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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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Proposed model depicting the formation of PymT-induced  vascular tumors in newborn mice (A) and the formation of End.  cell–induced vascular tumors in adult mice using mutant cell lines  and mutant mice (B). The black box indicates the tumor. The arrows in B indicate the nature of the injected End. cells and the recipient mice, i.e., (dashed arrows) demonstrate that the transfer  of wild-type End. cells into uPA−/− mice gives rise to vascular  tumors in only 25% of the mice; in contrast, no tumors developed  when utPA−/− End. cells were injected into uPA−/− mice  (solid arrows). The intensity of the lines in B (right) represents  the extent of host cell interaction with the injected End. cells.
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Figure 7: Proposed model depicting the formation of PymT-induced vascular tumors in newborn mice (A) and the formation of End. cell–induced vascular tumors in adult mice using mutant cell lines and mutant mice (B). The black box indicates the tumor. The arrows in B indicate the nature of the injected End. cells and the recipient mice, i.e., (dashed arrows) demonstrate that the transfer of wild-type End. cells into uPA−/− mice gives rise to vascular tumors in only 25% of the mice; in contrast, no tumors developed when utPA−/− End. cells were injected into uPA−/− mice (solid arrows). The intensity of the lines in B (right) represents the extent of host cell interaction with the injected End. cells.

Mentions: In conclusion, our studies have revealed that the pathogenesis of PymT-induced and End. cell–induced tumors is inherently different. In the former, the PymT virus infects endothelial cells in an existing vascular tree without the requirement for the PA/plasmin system in the initial transformation process (Fig. 7 A). Therefore, PymT-mediated vascular tumor formation appears to be PA/plasmin independent. On the other hand, in End. cell–induced tumors, the injected cells first have to invade host tissues and the basement membrane of existing blood vessels to gain access to the circulation to integrate within host vessels. This invasive process, which is reminiscent of tumor cell intravasation into the vascular tree, is dependent on both the host's and invading tumor cell's PA/plasmin status (Fig. 7 B). In addition, proliferation is impaired in cells entirely lacking PA activity. Defects in both invasion and proliferation, both of which appear to be PA dependent, are therefore likely responsible for the reduction in End. cell–induced tumor growth. Whether other proteases such as the MMPs, which have been shown to be involved in vascular tumor formation in vivo (Taraboletti et al., 1995), may play a role in this process has to be investigated in future experiments.


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)

Proposed model depicting the formation of PymT-induced  vascular tumors in newborn mice (A) and the formation of End.  cell–induced vascular tumors in adult mice using mutant cell lines  and mutant mice (B). The black box indicates the tumor. The arrows in B indicate the nature of the injected End. cells and the recipient mice, i.e., (dashed arrows) demonstrate that the transfer  of wild-type End. cells into uPA−/− mice gives rise to vascular  tumors in only 25% of the mice; in contrast, no tumors developed  when utPA−/− End. cells were injected into uPA−/− mice  (solid arrows). The intensity of the lines in B (right) represents  the extent of host cell interaction with the injected End. cells.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 7: Proposed model depicting the formation of PymT-induced vascular tumors in newborn mice (A) and the formation of End. cell–induced vascular tumors in adult mice using mutant cell lines and mutant mice (B). The black box indicates the tumor. The arrows in B indicate the nature of the injected End. cells and the recipient mice, i.e., (dashed arrows) demonstrate that the transfer of wild-type End. cells into uPA−/− mice gives rise to vascular tumors in only 25% of the mice; in contrast, no tumors developed when utPA−/− End. cells were injected into uPA−/− mice (solid arrows). The intensity of the lines in B (right) represents the extent of host cell interaction with the injected End. cells.
Mentions: In conclusion, our studies have revealed that the pathogenesis of PymT-induced and End. cell–induced tumors is inherently different. In the former, the PymT virus infects endothelial cells in an existing vascular tree without the requirement for the PA/plasmin system in the initial transformation process (Fig. 7 A). Therefore, PymT-mediated vascular tumor formation appears to be PA/plasmin independent. On the other hand, in End. cell–induced tumors, the injected cells first have to invade host tissues and the basement membrane of existing blood vessels to gain access to the circulation to integrate within host vessels. This invasive process, which is reminiscent of tumor cell intravasation into the vascular tree, is dependent on both the host's and invading tumor cell's PA/plasmin status (Fig. 7 B). In addition, proliferation is impaired in cells entirely lacking PA activity. Defects in both invasion and proliferation, both of which appear to be PA dependent, are therefore likely responsible for the reduction in End. cell–induced tumor growth. Whether other proteases such as the MMPs, which have been shown to be involved in vascular tumor formation in vivo (Taraboletti et al., 1995), may play a role in this process has to be investigated in future experiments.

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