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1
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Hasan MK, Widhopf Ii GF, Ghia EM, Kipps TJ. Wnt5a induces ROR1 dependent NF-κB activation to enhance MMP-9 expression and invasiveness in chronic lymphocytic leukemia. Leukemia 2025:10.1038/s41375-025-02616-4. [PMID: 40295829 DOI: 10.1038/s41375-025-02616-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 04/04/2025] [Accepted: 04/08/2025] [Indexed: 04/30/2025]
Abstract
Matrix metalloproteinase-9 (MMP-9) facilitates the extravasation and lymphoid-tissue infiltration of chronic lymphocytic leukemia (CLL) cells. Prior studies found that high level expression of MMP-9 in CLL associates more aggressive disease. We find that circulating CLL cells that express high levels the onco-embryonic protein ROR1 express significantly higher levels of MMP-9. Stimulation of CLL cells with Wnt5a could enhance expression and the release of MMP-9 into the culture media and increase the capacity of CLL cells to invade Matrigel in a Boyden-Chamber Assay. Such effects of Wnt5a could not be inhibited by BTK inhibitors such as ibrutinib or zanubrutinib, but could be blocked by zilovertamab, a humanized mAb specific for ROR1. We found that siRNA silencing of NF-κB-p65 or use of an NF-κB inhibitor (CAS 545380-34-5) blocked the capacity of Wnt5a to induce MMP-9 or enhance the invasive capacity of treated CLL cells. Moreover, siRNA directed silencing of MMP9 or treatment with an MMP-9 inhibitor (CAS 1177749-58-4) also blocked the invasive capability of CLL cells induced by Wnt5a. We conclude that Wnt5a-induced ROR1-signaling can induce expression of MMP-9 on CLL cells through activation of NF-κB, thereby enhancing the extravasation and lymphoid-tissue infiltration required for CLL cell trafficking.
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Affiliation(s)
- Md Kamrul Hasan
- Center for Novel Therapeutics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
| | - George F Widhopf Ii
- Center for Novel Therapeutics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Emanuela M Ghia
- Center for Novel Therapeutics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Thomas J Kipps
- Center for Novel Therapeutics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
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2
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Ayoub M, Susin SA, Bauvois B. Tumor Cell Survival Factors and Angiogenesis in Chronic Lymphocytic Leukemia: How Hot Is the Link? Cancers (Basel) 2024; 17:72. [PMID: 39796700 PMCID: PMC11719013 DOI: 10.3390/cancers17010072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/19/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025] Open
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of neoplastic CD5+/CD19+ B lymphocytes in the blood. These cells migrate to and proliferate in the bone marrow and lymphoid tissues. Despite the development of new therapies for CLL, drug resistance and disease relapse still occur; novel treatment approaches are therefore still needed. Inhibition of the angiogenesis involved in the progression of CLL might be a relevant therapeutic strategy. The literature data indicate that vascular endothelial growth factor, angiopoietin-2, and matrix metalloproteinase-9 are pro-angiogenic factors in CLL. A number of other CLL factors might have pro-angiogenic activity: fibroblast growth factor-2, certain chemokines (such as CXCL-12 and CXCL-2), tumor necrosis factor-α, insulin-like growth factor-1, neutrophil gelatinase-associated lipocalin, and progranulin. All these molecules contribute to the survival, proliferation, and migration of CLL cells. Here, we review the literature on these factors' respective expression profiles and roles in CLL. We also summarize the main results of preclinical and clinical trials of novel agents targeting most of these molecules in a CLL setting. Through the eradication of leukemic cells and the inhibition of angiogenesis, these therapeutic approaches might alter the course of CLL.
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Affiliation(s)
| | | | - Brigitte Bauvois
- Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm UMRS 1138, Drug Resistance in Hematological Malignancies Team, F-75006 Paris, France; (M.A.); (S.A.S.)
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3
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Abstract
In contrast to solid cancers, which often require genetic modifications and complex cellular reprogramming for effective metastatic dissemination, leukaemic cells uniquely possess the innate ability for migration and invasion. Dedifferentiated, malignant leukocytes retain the benign leukocytes' capacity for cell motility and survival in the circulation, while acquiring the potential for rapid and uncontrolled cell division. For these reasons, leukaemias, although not traditionally considered as metastatic diseases, are in fact models of highly efficient metastatic spread. Accordingly, they are often aggressive and challenging diseases to treat. In this Perspective, we discuss the key molecular processes that facilitate metastasis in a variety of leukaemic subtypes, the clinical significance of leukaemic invasion into specific tissues and the current pipeline of treatments targeting leukaemia metastasis.
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Affiliation(s)
- Andrew E Whiteley
- Department of Medicine, Duke University, Durham, NC, USA
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Trevor T Price
- Department of Medicine, Duke University, Durham, NC, USA
| | - Gaia Cantelli
- European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
| | - Dorothy A Sipkins
- Department of Medicine, Duke University, Durham, NC, USA.
