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

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 fragm...

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Bibliographic Details
Published in:Blood 2006-11, Vol.108 (9), p.3143-3151
Main Authors: Redondo-Muñoz, Javier, Escobar-Díaz, Elizabeth, Samaniego, Rafael, Terol, María José, García-Marco, José A, García-Pardo, Angeles
Format: Article
Language:English
Subjects:
Cell Adhesion
Cell Movement
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Integrin alpha4beta1 - physiology
Leukemia, B-Cell - enzymology
Leukemia, B-Cell - pathology
Leukemia, B-Cell - physiopathology
Matrix Metalloproteinase 9 - genetics
Neoplasm Invasiveness
Receptors, CXCR4 - physiology
Signal Transduction
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Summary: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.
ISSN:0006-4971