Urokinase-Type Plasminogen Activator in a Human Sarcoma Cellular Model for Metastasis in Athymic Mice.

摘要

Metastasis, the secondary spread of tumors, accounts for most fatalities in cancer patients, because current treatments do not effectively eradicate the metastatic cells. Focusing on properties that enable metastatic cells to disseminate and colonize may lead to more effective treatment strategies. In search for such property, this work focused on the hypothesis that metastatic competence may depend, in part, on elevated expression of urokinase-type plasminogen activator (uPA), particularly when the enzyme is bound to the surface membrane of the tumor cells. In this configuration, uPA can mediate local matrix proteolysis, leading to tissue degradation, and facilitating invasion and metastasis. To test this hypothesis, a human sarcoma model was developed, which was adequate for quantitative studies of metastasis in-vivo, in athymic mice. Immortalized human osteosarcoma (HOS) cells were transformed with either EJ-ras or v-Ki-ras oncogenes. Several of the transformant sublines could form grossly visible pulmonary tumors when implanted intravenously in athymic mice. The metastatic potential of these sublines correlated with their endogenous uPA activity (r=0.93, p<0.01). This correlation involved mainly the surface-bound uPA rather than the secreted enzyme. Of the transformant sublines, the one designated KRIB was the most efficient in forming experimental lung metastases (75%-88% tumor-bearing mice, median number of 7-10 visible tumors/animal within 35 days post-inoculation). KRIB cells also expressed the highest uPA activity ("20 Plough units/ 10[expn 6] cells), whereas severalother HOS transformants with lower metastatic potential exhibited lower uPA activity (between 4-9 Plough units/10[expn 6] cells). Furthermore, uPA was found to play a functional role in metastasis.