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
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4
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Das S, Amin SA, Jha T. Inhibitors of gelatinases (MMP-2 and MMP-9) for the management of hematological malignancies. Eur J Med Chem 2021; 223:113623. [PMID: 34157437 DOI: 10.1016/j.ejmech.2021.113623] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/18/2021] [Accepted: 06/03/2021] [Indexed: 12/30/2022]
Abstract
Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are collectively known as gelatinases whereas MMP-2 is gelatinase-A and MMP-9 is termed as gelatinase-B. Gelatinases and other matrix metalloproteinases (MMPs) have long been associated with solid tumor invasion, metastasis and angiogenesis. However, there is paucity of data available regarding the role of gelatinases in hematological malignancies. Recent studies have shown that gelatinases activities or functions are correlated with hematological malignancies. Strategies for designing more specific gelatinase inhibitors like catalytic (CAT) domain inhibitors and hemopexin (PEX) domain inhibitors as well as signaling pathway based or gelatinase expression inhibitors had been reported against hematologic malignant cells. Several substrate based non-selective to non-substrate based relatively selective synthetic matrix metalloproteinase inhibitors (MMPIs) had been developed. Few MMPIs had reached in clinical trials during the period of 1990s-2000s. Unfortunately the anti-tumor and anti-metastatic efficacies of these MMPIs were not justified with patients having several advanced stage solid tumor cancers in any substantial number of clinical trials. Till date not a single MMPI passed phase III clinical trials designed for advanced metastatic cancers due to adverse events as well as lack of ability to show uniformity in disease prolongation. With the best of our knowledge no clinical trial study has been reported with small molecule synthetic inhibitors against hematological malignancies. This review looks at the outcome of clinical trials of MMPIs for advanced stage solid tumors. This can therefore, act as a learning experience for future development of successful gelatinase inhibitors for the management of hematological malignancies.
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Affiliation(s)
- Sanjib Das
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India.
| | - Sk Abdul Amin
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India.
| | - Tarun Jha
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India.
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Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway. Biomedicines 2021; 9:biomedicines9020188. [PMID: 33668421 PMCID: PMC7918075 DOI: 10.3390/biomedicines9020188] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/08/2021] [Accepted: 02/09/2021] [Indexed: 11/18/2022] Open
Abstract
Besides their antiviral and immunomodulatory functions, type I (α/β) and II (γ) interferons (IFNs) exhibit either beneficial or detrimental effects on tumor progression. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal CD5+ B lymphocytes that escape death. Drug resistance and disease relapse still occur in CLL. The triggering of IFN receptors is believed to be involved in the survival of CLL cells, but the underlying molecular mechanisms are not yet characterized. We show here that both type I and II IFNs promote the survival of primary CLL cells by counteracting the mitochondrial (intrinsic) apoptosis pathway. The survival process was associated with the upregulation of signal transducer and activator of transcription-3 (STAT3) and its target anti-apoptotic Mcl-1. Furthermore, the blockade of the STAT3/Mcl-1 pathway by pharmacological inhibitors against STAT3, TYK2 (for type I IFN) or JAK2 (for type II IFN) markedly reduced IFN-mediated CLL cell survival. Similarly, the selective Src family kinase inhibitor PP2 notably blocked IFN-mediated CLL cell survival by downregulating the protein levels of STAT3 and Mcl-1. Our work reveals a novel mechanism of resistance to apoptosis promoted by IFNs in CLL cells, whereby JAKs (TYK2, JAK2) and Src kinases activate in concert a STAT3/Mcl-1 signaling pathway. In view of current clinical developments of potent STAT3 and Mcl-1 inhibitors, a combination of conventional treatments with these inhibitors might thus constitute a new therapeutic strategy in CLL.
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Relation of Neutrophil Gelatinase-Associated Lipocalin Overexpression to the Resistance to Apoptosis of Tumor B Cells in Chronic Lymphocytic Leukemia. Cancers (Basel) 2020; 12:cancers12082124. [PMID: 32751884 PMCID: PMC7465759 DOI: 10.3390/cancers12082124] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/22/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023] Open
Abstract
The resistance to apoptosis of chronic lymphocytic leukemia (CLL) cells partly results from the deregulated production of survival signals from leukemic cells. Despite the development of new therapies in CLL, drug resistance and disease relapse still occur. Recently, neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, has been suggested to have a critical role in the biology of tumors. Thus, we investigated the relevance of NGAL in CLL pathogenesis, analyzed the expression of its cellular receptor (NGAL-R) on malignant B cells and tested whether CLL cells are resistant to apoptosis through an autocrine process involving NGAL and NGAL-R. We observed that NGAL concentrations were elevated in the serum of CLL patients at diagnosis. After treatment (and regardless of the therapeutic regimen), serum NGAL levels normalized in CLL patients in remission but not in relapsed patients. In parallel, NGAL and NGAL-R were upregulated in leukemic cells from untreated CLL patients when compared to normal peripheral blood mononuclear cells (PBMCs), and returned to basal levels in PBMCs from patients in remission. Cultured CLL cells released endogenous NGAL. Anti-NGAL-R antibodies enhanced NGAL-R+ leukemia cell death. Conversely, recombinant NGAL protected NGAL-R+ CLL cells against apoptosis by activating a STAT3/Mcl-1 signaling pathway. Our results suggest that NGAL and NGAL-R, overexpressed in untreated CLL, participate in the deregulation of the apoptotic machinery in CLL cells, and may be potential therapeutic clues for CLL treatment.
