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Blood, 1 November 2006, Vol. 108, No. 9, pp. 3143-3151. Prepublished online as a Blood First Edition Paper on July 13, 2006; DOI 10.1182/blood-2006-03-007294. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2006-03-007294v1 108/9/3143    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Redondo-Muñoz, J. Articles by García-Pardo, A. Search for Related Content PubMed PubMed Citation Articles by Redondo-Muñoz, J. Articles by García-Pardo, A. Related Collections Neoplasia Cell Adhesion and Motility Signal Transduction Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA MMP-9 in B-cell chronic lymphocytic leukemia is up-regulated by 41 integrin or CXCR4 engagement via distinct signaling pathways, localizes to podosomes, and is involved in cell invasion and migration Javier Redondo-Muñoz, Elizabeth Escobar-Díaz, Rafael Samaniego, María José Terol, José A. García-Marco, and Ángeles García-Pardo From the Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain; Servicio de Inmunología, Hospital Gregorio Marañón, Madrid, Spain; Departamento de Hematología y Medicina Oncológica, Hospital Clínico, Valencia, Spain; and Servicio de Hematología, Hospital Puerta de Hierro, Madrid, Spain. 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-–activated human umbilical vein endothelial cells (HUVECs) up-regulated MMP-9 production, measured by gelatin zymography. This effect was mediated by 41 integrin and required PI3-K/Akt signaling. The chemokine CXCL12 also up-regulated MMP-9, independently of 41 and involving ERK1/2 but not Akt activity. Accordingly, 41 engagement activated the PI3-K/Akt/NF-B 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 41 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Dovas, J.-C. Gevrey, A. Grossi, H. Park, W. Abou-Kheir, and D. Cox Regulation of podosome dynamics by WASp phosphorylation: implication in matrix degradation and chemotaxis in macrophages J. Cell Sci., November 1, 2009; 122(21): 3873 - 3882. [Abstract] [Full Text] [PDF] R. Visone, L. Z. 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