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Activation of pro-uPA is critical for initial escape from the primary tumor and hematogenous dissemination of human carcinoma cells.

ABSTRACT: Urokinase-type plasminogen activator (uPA) and plasmin have long been implicated in cancer progression. However, the precise contributions of the uPA/plasmin system to specific steps involved in cancer cell dissemination have not been fully established. Herein, we have used a highly disseminating variant of the human PC-3 prostate carcinoma cell line, PC-hi/diss, as a prototype of aggressive carcinomas to investigate the mechanisms whereby pro-uPA activation and uPA-generated plasmin functionally contribute to specific stages of metastasis. The PC-hi/diss cells secrete and activate significant amounts of pro-uPA, leading to efficient generation of plasmin in solution and at the cell surface. In a mouse orthotopic xenograft model, treatment with the specific pro-uPA activation-blocking antibody mAb-112 significantly inhibited local invasion and distant metastasis of the PC-hi/diss cells. To mechanistically examine the uPA/plasmin-mediated aspects of tumor cell dissemination, the anti-pro-uPA mAb-112 and the potent serine protease inhibitor, aprotinin, were used in parallel in a number of in vivo assays modeling various rate-limiting steps in early metastatic spread. Our findings demonstrate that, by generating plasmin, activated tumor-derived uPA facilitates early stages of PC-hi/diss dissemination, specifically the escape from the primary tumor and tumor cell intravasation. Moreover, through a series of in vitro and in vivo analyses, we suggest that PC-hi/diss-invasive escape and dissemination may be enhanced by cleavage of stromal fibronectin by uPA-generated plasmin. Together, our findings point to inhibition of pro-uPA activation at the apex of the uPA/plasmin cascade as a therapy-valid approach to control onset of tumor escape and ensuing metastatic spread.

SUBMITTER: Bekes EM

PROVIDER: S-EPMC3182273 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Activation of pro-uPA is critical for initial escape from the primary tumor and hematogenous dissemination of human carcinoma cells.

Bekes Erin M EM Deryugina Elena I EI Kupriyanova Tatyana A TA Zajac Ewa E Botkjaer Kenneth A KA Andreasen Peter A PA Quigley James P JP

Neoplasia (New York, N.Y.) 20110901 9

Urokinase-type plasminogen activator (uPA) and plasmin have long been implicated in cancer progression. However, the precise contributions of the uPA/plasmin system to specific steps involved in cancer cell dissemination have not been fully established. Herein, we have used a highly disseminating variant of the human PC-3 prostate carcinoma cell line, PC-hi/diss, as a prototype of aggressive carcinomas to investigate the mechanisms whereby pro-uPA activation and uPA-generated plasmin functionall ...[more]

PMID: 21969814

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Dataset Information

Activation of pro-uPA is critical for initial escape from the primary tumor and hematogenous dissemination of human carcinoma cells.

Publications

Activation of pro-uPA is critical for initial escape from the primary tumor and hematogenous dissemination of human carcinoma cells.

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