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Rodriguez CM, Gilardoni MB, Remedi MM, Sastre D, Heller V, Pellizas CG, Donadio AC. Tumor-stroma interaction increases CD147 expression in neoplastic B lymphocytes in chronic lymphocytic leukemia. Blood Cells Mol Dis 2020; 82:102405. [PMID: 32007924 DOI: 10.1016/j.bcmd.2020.102405] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Chronic lymphocytic leukemia (CLL) microenvironment plays a critical role in disease pathogenesis. Matrix metalloproteinases (MMPs) are involved in CLL-B cell migration and survival. CD147 is associated with MMPs production by tumor and stromal cells. AIM To analyze CD147, MMP2 and MMP9 expression in CLL-B cells and its modulation by fibroblasts (Fb)-CLL-B cell interaction. METHODS CLL-B cells were co-cultured with Fb, as a simulation of CLL microenvironment. CD147 was evaluated in healthy donor (HD)-B cells and CLL-B cells by flow cytometry. MMP2 and MMP9 activity in CLL-plasma samples and conditioned media (CMs) was studied by zymography. RESULTS MMP9/MMP2 plasma levels were significantly higher in CLL patients than in HD. CD147 expression (median fluorescence intensity) in CLL patients characterized 3 groups: low- (19.1 ± 3.2; n=3), middle- (42.7 ± 12.8; n=18) and high- (76.5 ± 9.6; n=5) related to CD147 expression in HD-B cells. CD147 expression significantly increased in CLL-B cells after Fb-CLL-B cell co-culture. A significant increase in proMMP2 activity was observed in CMs obtained from Fb-CLL-B cell co-cultures in comparison with isolated CLL-B cells. CONCLUSIONS CD147 expression in CLL-B cells and MMPs secretion was induced by Fb-CLL-B cell contact, suggesting CD147 participation in the CLL pathophysiology.
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Affiliation(s)
- Cecilia M Rodriguez
- Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Córdoba, Argentina; Universidad Nacional de Córdoba, Hospital Nacional de Clínicas, Laboratorio de Oncohematología, Argentina
| | - Mónica B Gilardoni
- Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Córdoba, Argentina.
| | - María M Remedi
- Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Córdoba, Argentina
| | - Darío Sastre
- Universidad Nacional de Córdoba, Hospital Nacional de Clínicas, Laboratorio de Oncohematología, Argentina
| | - Viviana Heller
- Universidad Nacional de Córdoba, Hospital Nacional de Clínicas, Laboratorio de Oncohematología, Argentina
| | - Claudia G Pellizas
- Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Córdoba, Argentina
| | - Ana C Donadio
- Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Córdoba, Argentina
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8
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Matrix metalloproteinase-9 induces a pro-angiogenic profile in chronic lymphocytic leukemia cells. Biochem Biophys Res Commun 2019; 520:198-204. [DOI: 10.1016/j.bbrc.2019.09.127] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 09/27/2019] [Indexed: 12/25/2022]
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9
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Abstract
Matrix metalloproteinases (MMPs) are responsible for the degradation of extracellular matrix components and hence play a crucial role in physiological and pathologic processes. The imbalance between the expression of MMPs and their inhibitors can be effective in leukemic cell processes such as migration, angiogenesis, survival, and apoptosis, playing a key role in the progression and prognosis of leukemia. In this review, we discuss the potential involvement of MMPs and their inhibitors in the pathogenesis and progression of leukemia by examining their role in the prognosis of leukemia. Inducing leukemic cell growth, migration, invasiveness, and angiogenesis are the main roles of MMPs in leukemia progression mediated by their degradative activity. Given the important role of MMPs in leukemia progression, further clinical trials are needed to confirm the link between MMPs' expressions and leukemia prognosis. It is hoped to use MMPs as therapeutic targets to improve patients' health by recognizing the prognostic value of MMPs in leukemia and their effect on the progression of these malignancies and their response to treatment.
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10
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Aguilera-Montilla N, Bailón E, Uceda-Castro R, Ugarte-Berzal E, Santos A, Gutiérrez-González A, Pérez-Sánchez C, Van den Steen PE, Opdenakker G, García-Marco JA, García-Pardo A. MMP-9 affects gene expression in chronic lymphocytic leukemia revealing CD99 as an MMP-9 target and a novel partner in malignant cell migration/arrest. Oncogene 2019; 38:4605-4619. [DOI: 10.1038/s41388-019-0744-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 12/19/2018] [Accepted: 01/29/2019] [Indexed: 12/14/2022]
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11
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Redondo-Muñoz J, García-Pardo A, Teixidó J. Molecular Players in Hematologic Tumor Cell Trafficking. Front Immunol 2019; 10:156. [PMID: 30787933 PMCID: PMC6372527 DOI: 10.3389/fimmu.2019.00156] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 01/17/2019] [Indexed: 12/20/2022] Open
Abstract
The trafficking of neoplastic cells represents a key process that contributes to progression of hematologic malignancies. Diapedesis of neoplastic cells across endothelium and perivascular cells is facilitated by adhesion molecules and chemokines, which act in concert to tightly regulate directional motility. Intravital microscopy provides spatio-temporal views of neoplastic cell trafficking, and is crucial for testing and developing therapies against hematologic cancers. Multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL) are hematologic malignancies characterized by continuous neoplastic cell trafficking during disease progression. A common feature of these neoplasias is the homing and infiltration of blood cancer cells into the bone marrow (BM), which favors growth and survival of the malignant cells. MM cells traffic between different BM niches and egress from BM at late disease stages. Besides the BM, CLL cells commonly home to lymph nodes (LNs) and spleen. Likewise, ALL cells also infiltrate extramedullary organs, such as the central nervous system, spleen, liver, and testicles. The α4β1 integrin and the chemokine receptor CXCR4 are key molecules for MM, ALL, and CLL cell trafficking into and out of the BM. In addition, the chemokine receptor CCR7 controls CLL cell homing to LNs, and CXCR4, CCR7, and CXCR3 contribute to ALL cell migration across endothelia and the blood brain barrier. Some of these receptors are used as diagnostic markers for relapse and survival in ALL patients, and their level of expression allows clinicians to choose the appropriate treatments. In CLL, elevated α4β1 expression is an established adverse prognostic marker, reinforcing its role in the disease expansion. Combining current chemotherapies with inhibitors of malignant cell trafficking could represent a useful therapy against these neoplasias. Moreover, immunotherapy using humanized antibodies, CAR-T cells, or immune check-point inhibitors together with agents targeting the migration of tumor cells could also restrict their survival. In this review, we provide a view of the molecular players that regulate the trafficking of neoplastic cells during development and progression of MM, CLL, and ALL, together with current therapies that target the malignant cells.
