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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

Academic Article
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Overview

authors

  • Conn, E. M.
  • Botkjaer, K. A.
  • Kupriyanova, T. A.
  • Andreasen, P. A.
  • Deryugina, Elena
  • Quigley, James

publication date

  • October 2009

journal

  • American Journal of Pathology  Journal

abstract

  • 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.

subject 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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Identity

PubMed Central ID

  • PMC2751560

International Standard Serial Number (ISSN)

  • 0002-9440

Digital Object Identifier (DOI)

  • 10.2353/ajpath.2009.090384

PubMed ID

  • 19729488
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Additional Document Info

start page

  • 1638

end page

  • 1652

volume

  • 175

issue

  • 4

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