title: The chemokine receptor CXCR4 and the metalloproteinase MT1-MMP are mutually required during melanoma metastasis to lungs.
abstract: 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.
authors.affiliation: Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biológicas, Madrid, Spain.
authors.forename: Rubén A
authors.initials: RA
authors.lastname: Bartolomé
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferreiro
authors.forename: María E
authors.initials: ME
authors.lastname: Miquilena-Colina
authors.forename: Lorena
authors.initials: L
authors.lastname: Martínez-Prats
authors.forename: María L
authors.initials: ML
authors.lastname: Soto-Montenegro
authors.forename: David
authors.initials: D
authors.lastname: García-Bernal
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Vaquero
authors.forename: Reuven
authors.initials: R
authors.lastname: Agami
authors.forename: Rafael
authors.initials: R
authors.lastname: Delgado
authors.forename: Manuel
authors.initials: M
authors.lastname: Desco
authors.forename: Paloma
authors.initials: P
authors.lastname: Sánchez-Mateos
authors.forename: Joaquin
authors.initials: J
authors.lastname: Teixidó
mesh_terms: 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
chemical_list: D019718:Receptors, CXCR4; D019869:Phosphatidylinositol 3-Kinases; D053511:Matrix Metalloproteinase 14