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Affiliation(s)
- Javier Redondo-Muñoz
- Department of Immunology, Ophthalmology and ERL, Hospital 12 de Octubre Health Research Institute (imas12), School of Medicine, Complutense University, Madrid, Spain.,Manchester Collaborative Centre for Inflammation Research, Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
| | - Angeles García-Pardo
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain
| | - Joaquin Teixidó
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain
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12
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Bailón E, Aguilera-Montilla N, Gutiérrez-González A, Ugarte-Berzal E, Van den Steen PE, Opdenakker G, García-Marco JA, García-Pardo A. A catalytically inactive gelatinase B/MMP-9 mutant impairs homing of chronic lymphocytic leukemia cells by altering migration regulatory pathways. Biochem Biophys Res Commun 2018; 495:124-130. [DOI: 10.1016/j.bbrc.2017.10.129] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 10/25/2017] [Indexed: 11/30/2022]
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13
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Gusella M, Bolzonella C, Paolini R, Rodella E, Bertolaso L, Scipioni C, Bellini S, Cuneo A, Pasini F, Ramazzina E. Plasma matrix metalloprotease 9 correlates with blood lymphocytosis, leukemic cell invasiveness, and prognosis in B-cell chronic lymphocytic leukemia. Tumour Biol 2017; 39:1010428317694325. [DOI: 10.1177/1010428317694325] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The complex biology underlying chronic lymphocytic leukemia cell migration and tissue invasiveness is not yet completely understood and might provide novel predictive markers and therapeutic targets. A total of 36 patients out of treatment from at least 3 months were enrolled and followed up for a median period of 44.2 months (range: 4.4–99.2). Matrix metalloprotease 9 and tissue inhibitor of metalloproteases 1 plasma levels and production/release from lymphoid cells were measured by zymography and enzyme-linked immunosorbent assay (ELISA) analysis. Malignant and normal lymphocyte mobility and matrix-degradation capability were studied using a Boyden chamber system, with and without autologous plasma. Free matrix metalloprotease 9 plasma levels were related with blood lymphocytosis, especially in more advanced stages (p = 0.003), and higher concentrations were associated with an increased disease progression risk (hazard ratio = 9.0, 95% confidence interval = 1.5–13.8). Leukemic cells expressed and secreted very little matrix metalloprotease 9. On the contrary, normal lymphocytes derived from the same leukemic patients showed matrix metalloprotease 9 intracellular levels that were lower in subjects with higher blood lymphocytosis (p = 0.024) and more advanced stages (p = 0.03); the released quantities were inversely associated with matrix metalloprotease 9 plasma concentrations (p = 0.035). Leukemic cells had a reduced spontaneous mobility and matrix-degradation capability that were stimulated by autologous plasma (p = 0.001) and normal lymphocytes (p = 0.005), respectively. Matrix metalloprotease 9 affected cell invasiveness depending on concentration and disease stage. In conclusion, chronic lymphocytic leukemia cells have a reduced mobility, matrix-degradation capability, and matrix metalloprotease 9 production compared to their own autologous normal lymphocytes. They are exposed to matrix metalloprotease 9 of prevalently systemic origin whose higher levels are associated with both leukemic and normal lymphocyte accumulation in the peripheral blood and have a negative prognostic value.
