The chemokine receptor CXCR4 and the metalloproteinase MT1-MMP are mutually required during melanoma metastasis to lungs.
Melanoma is the most aggressive skin cancer once metastasis begins; therefore, it is important to characterize the molecular players involved in melanoma dissemination. The chemokine receptor CXCR4 and the membrane-bound metalloproteinase MT1-MMP are expressed on melanoma cells and represent candidate molecules for the control of metastasis. Using human melanoma transfectants that either overexpress or silence CXCR4 or MT1-MMP, or that have a combination of overexpression and interference of these proteins, we show that CXCR4 and MT1-MMP coordinate their activities at different steps along melanoma cell metastasis into the lungs. Results from in vivo xenograft mouse models of melanoma lung colonization and mice survival and short-term, homing nested polymerase chain reaction experiments from lung samples indicated that CXCR4 is required at early phases of melanoma cell arrival in the lungs. In contrast, MT1-MMP is not needed for these initial steps but promotes subsequent invasion and dissemination of the tumor with CXCR4. Investigation of potential cross talk between CXCR4 and MT1-MMP revealed that MT1-MMP accumulates intracellularly after melanoma cell stimulation with the CXCR4 ligand CXCL12, and that this process involves the activation of the Rac-Erk1/2 pathway. Subsequent to cell contact with specific basement membrane proteins, MT1-MMP redistributes to the cell membrane in a phosphatidylinositol 3-kinase-dependent manner. These results suggest that combination therapies that target CXCR4 and MT1-MMP should improve the limitations of the current therapies for metastatic melanoma.
Bartolomé
Rubén A
RA
Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biológicas, Madrid, Spain.
Ferreiro
Sergio
S
Miquilena-Colina
María E
ME
Martínez-Prats
Lorena
L
Soto-Montenegro
María L
ML
García-Bernal
David
D
Vaquero
Juan J
JJ
Agami
Reuven
R
Delgado
Rafael
R
Desco
Manuel
M
Sánchez-Mateos
Paloma
P
Teixidó
Joaquin
J
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000502:physiology; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D014162:Transfection
D019718:Receptors, CXCR4; D019869:Phosphatidylinositol 3-Kinases; D053511:Matrix Metalloproteinase 14