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The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies.

Bajou K, Masson V, Gerard RD, Schmitt PM, Albert V, Praus M, Lund LR, Frandsen TL, Brunner N, Dano K, Fusenig NE, Weidle U, Carmeliet G, Loskutoff D, Collen D, Carmeliet P, Foidart JM, Noël A - J. Cell Biol. (2001)

Bottom Line: Paradoxically, however, high levels of PA inhibitor 1 (PAI-1) are predictive of a poor prognosis for survival of patients with cancer.We anticipated that PAI-1 facilitated endothelial cell migration via its known interaction with vitronectin (VN) and integrins.Single deficiency of uPA, tissue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies of uPA and tPA did not impair tumor angiogenesis, whereas lack of Plg reduced it.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Tumor and Developmental Biology, University of Liège, Tour de Pathologie (B23), B-4000 Liège, Belgium.

ABSTRACT
The plasminogen (Plg)/plasminogen activator (PA) system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumor cell migration. Consequently, urokinase-type PA (uPA)/plasmin antagonists are currently being developed for suppression of tumor growth and angiogenesis. Paradoxically, however, high levels of PA inhibitor 1 (PAI-1) are predictive of a poor prognosis for survival of patients with cancer. We demonstrated previously that PAI-1 promoted tumor angiogenesis, but by an unresolved mechanism. We anticipated that PAI-1 facilitated endothelial cell migration via its known interaction with vitronectin (VN) and integrins. However, using adenoviral gene transfer of PAI-1 mutants, we observed that PAI-1 promoted tumor angiogenesis, not by interacting with VN, but rather by inhibiting proteolytic activity, suggesting that excessive plasmin proteolysis prevents assembly of tumor vessels. Single deficiency of uPA, tissue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies of uPA and tPA did not impair tumor angiogenesis, whereas lack of Plg reduced it. Overall, these data indicate that plasmin proteolysis, even though essential, must be tightly controlled during tumor angiogenesis, probably to allow vessel stabilization and maturation. These data provide insights into the clinical paradox whereby PAI-1 promotes tumor progression and warrant against the uncontrolled use of uPA/plasmin antagonists as tumor angiogenesis inhibitors.

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Invasive behavior of malignant mouse keratinocytes (PDVA cells), 2 wk after implantation. In WT (a), uPA−/− (b), tPA−/− (c), tPA−/−/uPA−/− (d), and uPAR−/− (e) mice, the collagen gel has been remodelled and malignant cells formed tumor sprouts intermingled with host tissue. The dotted line delineates the bottom of the collagen gel in Plg−/− (f) and PAI-1−/− mice (g). Histological sections were stained with hematoxylin and eosin. C, carcinoma cells; G, collagen gel; H, host connective tissue. Bar, 100 μm.
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Figure 1: Invasive behavior of malignant mouse keratinocytes (PDVA cells), 2 wk after implantation. In WT (a), uPA−/− (b), tPA−/− (c), tPA−/−/uPA−/− (d), and uPAR−/− (e) mice, the collagen gel has been remodelled and malignant cells formed tumor sprouts intermingled with host tissue. The dotted line delineates the bottom of the collagen gel in Plg−/− (f) and PAI-1−/− mice (g). Histological sections were stained with hematoxylin and eosin. C, carcinoma cells; G, collagen gel; H, host connective tissue. Bar, 100 μm.

Mentions: Malignant murine keratinocytes (PDVA cells; Fusenig et al. 1978) cultured on a collagen gel were implanted onto the dorsal muscle fascia of WT and transgenic mice. In response to angiogenic stimuli (produced by tumor cells; Skobe et al. 1997), new blood vessels formed in the underlying stroma, invaded the collagen gel, and reached the malignant epithelial layer. Thereafter, the malignant keratinocytes formed tumor sprouts that invaded downwards into the granulation tissue (Fig. 1 a). Within 2 wk after transplantation, these tumor islets were intermingled with closely apposed new vessels. The degree of tumor cell invasion was scored by calculating the average distance over which the tumor cells infiltrated in the host mesenchyme, whereas tumor angiogenesis was semiquantitatively scored after staining for collagen type IV, a component of the capillary basement membrane (Fig. 2 a). Compared with WT mice, tumor angiogenesis (score +++) developed to a similar degree and invasion of tumor cells occurred over a similar distance (>150 μm, ++ or +++) in uPA−/−, tPA−/−, uPAR−/− mice, and double tPA−/−/uPA−/− mice (Fig. 1, b–e, and Fig. 2, b–e). Both tumor invasion and stromal angiogenesis were reduced in Plg−/− mice (Table , Fig. 1 f and 2 f).


The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies.