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Affiliation(s)
- Milena Gusella
- Department of Oncology, Azienda ULSS 18 Rovigo, Rovigo, Italy
| | | | | | | | - Laura Bertolaso
- Department of Oncology, Azienda ULSS 18 Rovigo, Rovigo, Italy
| | - Cinzia Scipioni
- Department of Transfusion Medicine, Azienda ULSS 18 Rovigo, Rovigo, Italy
| | - Silvia Bellini
- Department of Transfusion Medicine, Azienda ULSS 18 Rovigo, Rovigo, Italy
| | - Antonio Cuneo
- Department of Medical Sciences, Section of Hematology, University of Ferrara, Ferrara, Italy
| | - Felice Pasini
- Department of Oncology, Azienda ULSS 18 Rovigo, Rovigo, Italy
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Bchir S, Nasr HB, Bouchet S, Benzarti M, Garrouch A, Tabka Z, Susin S, Chahed K, Bauvois B. Concomitant elevations of MMP-9, NGAL, proMMP-9/NGAL and neutrophil elastase in serum of smokers with chronic obstructive pulmonary disease. J Cell Mol Med 2016; 21:1280-1291. [PMID: 28004483 PMCID: PMC5487915 DOI: 10.1111/jcmm.13057] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 11/10/2016] [Indexed: 12/22/2022] Open
Abstract
A growing body of evidence points towards smoking‐related phenotypic differences in chronic obstructive pulmonary disease (COPD). As COPD is associated with systemic inflammation, we determined whether smoking status is related to serum levels of matrix metalloproteinase‐9 (pro‐ and active MMP‐9), neutrophil gelatinase‐associated lipocalin (NGAL) and the proMMP‐9/NGAL complex in patients with COPD. Serum samples were collected in 100 stable‐phase COPD patients (82 smokers, 18 never‐smokers) and 28 healthy adults (21 smokers, 7 never‐smokers). Serum levels of studied factors were measured in ELISA. Our data provide the first evidence of simultaneously elevated serum levels of MMP‐9, NGAL and proMMP‐9/NGAL in COPD smokers. While the triad discriminated between smokers and non‐smokers in the COPD group, MMP‐9 and proMMP‐9/NGAL (but not NGAL) discriminated between smokers with and without COPD. Adjustment for age and smoking pack‐years did not alter the findings. Serum MMP‐9, NGAL and proMMP‐9/NGAL levels were not correlated with the GOLD stage or FEV1 decline. Furthermore, serum levels of neutrophil elastase (NE) and MMP‐3 (but not of IL‐6 and MMP‐12) were also higher in COPD smokers than in healthy smokers before and after adjustment for age and pack‐years. Among COPD smokers, levels of MMP‐9, NGAL and proMMP‐9/NGAL were positively correlated with NE (P < 0.0001) but not with the remaining factors. Gelatin zymography detected proMMP‐9 in serum samples of healthy and COPD smoking groups. Our results suggest that associated serum levels of proMMP‐9, NGAL, proMMP‐9/NGAL and NE may reflect the state of systemic inflammation in COPD related to cigarette smoking.
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Affiliation(s)
- Sarra Bchir
- Unité de recherche UR12ES06, Physiologie de l'Exercice et Physiopathologie de l'Intégré au Moléculaire, Biologie, Médecine et Santé, Faculté de Médecine de Sousse, Université de Sousse, Sousse, Tunisia.,Institut Supérieur de Biotechnologie de Monastir, Université de Monastir, Monastir, Tunisia.,Centre de Recherche des Cordeliers, INSERM UMRS1138, Sorbonne Universités UPMC Paris 06, Université Paris Descartes Sorbonne Paris Cité, Paris, France
| | - Hela Ben Nasr
- Unité de recherche UR12ES06, Physiologie de l'Exercice et Physiopathologie de l'Intégré au Moléculaire, Biologie, Médecine et Santé, Faculté de Médecine de Sousse, Université de Sousse, Sousse, Tunisia
| | - Sandrine Bouchet
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Sorbonne Universités UPMC Paris 06, Université Paris Descartes Sorbonne Paris Cité, Paris, France.,Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Mohamed Benzarti
- Service de Pneumo-Allergologie, CHU Farhat Hached, Sousse, Tunisia
| | | | - Zouhair Tabka
- Unité de recherche UR12ES06, Physiologie de l'Exercice et Physiopathologie de l'Intégré au Moléculaire, Biologie, Médecine et Santé, Faculté de Médecine de Sousse, Université de Sousse, Sousse, Tunisia
| | - Santos Susin
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Sorbonne Universités UPMC Paris 06, Université Paris Descartes Sorbonne Paris Cité, Paris, France
| | - Karim Chahed
- Unité de recherche UR12ES06, Physiologie de l'Exercice et Physiopathologie de l'Intégré au Moléculaire, Biologie, Médecine et Santé, Faculté de Médecine de Sousse, Université de Sousse, Sousse, Tunisia.,Faculté des Sciences de Sfax, Université de Sfax, Sfax, Tunisia
| | - Brigitte Bauvois
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Sorbonne Universités UPMC Paris 06, Université Paris Descartes Sorbonne Paris Cité, Paris, France
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15
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Tumor necrosis factor α in the onset and progression of leukemia. Exp Hematol 2016; 45:17-26. [PMID: 27833035 DOI: 10.1016/j.exphem.2016.10.005] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 09/30/2016] [Accepted: 10/06/2016] [Indexed: 12/17/2022]
Abstract
Tumor necrosis factor alpha (TNF-α), originally described as an anti-neoplastic cytokine, has been found, in apparent contradiction to its name, to play an important role in promoting the development and progression of malignant disease. Targeting TNF-α with TNF antagonists has elicited an objective response in certain solid tumors in phase I and II clinical trials. This review focuses on the relationship of TNF-α expressed by leukemia cells and adverse clinical features of leukemia. TNF-α is involved in all steps of leukemogenesis, including cellular transformation, proliferation, angiogenesis, and extramedullary infiltration. TNF-α is also an important factor in the tumor microenvironment and assists leukemia cells in immune evasion, survival, and resistance to chemotherapy. TNF-α may be a potent target for leukemia therapy.
