Lack of correlation between tumorigenicity and level of plasminogen activator in fibroblasts transformed by Rous sarcoma virus

Wolf, B.; Goldberg, Andrew V.

doi:10.1073/pnas.75.10.4967

Cited by 18 publications

(8 citation statements)

References 33 publications

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“…Thus, it is possible that release of this factor may be involved in transformation, either through a plasminogen activator-mediated proteolysis or by a transformation-induced stimulation of endogenous membrane proteases. It must be pointed out, however, that the correlation between plasminogen activator release and transformation is still controversial (Wolf and Goldberg, 1978). In any event, these questions can be answered once the factor has been purified and its receptors identified.…”

Section: Discussionmentioning

confidence: 99%

Mitogenic proteins of the 3T3 plasma membrane

Lieberman¹

1983

Journal Cellular Physiology

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A mitogenic factor from 3T3 plasma membranes has been identified and partially characterized. The factor appears to be a peripheral membrane protein that can be released by mild trypsin, chymotrypsin, or plasmin treatment. This component is sensitive to heat and acid, and has a molecular weight in the range of 150,000-200,000 daltons as determined by gel filtration. A similar mitogenic activity has also been found on the membranes of both SV-40-transformed 3T3 cells and human fibroblasts. The factor appears to be distinct from all previously described mitogenic components.

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Section: Discussionmentioning

confidence: 99%

Mitogenic proteins of the 3T3 plasma membrane

Lieberman¹

1983

Journal Cellular Physiology

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“…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%

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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“…While not re quired for the transformed phenotype [4,5], such enzymes have been implicated in the process of invasion and metastasis [1][2][3]6]. In addition to tumor cells, some normal cells such as macrophages and polymorphonu clear leukocytes can contribute proteinases to the extracellular environment when they are stimulated [7,8].…”

Section: Introductionmentioning

confidence: 99%

<i>Corynebacterium parvu</i><i>m</i>, but not BCG, Induces Elevations in Plasma Proteinase Activity Similar to Those Observed in Tumor-Bearing Mice

Hart¹

1987

Pathophysiol Haemos Thromb

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Intraperitoneal administration of Corynebacterium parvum to BALB/c, C57B1/6 or C3H/HeJ mice lead to the induction of elevated levels of neutral proteinase activity (¹²⁵I-caseinolytic activity) similar to those observed previously in animals bearing the BCL₁ leukemia or the B16-F10 melanoma. Enhanced activity reached a peak at 7–14 days postin-jection of the C. parvum and then gradually returned to normal levels by 20–25 days postin-jection. Increased plasma proteinase activity could be induced by C. parvum whole cells or the pyridine extract residue of C. parvum but not by BCG or the pyridine extract of C. parvum. BCG did not interfere with the induction of elevated levels of activity by C. parvum. Splenectomized animals responded the same as normal mice indicating that the splenomegaly accompanying the onset of increased plasma proteinase activity was not responsible for the changes. Administration of C. parvum via a subcutaneous site rather than intraperitoneally failed to induce systemic changes in proteinase activity while still inducing splenomegaly. Treatment of animals with C. parvum before or after transplantation of the BCL₁ leukemia or the B16-F10 melanoma failed to alter the course of the disease or enhance the increased proteinase activity of plasma over that observed in plasma from animals bearing tumors alone. These observations support the hypothesis that the induction of disturbances in plasma proteinase activity in tumor-bearing animals is due to alterations in host systems and that C. parvum, in contrast to BCG, contains components which can mimic the effect of some tumors on host systems.

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Lack of correlation between tumorigenicity and level of plasminogen activator in fibroblasts transformed by Rous sarcoma virus

Cited by 18 publications

References 33 publications

Mitogenic proteins of the 3T3 plasma membrane

Mitogenic proteins of the 3T3 plasma membrane

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

<i>Corynebacterium parvu</i><i>m</i>, but not BCG, Induces Elevations in Plasma Proteinase Activity Similar to Those Observed in Tumor-Bearing Mice

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