Bajou K, Masson V, Gerard RD, Schmitt PM, Albert V, Praus M, Lund LR, Frandsen TL, Brunner N, Dano K, Fusenig NE, Weidle U, Carmeliet G, Loskutoff D, Collen D, Carmeliet P, Foidart JM, Noël A - J. Cell Biol. (2001)

Invasive behavior of malignant mouse keratinocytes (PDVA cells), 2 wk after implantation. In WT (a), uPA−/− (b), tPA−/− (c), tPA−/−/uPA−/− (d), and uPAR−/− (e) mice, the collagen gel has been remodelled and malignant cells formed tumor sprouts intermingled with host tissue. The dotted line delineates the bottom of the collagen gel in Plg−/− (f) and PAI-1−/− mice (g). Histological sections were stained with hematoxylin and eosin. C, carcinoma cells; G, collagen gel; H, host connective tissue. Bar, 100 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195770&req=5

Figure 1: Invasive behavior of malignant mouse keratinocytes (PDVA cells), 2 wk after implantation. In WT (a), uPA−/− (b), tPA−/− (c), tPA−/−/uPA−/− (d), and uPAR−/− (e) mice, the collagen gel has been remodelled and malignant cells formed tumor sprouts intermingled with host tissue. The dotted line delineates the bottom of the collagen gel in Plg−/− (f) and PAI-1−/− mice (g). Histological sections were stained with hematoxylin and eosin. C, carcinoma cells; G, collagen gel; H, host connective tissue. Bar, 100 μm.
Mentions: Malignant murine keratinocytes (PDVA cells; Fusenig et al. 1978) cultured on a collagen gel were implanted onto the dorsal muscle fascia of WT and transgenic mice. In response to angiogenic stimuli (produced by tumor cells; Skobe et al. 1997), new blood vessels formed in the underlying stroma, invaded the collagen gel, and reached the malignant epithelial layer. Thereafter, the malignant keratinocytes formed tumor sprouts that invaded downwards into the granulation tissue (Fig. 1 a). Within 2 wk after transplantation, these tumor islets were intermingled with closely apposed new vessels. The degree of tumor cell invasion was scored by calculating the average distance over which the tumor cells infiltrated in the host mesenchyme, whereas tumor angiogenesis was semiquantitatively scored after staining for collagen type IV, a component of the capillary basement membrane (Fig. 2 a). Compared with WT mice, tumor angiogenesis (score +++) developed to a similar degree and invasion of tumor cells occurred over a similar distance (>150 μm, ++ or +++) in uPA−/−, tPA−/−, uPAR−/− mice, and double tPA−/−/uPA−/− mice (Fig. 1, b–e, and Fig. 2, b–e). Both tumor invasion and stromal angiogenesis were reduced in Plg−/− mice (Table , Fig. 1 f and 2 f).

Bottom Line: Paradoxically, however, high levels of PA inhibitor 1 (PAI-1) are predictive of a poor prognosis for survival of patients with cancer.We anticipated that PAI-1 facilitated endothelial cell migration via its known interaction with vitronectin (VN) and integrins.Single deficiency of uPA, tissue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies of uPA and tPA did not impair tumor angiogenesis, whereas lack of Plg reduced it.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Tumor and Developmental Biology, University of Liège, Tour de Pathologie (B23), B-4000 Liège, Belgium.

ABSTRACT
The plasminogen (Plg)/plasminogen activator (PA) system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumor cell migration. Consequently, urokinase-type PA (uPA)/plasmin antagonists are currently being developed for suppression of tumor growth and angiogenesis. Paradoxically, however, high levels of PA inhibitor 1 (PAI-1) are predictive of a poor prognosis for survival of patients with cancer. We demonstrated previously that PAI-1 promoted tumor angiogenesis, but by an unresolved mechanism. We anticipated that PAI-1 facilitated endothelial cell migration via its known interaction with vitronectin (VN) and integrins. However, using adenoviral gene transfer of PAI-1 mutants, we observed that PAI-1 promoted tumor angiogenesis, not by interacting with VN, but rather by inhibiting proteolytic activity, suggesting that excessive plasmin proteolysis prevents assembly of tumor vessels. Single deficiency of uPA, tissue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies of uPA and tPA did not impair tumor angiogenesis, whereas lack of Plg reduced it. Overall, these data indicate that plasmin proteolysis, even though essential, must be tightly controlled during tumor angiogenesis, probably to allow vessel stabilization and maturation. These data provide insights into the clinical paradox whereby PAI-1 promotes tumor progression and warrant against the uncontrolled use of uPA/plasmin antagonists as tumor angiogenesis inhibitors.

Show MeSH
Related in: MedlinePlus