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16
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Targeting CD13 (aminopeptidase-N) in turn downregulates ADAM17 by internalization in acute myeloid leukaemia cells. Oncotarget 2015; 5:8211-22. [PMID: 25246708 PMCID: PMC4226678 DOI: 10.18632/oncotarget.1788] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Secreted matrix metalloproteinases (MMP)-2 and MMP-9 and membrane-anchored aminopeptidase-N/CD13 are abnormally expressed in human acute myeloid leukaemia (AML). We previously showed that CD13 ligation by anti-CD13 monoclonal antibodies can induce apoptosis in AML cells. Here, we assessed ADAM17 expression in primary blood blasts CD13+CD33+ from patients with AML. Primary AML cells expressed ADAM17 transcript and its surface expression was higher in subtype M4 (myelomonocytic) and M5 (monocytic) AML specimens than in M0 and M1/M2 (early and granulocytic) specimens. In AML cell lines defining distinct AML subfamilies (HL-60/M2, NB4/M3, THP-1/M5, U937/M5) and primary AML cells cultured ex vivo, anti-CD13 antibodies downregulated surface CD13 and ADAM17 without affecting MMP-2/-9 release. Knockdown of CD13 by siRNA prevented anti-CD13-mediated ADAM17 downregulation, indicating that CD13 is required for ADAM17 downregulation. Soluble ADAM17 was not detected in the medium of anti-CD13 treated cells, suggesting that ADAM17 was not shed. After ligation by anti-CD13, CD13 and ADAM17 were internalized. Subsequently, we found that ADAM17 interacts with CD13. We postulate that the interaction of ADAM17 with CD13 and its downregulation following CD13 engagement has important implications in AML for the known roles of ADAM17 in tumour-associated cell growth, migration and invasion.
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Dal Bo M, Tissino E, Benedetti D, Caldana C, Bomben R, Del Poeta G, Gaidano G, Rossi FM, Zucchetto A, Gattei V. Microenvironmental Interactions in Chronic Lymphocytic Leukemia: The Master Role of CD49d. Semin Hematol 2014; 51:168-76. [DOI: 10.1053/j.seminhematol.2014.05.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Amigo-Jiménez I, Bailón E, Ugarte-Berzal E, Aguilera-Montilla N, García-Marco JA, García-Pardo A. Matrix metalloproteinase-9 is involved in chronic lymphocytic leukemia cell response to fludarabine and arsenic trioxide. PLoS One 2014; 9:e99993. [PMID: 24956101 PMCID: PMC4067296 DOI: 10.1371/journal.pone.0099993] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Accepted: 05/21/2014] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Matrix metalloproteinase-9 (MMP-9) contributes to chronic lymphocytic leukemia (CLL) pathology by regulating cell migration and preventing spontaneous apoptosis. It is not known if MMP-9 is involved in CLL cell response to chemotherapy and we address this in the present study, using arsenic trioxide (ATO) and fludarabine as examples of cytotoxic drugs. METHODS We used primary cells from the peripheral blood of CLL patients and MEC-1 cells stably transfected with an empty vector or a vector containing MMP-9. The effect of ATO and fludarabine was determined by flow cytometry and by the MTT assay. Expression of mRNA was measured by RT-PCR and qPCR. Secreted and cell-bound MMP-9 was analyzed by gelatin zymography and flow cytometry, respectively. Protein expression was analyzed by Western blotting and immunoprecipitation. Statistical analyses were performed using the two-tailed Student's t-test. RESULTS In response to ATO or fludarabine, CLL cells transcriptionally upregulated MMP-9, preceding the onset of apoptosis. Upregulated MMP-9 primarily localized to the membrane of early apoptotic cells and blocking apoptosis with Z-VAD prevented MMP-9 upregulation, thus linking MMP-9 to the apoptotic process. Culturing CLL cells on MMP-9 or stromal cells induced drug resistance, which was overcome by anti-MMP-9 antibodies. Accordingly, MMP-9-MEC-1 transfectants showed higher viability upon drug treatment than Mock-MEC-1 cells, and this effect was blocked by silencing MMP-9 with specific siRNAs. Following drug exposure, expression of anti-apoptotic proteins (Mcl-1, Bcl-xL, Bcl-2) and the Mcl-1/Bim, Mcl-1/Noxa, Bcl-2/Bax ratios were higher in MMP-9-cells than in Mock-cells. Similar results were obtained upon culturing primary CLL cells on MMP-9. CONCLUSIONS Our study describes for the first time that MMP-9 induces drug resistance by modulating proteins of the Bcl-2 family and upregulating the corresponding anti-apoptotic/pro-apoptotic ratios. This is a novel role for MMP-9 contributing to CLL progression. Targeting MMP-9 in combined therapies may thus improve CLL response to treatment.
