Rous-sarcoma-virus-transformed fibroblasts having low levels of plasminogen activator.

Wolf, B.; Goldberg, Andrew V.

doi:10.1073/pnas.73.10.3613

Cited by 31 publications

(12 citation statements)

References 30 publications

(22 reference statements)

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“…Protease activity has also been theorized to be the basis for growth of transformed cells in semisolid medium (2,7,10,11,16,22). Shin and coworkers demonstrated that tumorigenicity of virus-transformed cells in nude mice correlated specifically with anchorage-independent growth in vitro (20).…”

Section: Discussionmentioning

confidence: 99%

“…However, studies investigating the in vitro properties of chemically transformed hamster cells and human osteosarcoma cells show negative correlations between PA production and growth in semisolid agar (2,11). Cell clones selected from Rous sarcoma virus-transformed fibroblasts grown in soft agar show a variability in PA levels, but no difference in tumorigenic potential (22,23). It has also been shown that PA production is not sufficient to cause the absence of large external transformation-sensitive (LETS) protein (15).…”

Section: Discussionmentioning

confidence: 99%

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Tumorigenicity of herpesvirus-transformed cells correlates with production of plasminogen activator.

1981

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Our studies first demonstrated that established hamster cell lines transformed in vitro by herpesviruses activate plasminogen more effectively than normal hamster fibroblasts. This ability is probably due to increased levels of the enzyme plasminogen activator (PA). In the studies described here, the 333-8-9 cell line, originally transformed by herpes simplex virus type 2 strain 333, was used to derive subclonal lines that maintained stable PA phenotypes over the course of long in vitro passage. We were interested in correlating tumor formation by the subclones with their fibrinolytic capacity. Cells were, therefore, single-cell subcloned twice, and resulting cultures were tested for ability to activate plasminogen in vitro. PA activity was then quantitated by [I251]fibrin lysis assay, and high-and low-activity subclones were isolated; these retained high-or low-activity phenotypes. Syngeneic newborn hamsters were inoculated with these subclones and observed for the appearance of palpable tumors. A strong correlation between enzyme activity and tumor formation was observed in four separate trials; animals receiving high-PA subclones developed tumors more rapidly than those inoculated with the parental cell line. Tumors were also excised from test animals, and the cell lines established from the tumors were tested in vitro at different passages for their ability to activate plasminogen. These tumor cells were then reinoculated into syngeneic animals to confirm the tumorigenicity of cell lines with high fibrinolytic activity. In these experiments, the positive correlation between PA production and tumorigenicity was confirmed.Plasminogen activator (PA) is a serine protease which activates plasminogen to plasmin, a fibrinolytic enzyme (21). Many different cell types produce PA; certain types of normal cells, cells transformed by chemicals or viruses, and tumor cells exhibit relatively high enzyme levels (7,14,21). Cell types that produce elevated levels of PA are generally invasive, which may be a direct result of their ability to generate protease activity and consequently to disrupt the surrounding tissue milieu (13).We have demonstrated that herpesvirustransformed cells activate plasminogen more efficiently than hamster embryo fibroblasts. These studies include cells transformed by herpes simplex virus types 1 or 2 (HSV-1, HSV-2) or cytomegalovirus (1, 9,24). Because hamster cell lines transformed by HSV-1 or HSV-2 also produce metastatic tumors when inoculated into syngeneic animals (5, 6), we wanted to assess the relationship between PA production and the tumorigenic potential of the herpesvirus-transformed cells. We selected a hamster cell line transformed by partially inactivated HSV-2 strain 333 for these experiments because we had utilized this cell line and virus strain previously (1, 5) and because it is known to produce metastatic lung nodules in an experimental hamster system (17).Other investigators have attempted to correlate PA activity with transformation and tumorigenicity in other animal systems...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tumorigenicity of herpesvirus-transformed cells correlates with production of plasminogen activator.

