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The Rochelle Belfer Chemotherapy Foundation Laboratory, Department of Medicine, Division of Neoplastic Diseases, Mount
Sinai School of Medicine, New York 10029
Considerable evidence links urokinase plasminogen activator (uPA) bound to its surface receptor
(uPAR) with enhanced invasiveness of cancer cells. By
blocking uPAR expression in human epidermoid carcinoma cells (HEp3), we have now identified an additional and novel in vivo function for this receptor by
showing that receptor-deficient cells enter a state of
dormancy reminiscent of that observed in human cancer metastasis. Its main characteristic is survival without signs of progressive growth. Five clones transfected
with a vector expressing uPAR antisense RNA under
the 
-actin promoter were isolated and shown to have
uPAR (at the mRNA and protein levels) reduced by 50 to 80%; four clones, transfected with vector alone and
having uPAR levels similar to those of parental cells,
served as controls. In confirmation of our previous results, reduced uPAR always coincided with a significantly reduced invasiveness. Each of the control clones
produced rapidly growing, highly metastatic tumors
within 2 wk of inoculation on chorioallantoic membranes (CAMs) of chick embryos. In contrast, each of
the clones with low surface uPAR, whose proliferation
rate in culture was indistinguishable from controls, remained dormant for up to 5 mo when inoculated on
CAMs. Thus, the reduction in uPAR altered the phenotype of HEp3 tumor cells from tumorigenic to dormant. Although protracted, tumor dormancy was not
permanent since in spite of maintaining low uPAR levels, each of the in vivo-passaged antisense clones eventually reemerged from dormancy to initiate progressive
growth and to form metastases at a level of 20 to 90%
of that of fully malignant control. This observation suggested that other factors, whose expression is dependent on cumulative and prolonged in vivo effects, can
compensate for the lack of a full complement of surface uPAR required for the expression of malignant properties. These "reemerged," uPAR-deficient clones were
easily distinguishable from the vector-transfected controls by the fact that after only 1 wk in culture, the invasion of CAM by all five clones and tumorigenicity of
four of the five clones were reduced back to the values
observed before in vivo maintenance. In contrast, dissociated and in vitro-grown cells of control tumors
were fully invasive and produced large, metastatic tumors when reinoculated on CAMs. Quantitation of the percent of apoptotic and S-phase cells in vivo, in the
control and uPAR-deficient, dormant clones, showed
that the mechanism responsible for the dormancy was a
diminished proliferation.
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