TY - JOUR
T1 - An autocrine loop directed by the vascular endothelial growth factor promotes invasiveness of human melanoma cells
AU - Lacal, Pedro Miguel
AU - Ruffini, Federica
AU - Pagani, Elena
AU - D'Atri, Stefania
PY - 2005/12
Y1 - 2005/12
N2 - 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.
AB - 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.
KW - Melanoma metastatisation
KW - VEGF
KW - VEGFR-2
UR - http://www.scopus.com/inward/record.url?scp=33644829930&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33644829930&partnerID=8YFLogxK
M3 - Article
C2 - 16273219
AN - SCOPUS:33644829930
VL - 27
SP - 1625
EP - 1632
JO - International Journal of Oncology
JF - International Journal of Oncology
SN - 1019-6439
IS - 6
ER -