An autocrine loop directed by the vascular endothelial growth factor promotes invasiveness of human melanoma cells.
The vascular endothelial growth factor-A (VEGF-A) is a cytokine that promotes angiogenesis through the activation of two tyrosine kinase receptors, VEGFR-1 and VEGFR-2, on vascular endothelial cells. Moreover, several experimental evidences indicate that VEGF-A may also play a role in tumor progression by acting on neoplastic cells expressing VEGFRs. In this study we show that human melanoma cells that simultaneously produce VEGF-A and express VEGFRs exhibit a higher spontaneous ability to invade the extracellular matrix (ECM) than melanoma cells not expressing either VEGF-A or VEGFRs. Exposure of VEGFR expressing melanoma cells to exogenous VEGF-A further increases their ability to invade the ECM. Moreover, an inhibitor of VEGFR tyrosine kinase activity is able to abrogate VEGF-A-induced stimulation of ECM invasion. A cell clone (13443/N2) derived from a VEGF-A responsive melanoma cell line and expressing high levels of VEGFR-2 invades the ECM eight-fold more efficiently than a cell clone derived from the same cell line and expressing extremely low levels of the receptor. Exposure of 13443/N2 cells to VEGF-E, which selectively binds and activates VEGFR-2, increases their ability to invade the ECM. Finally, the expression of the VEGF-A mRNA antisense sequence in 13443/N2 cells markedly reduces the release of VEGF-A and ECM invasion. In conclusion, our data show for the first time that a VEGF-A-driven autocrine loop promotes human melanoma cell ability to invade the ECM, and strongly support the hypothesis that activation of VEGFR-2 plays a primary role in this process.
Lacal
Pedro Miguel
PM
Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata-IRCCS, I-00167 Rome, Italy. p.lacal@idi.it
Ruffini
Federica
F
Pagani
Elena
E
D'Atri
Stefania
S
D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009361:Neoplasm Invasiveness; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000502:physiology
D016376:Oligonucleotides, Antisense; D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2