Plasticity in urokinase-type plasminogen activator receptor (uPAR) display in colon cancer yields metastable subpopulations oscillating in cell surface uPAR density--implications in tumor progression.
It is becoming increasingly clear that tumor growth and progression is not entirely due to genetic aberrations but also reflective of tumor cell plasticity. It follows therefore that proteins contributing to tumor progression oscillate in their expression a contention yet to be shown. Because the urokinase-type plasminogen activator receptor (uPAR) promotes tumor growth and invasion, we determined whether its expression is itself plastic. In fluorescence-activated cell sorting (FACS), three independent colon cancer clonal populations revealed the expected Gaussian distribution for cell surface uPAR display. However, subcloning of cells collected from the trailing edge of the FACS yielded subpopulations, displaying low cell surface uPAR number. Importantly, these subclones spontaneously reverted to cells enriched in uPAR display, indicating a metastable phenotype. uPAR display plasticity was associated with divergent in vivo behavior with weak tumor growth and progression segregating with receptor deficiency. Mechanistically, reduced uPAR display reflected not repressed gene expression but a switch in uPAR protein trafficking from membrane insertion to shedding. To our knowledge, this is the first demonstration that uPAR cell surface density is oscillatory and we propose that such an event might well contribute to tumor progression.
Yang
Lin
L
Department of Cancer Biology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Avila
Hector
H
Wang
Heng
H
Trevino
Jose
J
Gallick
Gary E
GE
Kitadai
Yasuhiko
Y
Sasaki
Takamitsu
T
Boyd
Douglas D
DD
D017398:Alternative Splicing; D002455:Cell Division; D002999:Clone Cells; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005434:Flow Cytometry; D006801:Humans; D011956:Receptors, Cell Surface / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic
D017931:DNA Primers; D004273:DNA, Neoplasm; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator