and lining the tumor vasculature (Figure 3c,d). As described previously for both mammary adenocarcinoma and lung carcinoma (Bugge et al, 1997(Bugge et al, , 1998, loss of Plg did not lead to an obvious increase in tumor-associated fibrin(ogen) deposition, suggesting that proteases different from Plg can serve as fibrinolysins in the context of tumor progression (Hiraoka et al, 1998;Hotary et al, 2002). Plg-sufficient and Plg-deprived tumors did also not demonstrate an obvious difference in the deposition of collagen, as visualized by Masson's Trichrome staining (data not shown).…”

“…First, tumor cells were injected into Plg-deficient (Plg7/7) mice and matched control mice to determine the overall effect of wholesale loss of Plg on orthotopic growth of T-241 fibrosarcoma (Figure 2). The complete ablation of Plg did not prevent sarcoma growth but was associated with a significant reduction in tumor burden, as observed previously for carcinoma growth in Plg7/7 mice (Bugge et al, 1997). This reduction was apparent at the earliest time point where tumor volumes could be determined and persisted throughout the observation period (Figure 2).…”

“…The direct causal relationship between Plg activator expression and tumor progression was furthermore demonstrated in a number of studies using the chick chorio-allantoic membrane metastasis model, and the mouse spontaneous and experimental metastasis models. These studies have employed a variety of strategies to inhibit Plg activator function including antisense RNA techniques (Kook et al, 1994;Yu and Schultz, 1990), anti-catalytic Plg activator antibodies (Hearing et al, 1988;Kobayashi et al, 1994b;Ossowski, 1988;Ossowski and Reich, 1983), natural and synthetic Plg activator inhibitors or uPAR antagonists (Crowley et al, 1993;Kobayashi et al, 1994a;Min et al, 1996;Mueller et al, 1995;Rabbani et al, 1995), and, lately, also genetically engineered mice with targeted deficiencies in components of the PA system (Bugge et al, 1997(Bugge et al, , 1998Sabapathy et al, 1997;Shapiro et al, 1996). Collectively, these studies have firmly established the PA system as an important contributor to tumor progression.…”

Urokinase Plasminogen Activator and Plasmin Efficiently Convert Hemofiltrate CC Chemokine 1 into Its Active [9–74] Processed Variant

“…Increased levels of uPA, uPAR, and, somewhat unexpectedly, PAI-1, have been shown in a variety of human tumors, and have been established as independent markers of poor prognosis (61)(62)(63). Studies of tumor development in plasmin-or urokinasedeficient mice have confirmed that both urokinase and plasmin contribute to tumor-associated pericellular proteolysis, but that other proteases could efficiently substitute for each deficiency (64,65). The effect of uPA in tumor development is not limited to proteolysis, as signal transduction by uPAR is believed to facilitate cancer cell proliferation (66 -68).…”