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MESH Headings
- Aged
- Aged, 80 and over
- Apoptosis/drug effects
- Arsenic Trioxide
- Arsenicals/pharmacology
- Arsenicals/therapeutic use
- Cell Membrane/drug effects
- Cell Membrane/metabolism
- Down-Regulation/drug effects
- Drug Resistance, Neoplasm/drug effects
- Female
- HEK293 Cells
- Humans
- Hyaluronan Receptors/metabolism
- Integrin alpha4beta1/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/enzymology
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Male
- Matrix Metalloproteinase 9/genetics
- Matrix Metalloproteinase 9/metabolism
- Middle Aged
- Myeloid Cell Leukemia Sequence 1 Protein/metabolism
- Oxides/pharmacology
- Oxides/therapeutic use
- Proto-Oncogene Proteins c-bcl-2/metabolism
- Proto-Oncogene Proteins c-fos/genetics
- Proto-Oncogene Proteins c-jun/genetics
- Transcription, Genetic/drug effects
- Up-Regulation/drug effects
- Vidarabine/analogs & derivatives
- Vidarabine/pharmacology
- Vidarabine/therapeutic use
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Affiliation(s)
- Irene Amigo-Jiménez
- Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Elvira Bailón
- Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Estefanía Ugarte-Berzal
- Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Noemí Aguilera-Montilla
- Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | | | - Angeles García-Pardo
- Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
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19
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Ugarte-Berzal E, Bailón E, Amigo-Jiménez I, Albar JP, García-Marco JA, García-Pardo A. A novel CD44-binding peptide from the pro-matrix metalloproteinase-9 hemopexin domain impairs adhesion and migration of chronic lymphocytic leukemia (CLL) cells. J Biol Chem 2014; 289:15340-9. [PMID: 24739387 PMCID: PMC4140891 DOI: 10.1074/jbc.m114.559187] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 04/10/2014] [Indexed: 11/06/2022] Open
Abstract
(pro)MMP-9 binds to CLL cells through the PEX9 domain and contributes to CLL progression. To biochemically characterize this interaction and identify potential therapeutic targets, we prepared GST-PEX9 forms containing structural blades B1B2 or B3B4. We recently described a sequence in blade B4 (P3 sequence) that bound α4β1 integrin and partially impaired cell adhesion and migration. We have now studied the possible contribution of the B1B2 region to cell interaction with PEX9. CLL cells bound to GST-B1B2 and CD44 was the primary receptor. GST-B1B2 inhibited CLL cell migration as effectively as GST-B3B4. Overlapping synthetic peptides spanning the B1B2 region identified the sequence FDAIAEIGNQLYLFKDGKYW, present in B1 and contained in peptide P6, as the most effective site. P6 inhibited cell adhesion to PEX9 in a dose-dependent manner and with an IC50 value of 90 μM. P6 also inhibited cell adhesion to hyaluronan but had no effect on adhesion to VCAM-1 (α4β1 integrin ligand), confirming its specific interaction with CD44. Spatial localization analyses mapped P6 to the central cavity of PEX9, in close proximity to the previously identified P3 sequence. Both P6 and P3 equally impaired cell adhesion to (pro)MMP-9. Moreover, P6 synergistically cooperated with P3, resulting in complete inhibition of CLL cell binding to PEX9, chemotaxis, and transendothelial migration. Thus, P6 is a novel sequence in PEX9 involved in cell-PEX9/(pro)MMP-9 binding by interacting with CD44. Targeting both sites, P6 and P3, should efficiently prevent (pro)MMP-9 binding to CLL cells and its pathological consequences.
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MESH Headings
- Aged
- Amino Acid Sequence
- Cell Adhesion/physiology
- Cell Movement/physiology
- Disease Progression
- Drug Design
- Enzyme Precursors/chemistry
- Enzyme Precursors/metabolism
- Female
- Hemopexin/chemistry
- Hemopexin/metabolism
- Humans
- Hyaluronan Receptors/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Male
- Matrix Metalloproteinase 9/chemistry
- Matrix Metalloproteinase 9/metabolism
- Middle Aged
- Molecular Sequence Data
- Peptides/chemical synthesis
- Peptides/metabolism
- Protein Binding/physiology
- Protein Structure, Tertiary
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Affiliation(s)
- Estefanía Ugarte-Berzal
- From the Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain
| | - Elvira Bailón
- From the Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain
| | - Irene Amigo-Jiménez
- From the Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain
| | - Juan Pablo Albar
- the Proteomics Facility, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain, and
| | - José A García-Marco
- Servicio de Hematología, Hospital Universitario Puerta de Hierro, 28222 Madrid, Spain
| | - Angeles García-Pardo
- From the Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain,
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20
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Bouchet S, Bauvois B. Neutrophil Gelatinase-Associated Lipocalin (NGAL), Pro-Matrix Metalloproteinase-9 (pro-MMP-9) and Their Complex Pro-MMP-9/NGAL in Leukaemias. Cancers (Basel) 2014; 6:796-812. [PMID: 24713998 PMCID: PMC4074804 DOI: 10.3390/cancers6020796] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 03/21/2014] [Accepted: 03/25/2014] [Indexed: 12/22/2022] Open
Abstract
Matrix metalloproteinase (MMP)-9 and neutrophil gelatinase-associated lipocalin (NGAL) have gained attention as cancer biomarkers. The inactive zymogen form of MMP-9 (pro-MMP-9) also exists as a disulphide-linked heterodimer bound to NGAL in humans. Leukaemias represent a heterogeneous group of neoplasms, which vary in their clinical behavior and pathophysiology. In this review, we summarize the current literature on the expression profiles of pro-MMP-9 and NGAL as prognostic factors in leukaemias. We also report the expression of the pro-MMP-9/NGAL complex in these diseases. We discuss the roles of (pro)-MMP-9 (active and latent forms) and NGAL in tumour development, and evaluate the mechanisms by which pro-MMP-9/NGAL may influence the actions of (pro)-MMP-9 and NGAL in cancer. Emerging knowledge about the coexpression and the biology of (pro)-MMP-9, NGAL and their complex in cancer including leukaemia may improve treatment outcomes.
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Affiliation(s)
- Sandrine Bouchet
- INSERM U1138, Université Pierre et Marie Curie, Université Paris-Descartes, Centre de Recherche des Cordeliers, Paris 75006, France.
| | - Brigitte Bauvois
- INSERM U1138, Université Pierre et Marie Curie, Université Paris-Descartes, Centre de Recherche des Cordeliers, Paris 75006, France.
