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

Neoplasia. 2011 Sep;13(9):806-21. doi: 10.1593/neo.11704.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Aprotinin / pharmacology
  • Cell Line, Tumor
  • Cell Movement
  • Chick Embryo
  • Enzyme Activation
  • Fibrinolysin / metabolism*
  • Fibronectins / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Metastasis*
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Serine Proteinase Inhibitors / pharmacology
  • Transplantation, Heterologous
  • Tumor Escape
  • Urokinase-Type Plasminogen Activator / immunology
  • Urokinase-Type Plasminogen Activator / metabolism*


  • Antibodies, Monoclonal
  • Fibronectins
  • Serine Proteinase Inhibitors
  • Aprotinin
  • Fibrinolysin
  • Urokinase-Type Plasminogen Activator