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Polyoma middle T-induced vascular tumor formation: the role of the plasminogen activator/plasmin system.

Sabapathy KT, Pepper MS, Kiefer F, Möhle-Steinlein U, Tacchini-Cottier F, Fetka I, Breier G, Risau W, Carmeliet P, Montesano R, Wagner EF - J. Cell Biol. (1997)

Bottom Line: In addition, the lack of either uPA or tissue-type PA (tPA) activity is not limiting for the establishment and proliferation of End. cells in vitro, although the combined loss of both PA activities leads to a marked reduction in proliferation rates.Furthermore, the in vitro morphogenetic properties of mutant End. cells in fibrin gels could only be correlated with an altered proteolytic status in cells lacking both uPA and tPA.Thus, genetic alterations in the PA/plasmin system affect vascular tumor development, indicating that this system is a causal component in PymTmediated oncogenesis.

View Article: PubMed Central - PubMed

Affiliation: Research Institute of Molecular Pathology, University of Vienna, A-1030 Vienna, Austria.

ABSTRACT
The middle T antigen of murine Polyomavirus (PymT) rapidly transforms endothelial cells, leading to the formation of vascular tumors in newborn mice. Transformed endothelial (End.) cell lines established from such tumors exhibit altered proteolytic activity as a result of increased expression of urokinase-type plasminogen activator (uPA) and are capable of inducing vascular tumors efficiently when injected into adult mice. In this study we have used mice lacking components of the PA/plasmin system to analyze the role of this system in the transformation process and in tumor growth. We found that the proteolytic status of the host is not a critical determinant for PymT-induced vascular tumor formation. In addition, the lack of either uPA or tissue-type PA (tPA) activity is not limiting for the establishment and proliferation of End. cells in vitro, although the combined loss of both PA activities leads to a marked reduction in proliferation rates. Furthermore, the in vitro morphogenetic properties of mutant End. cells in fibrin gels could only be correlated with an altered proteolytic status in cells lacking both uPA and tPA. However, in contrast with tumors induced by PymT itself, the tumorigenic potential of mutant and wild-type End. cell lines was found to be highly dependent on the proteolytic status of both the tumor cells and the host. Thus, genetic alterations in the PA/plasmin system affect vascular tumor development, indicating that this system is a causal component in PymTmediated oncogenesis.

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PymT virus–induced vascular tumors in newborn mice lacking utPA (A and B) and Plg (C). H/E (A and C) and vWF (B)  staining is shown. (Arrowheads) Endothelial cells lining the tumors. Bar, 50 μm.
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Figure 1: PymT virus–induced vascular tumors in newborn mice lacking utPA (A and B) and Plg (C). H/E (A and C) and vWF (B) staining is shown. (Arrowheads) Endothelial cells lining the tumors. Bar, 50 μm.

Mentions: To determine if PA/plasmin-dependent proteolytic activity is an essential requirement for the formation of vascular tumors by PymT, we inoculated newborn mice lacking uPA, tPA, utPA, PAI-1, or Plg with the PymT transducing retrovirus N-TkmT (Williams et al., 1988). The frequency of tumor formation was almost 100% in all mutant mice tested, and the time required for the development of lethal tumors (latency) varied only slightly (Table I). The high penetrance in Plg−/− mice was unexpected and no delay or inhibition of tumor formation was observed. Most mice were terminally ill within 8–10 d, and only the doublemutant pups lacking uPA and tPA succumbed after a slightly longer period of 12–14 d (Table I). These utPA−/− tumors retained the characteristic morphologic properties of PymT-induced tumors (Fig. 1, A and B). All tumors appeared as blood-filled/hemorrhagic cysts lined by endothelial cells and were not different from similar tumors induced by PymT in control mice (Kiefer et al., 1994b). Representative sections through a typical lesion that formed in a double mutant (utPA−/−) mouse as well as in a Plg−/− mouse are shown in Fig. 1. Staining with anti-vWF antibody shows endothelial cells lining these cysts (Fig. 1 B). These results indicate that the PA/plasmin-dependent proteolytic status of the host is apparently not a critical determinant in the transformation of endothelial cells by PymT and in the formation of vascular tumors in newborn mice.


