title: MMP-9 in B-cell chronic lymphocytic leukemia is up-regulated by alpha4beta1 integrin or CXCR4 engagement via distinct signaling pathways, localizes to podosomes, and is involved in cell invasion and migration.
abstract: B-cell chronic lymphocytic leukemia (B-CLL) progression is determined by malignant cell extravasation and lymphoid tissue infiltration. We have studied the role and regulation of matrix metalloproteinase-9 (MMP-9) in B-CLL cell migration and invasion. Adhesion of B-CLL cells to the fibronectin fragment FN-H89, VCAM-1, or TNF-alpha-activated human umbilical vein endothelial cells (HUVECs) up-regulated MMP-9 production, measured by gelatin zymography. This effect was mediated by alpha4beta1 integrin and required PI3-K/Akt signaling. The chemokine CXCL12 also up-regulated MMP-9, independently of alpha4beta1 and involving ERK1/2 but not Akt activity. Accordingly, alpha4beta1 engagement activated the PI3-K/Akt/NF-kappaB pathway, while CXCL12/CXCR4 interaction activated ERK1/2/c-Fos signaling. Anti-MMP-9 antibodies, the MMP-9 inhibitor TIMP-1, or transfection with 3 different MMP-9 siRNAs significantly blocked migration through Matrigel or HUVECs. Cell-associated MMP-9 was mainly at the membrane and contained the proactive and mature forms. Moreover, B-CLL cells formed podosomes upon adhesion to FN-H89, VCAM-1, or fibronectin; MMP-9 localized to podosomes in a PI3-K-dependent manner and degraded a fibronectin/gelatin matrix. Our results are the first to show that MMP-9 is physiologically regulated by alpha4beta1 integrin and CXCL12 and plays a key role in cell invasion and transendothelial migration, thus contributing to B-CLL progression. MMP-9 could therefore constitute a target for treatment of this malignancy.
authors.affiliation: Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Redondo-Muñoz
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Escobar-Díaz
authors.forename: Rafael
authors.initials: R
authors.lastname: Samaniego
authors.forename: María José
authors.initials: MJ
authors.lastname: Terol
authors.forename: José A
authors.initials: JA
authors.lastname: García-Marco
authors.forename: Angeles
authors.initials: A
authors.lastname: García-Pardo
mesh_terms: D002448:Cell Adhesion; D002465:Cell Movement; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039041:Integrin alpha4beta1 / Q000502:physiology*; D015448:Leukemia, B-Cell / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D009361:Neoplasm Invasiveness; D019718:Receptors, CXCR4 / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D039041:Integrin alpha4beta1; D019718:Receptors, CXCR4; D020780:Matrix Metalloproteinase 9