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Comparative analysis of metastasis variants derived from human prostate carcinoma cells: roles in intravasation of VEGF-mediated angiogenesis and uPA-mediated invasion

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  • Erin M Conn
  • ,
  • Kenneth Alrø Bøtkjær
  • ,
  • Tatyana A Kupriyanova
  • ,
  • Peter A Andreasen, Denmark
  • Elena I Deryugina
  • ,
  • James P Quigley
To analyze the process of tumor cell intravasation, we used the human tumor-chick embryo spontaneous metastasis model to select in vivo high (PC-hi/diss) and low (PC-lo/diss) disseminating variants from the human PC-3 prostate carcinoma cell line. These variants dramatically differed in their intravasation and dissemination capacities in both chick embryo and mouse spontaneous metastasis models. Concomitant with enhanced intravasation, PC-hi/diss exhibited increased angiogenic potential in avian and murine models. PC-hi/diss angiogenesis and intravasation were dependent on increased secretion of vascular endothelial growth factor (VEGF), since treating developing tumors with a function-blocking anti-VEGF antibody simultaneously inhibited both processes without affecting primary tumor growth. PC-hi/diss cells were also more migratory and invasive, suggestive of heightened ability to escape from primary tumors due to matrix-degrading activity. Consistent with this suggestion, PC-hi/diss cells produced more of the serine protease urokinase-type plasminogen activator (uPA) as compared with PC-lo/diss. The functional role of uPA in PC-hi/diss dissemination was confirmed by inhibition of invasion, angiogenesis, and intravasation with specific function-blocking antibodies that prevented uPA activation and blocked uPA activity. These processes were similarly sensitive to aprotinin, a potent inhibitor of serine proteases, including uPA-generated plasmin. Thus, our comparison of the PC-3 intravasation variants points to key roles for the uPA-plasmin system in PC-hi/diss intravasation, possibly via (1) promoting tumor cell matrix invasion and (2) facilitating development of VEGF-dependent angiogenic blood vessels.
Original languageEnglish
JournalAmerican Journal of Pathology
Pages (from-to)1638-52
Number of pages15
Publication statusPublished - 1 Oct 2009

    Research areas

  • Animals, Cell Adhesion, Cell Line, Tumor, Cell Movement, Chick Embryo, Disease Models, Animal, Humans, Male, Mice, Neoplasm Invasiveness, Neoplasm Metastasis, Neovascularization, Pathologic, Prostatic Neoplasms, Urokinase-Type Plasminogen Activator, Vascular Endothelial Growth Factor A

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