Polyoma middle T-induced vascular tumor formation: the role of the plasminogen activator/plasmin system.

Sabapathy KT, Pepper MS, Kiefer F, Möhle-Steinlein U, Tacchini-Cottier F, Fetka I, Breier G, Risau W, Carmeliet P, Montesano R, Wagner EF - J. Cell Biol. (1997)

PymT virus–induced vascular tumors in newborn mice lacking utPA (A and B) and Plg (C). H/E (A and C) and vWF (B)  staining is shown. (Arrowheads) Endothelial cells lining the tumors. Bar, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2139839&req=5

Figure 1: PymT virus–induced vascular tumors in newborn mice lacking utPA (A and B) and Plg (C). H/E (A and C) and vWF (B) staining is shown. (Arrowheads) Endothelial cells lining the tumors. Bar, 50 μm.
Mentions: To determine if PA/plasmin-dependent proteolytic activity is an essential requirement for the formation of vascular tumors by PymT, we inoculated newborn mice lacking uPA, tPA, utPA, PAI-1, or Plg with the PymT transducing retrovirus N-TkmT (Williams et al., 1988). The frequency of tumor formation was almost 100% in all mutant mice tested, and the time required for the development of lethal tumors (latency) varied only slightly (Table I). The high penetrance in Plg−/− mice was unexpected and no delay or inhibition of tumor formation was observed. Most mice were terminally ill within 8–10 d, and only the doublemutant pups lacking uPA and tPA succumbed after a slightly longer period of 12–14 d (Table I). These utPA−/− tumors retained the characteristic morphologic properties of PymT-induced tumors (Fig. 1, A and B). All tumors appeared as blood-filled/hemorrhagic cysts lined by endothelial cells and were not different from similar tumors induced by PymT in control mice (Kiefer et al., 1994b). Representative sections through a typical lesion that formed in a double mutant (utPA−/−) mouse as well as in a Plg−/− mouse are shown in Fig. 1. Staining with anti-vWF antibody shows endothelial cells lining these cysts (Fig. 1 B). These results indicate that the PA/plasmin-dependent proteolytic status of the host is apparently not a critical determinant in the transformation of endothelial cells by PymT and in the formation of vascular tumors in newborn mice.

Bottom Line: In addition, the lack of either uPA or tissue-type PA (tPA) activity is not limiting for the establishment and proliferation of End. cells in vitro, although the combined loss of both PA activities leads to a marked reduction in proliferation rates.Furthermore, the in vitro morphogenetic properties of mutant End. cells in fibrin gels could only be correlated with an altered proteolytic status in cells lacking both uPA and tPA.Thus, genetic alterations in the PA/plasmin system affect vascular tumor development, indicating that this system is a causal component in PymTmediated oncogenesis.

View Article: PubMed Central - PubMed

Affiliation: Research Institute of Molecular Pathology, University of Vienna, A-1030 Vienna, Austria.

ABSTRACT
The middle T antigen of murine Polyomavirus (PymT) rapidly transforms endothelial cells, leading to the formation of vascular tumors in newborn mice. Transformed endothelial (End.) cell lines established from such tumors exhibit altered proteolytic activity as a result of increased expression of urokinase-type plasminogen activator (uPA) and are capable of inducing vascular tumors efficiently when injected into adult mice. In this study we have used mice lacking components of the PA/plasmin system to analyze the role of this system in the transformation process and in tumor growth. We found that the proteolytic status of the host is not a critical determinant for PymT-induced vascular tumor formation. In addition, the lack of either uPA or tissue-type PA (tPA) activity is not limiting for the establishment and proliferation of End. cells in vitro, although the combined loss of both PA activities leads to a marked reduction in proliferation rates. Furthermore, the in vitro morphogenetic properties of mutant End. cells in fibrin gels could only be correlated with an altered proteolytic status in cells lacking both uPA and tPA. However, in contrast with tumors induced by PymT itself, the tumorigenic potential of mutant and wild-type End. cell lines was found to be highly dependent on the proteolytic status of both the tumor cells and the host. Thus, genetic alterations in the PA/plasmin system affect vascular tumor development, indicating that this system is a causal component in PymTmediated oncogenesis.

Show MeSH
Related in: MedlinePlus