1981

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“…Some normal cells have high levels of PA activity (1)(2)(3)28). For some clonal isolates of tumorigenic cell lines, no correlation between levels of PA activity and malignant transformation has been observed (8,15,27,31). Studies of a human epidermal carcinoma that metastasizes with a high efficiency into the organs of chicken embryos have shown that anchorage independence and serum independence inversely correlate with metastatic ability and tumorigenicity but directly correlate with enhanced levels of PA activity (19,20 (20).…”

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confidence: 99%

Modulation of the Plasminogen Activator Activity of a Transformed Cell Line by Cell Density

1982

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The effects of variations in cell density on the expression of the plasminogen activator activity of a tumorigenic rat cell line were analyzed. At low cell densities, the plasminogen activator activity per cell was high and independent of cell density. As the cell density increased, the plasminogen activator activity per cell decreased until it eventually became inversely proportional to cell density. Inhibition of the plasminogen activator activity per cell by increases in cell density was not the result of the presence of a soluble inhibitor but seemed to require cellto-cell contact. The Vmax per cell for the activation of plasminogen changed at high cell densities, but the Km did not change. This change in the Vmax per cell was in part the result of a change in the catalytic rate constant for the conversion of plasminogen to plasmin. This was inferred from studies on the kinetics of inhibition of plasminogen activator activity by diisopropyl fluorophosphate as a function of cell density. For cells growing at high densities, the rate of inhibition was constant, exhibiting a second-order rate constant of 2.6 x 10-2 M-1 s-1. For cells growing at low densities, the plasminogen activator activity was inhibited at two different rates, one exhibiting a second-order rate constant of 2.6 x 10-2 MW-I s-i and the other exhibiting a second-order rate constant of 9.4 x 10-2 M-l s-1.We discuss the importance of cell density in assays of the plasminogen activator activity of cells, the use of this cell line to study the biochemical basis of the density dependence of plasminogen activator activity, and the density-dependent role of plasminogen activator activity in tumor formation and metastasis.

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“…They have reported the appearance of plasminogen activator in cell cultures associated with oncogenic transformation, although Mott et al (1974) and Wolf & Goldberg (1976) revealed lack of correlation in established cell lines. Rosenthal et al (1977) and Nagy et al (1977) showed that fibrinolytic activity Qf cancer cells was very varied, and that it was closely associated with the passage history of the cultured cells.…”

Section: Discussionmentioning

confidence: 99%

Thromboplastic and fibrinolytic activities of cultured human cancer cell lines

Kinjo¹,

Oka²,

Naito³

et al. 1979

Br J Cancer

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Thromboplastic and fibrinolytic activities of 14 lines of cultured human cancer cells were estimated by modified Astrup's methods. High tissue thromboplastic activity was found in one line of urinary-bladder cancer, 2 lines of gastric cancer and one line of lung cancer, but no activity was found in 6 lines of lung cancer. High fibrinolytic activity was noted in one line of gastric cancer and 2 lines of lung cancer, but no activity was seen in 6 lines of lung cancer and one line of gastric cancer. No plasmin activity was found. The tumour cell lines could be classified into 3 groups on the basis of the 2 activities. Cancer cell lines could also be classified into 2 groups: with high or low release of thromboplastin into culture media. Fibrinolytic activity was found in the culture media of all cell lines with high fibrinolytic activity. Fibrinolytic activity, but not thromboplastic activity, seemed to be influenced by the constituents of culture media. No definite correlation was found between the 2 activities and the histological types of the parent tumours of the cultured cells. Images Fig. 1 Fig. 2 Fig. 3

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Rous-sarcoma-virus-transformed fibroblasts having low levels of plasminogen activator.

Cited by 31 publications

References 30 publications

Tumorigenicity of herpesvirus-transformed cells correlates with production of plasminogen activator.

Tumorigenicity of herpesvirus-transformed cells correlates with production of plasminogen activator.

Modulation of the Plasminogen Activator Activity of a Transformed Cell Line by Cell Density

Thromboplastic and fibrinolytic activities of cultured human cancer cell lines

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