Comparative analysis of metastasis variants derived from human prostate carcinoma cells: roles in intravasation of VEGF-mediated angiogenesis and uPA-mediated invasion.
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.
Conn
Erin M
EM
The Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Botkjaer
Kenneth A
KA
Kupriyanova
Tatyana A
TA
Andreasen
Peter A
PA
Deryugina
Elena I
EI
Quigley
James P
JP
D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002642:Chick Embryo; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000473:pathology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A; D014568:Urokinase-Type Plasminogen Activator