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21
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Folgosa L, Zellner HB, El Shikh ME, Conrad DH. Disturbed follicular architecture in B cell A disintegrin and metalloproteinase (ADAM)10 knockouts is mediated by compensatory increases in ADAM17 and TNF-α shedding. THE JOURNAL OF IMMUNOLOGY 2013; 191:5951-8. [PMID: 24227779 DOI: 10.4049/jimmunol.1302042] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
B cell A disintegrin and metalloproteinase 10 (ADAM10) is required for the development and maintenance of proper secondary lymphoid tissue architecture; however, the underlying mechanism remains unclear. In this study, we show disturbances in naive lymph node architecture from B cell-specific ADAM10-deficient mice (ADAM10(B-/-)) including loss of B lymphocyte/T lymphocyte compartmentalization, attenuation of follicular dendritic cell reticula, excessive collagen deposition, and increased high endothelial venule formation. Because TNF-α signaling is critical for secondary lymphoid tissue architecture, we examined compensatory changes in ADAM17 and TNF-α in ADAM10(B-/-) B cells. Surprisingly, defective follicular development in these mice was associated with increased rather than decreased TNF-α expression. In this article, we describe an increase in TNF-α message, mRNA stability, soluble protein release, and membrane expression in ADAM10(B-/-) B cells compared with wild type (WT), which coincides with increased ADAM17 message and protein. To assess the mechanistic contribution of excessive TNF-α to abnormal lymphoid architecture in ADAM10(B-/-) mice, we performed a bone marrow reconstitution study. Rectification of WT architecture was noted only in irradiated WT mice reconstituted with ADAM10(B-/-) + TNF knockout bone marrow because of normalization of TNF-α levels not seen in ADAM10(B-/-) alone. We conclude that ADAM17 overcompensation causes excessive TNF-α shedding and further upregulation of TNF-α expression, creating an aberrant signaling environment within B cell cortical regions of ADAM10(B-/-) lymph nodes, highlighting a key interplay between B cell ADAM10 and ADAM17 with respect to TNF-α homeostasis.
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Affiliation(s)
- Lauren Folgosa
- Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298
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22
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Ribatti D. Angiogenesis as a treatment target in leukemia. Int J Hematol Oncol 2013. [DOI: 10.2217/ijh.13.18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
SUMMARY The importance of angiogenesis in the growth and survival of leukemia has been well established and confirmed by several studies. In the last 20 years, several antiangiogenic agents have been used in preclinical and clinical studies of the treatment of leukemia. This review article summarizes the literature focusing on the relationship between angiogenesis and disease progression, and the advantages and limits of the antiangiogenic treatment of leukemia.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neuroscience, & Sensory Organs, University of Bari Medical School, Piazza Giulio Cesare, 11, 70124 Bari, Italy
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23
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Gesuete R, Packard AEB, Vartanian KB, Conrad VK, Stevens SL, Bahjat FR, Yang T, Stenzel-Poore MP. Poly-ICLC preconditioning protects the blood-brain barrier against ischemic injury in vitro through type I interferon signaling. J Neurochem 2012; 123 Suppl 2:75-85. [PMID: 23050645 DOI: 10.1111/j.1471-4159.2012.07946.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Preconditioning with a low dose of harmful stimulus prior to injury induces tolerance to a subsequent ischemic challenge resulting in neuroprotection against stroke. Experimental models of preconditioning primarily focus on neurons as the cellular target of cerebral protection, while less attention has been paid to the cerebrovascular compartment, whose role in the pathogenesis of ischemic brain injury is crucial. We have shown that preconditioning with polyinosinic polycytidylic acid (poly-ICLC) protects against cerebral ischemic damage. To delineate the mechanism of poly-ICLC protection, we investigated whether poly-ICLC preconditioning preserves the function of the blood-brain barrier (BBB) in response to ischemic injury. Using an in vitro BBB model, we found that poly-ICLC treatment prior to exposure to oxygen-glucose deprivation maintained the paracellular and transcellular transport across the endothelium and attenuated the drop in transendothelial electric resistance. We found that poly-ICLC treatment induced interferon (IFN) β mRNA expression in astrocytes and microglia and that type I IFN signaling in brain microvascular endothelial cells was required for protection. Importantly, this implicates a potential mechanism underlying neuroprotection in our in vivo experimental stroke model, where type I IFN signaling is required for poly-ICLC-induced neuroprotection against ischemic injury. In conclusion, we are the first to show that preconditioning with poly-ICLC attenuates ischemia-induced BBB dysfunction. This mechanism is likely an important feature of poly-ICLC-mediated neuroprotection and highlights the therapeutic potential of targeting BBB signaling pathways to protect the brain against stroke.
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Affiliation(s)
- Raffaella Gesuete
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon 97239, USA
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24
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Enhanced CD21 expression and shedding in chronic lymphatic leukemia: a possible pathomechanism in disease progression. Int J Hematol 2012; 96:350-6. [PMID: 22899340 DOI: 10.1007/s12185-012-1147-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2012] [Revised: 07/06/2012] [Accepted: 07/09/2012] [Indexed: 10/28/2022]
Abstract
CD21 is a 145-kDa membrane glycoprotein mainly expressed on B cells and follicular dendritic cells, and is involved in B-cell activation, survival and proliferation. CD21 can be cleaved to give soluble CD21 (sCD21), which is constantly shed in healthy persons. We show here that plasma sCD21 levels are higher, while B-cell surface CD21 expression levels are lower in B-cell chronic lymphocytic leukemia (B-CLL) patients, but not in multiple myeloma (MM) patients. High sCD21 levels in the blood are positively correlated to the number of cells with high CD21 surface expression and the relative amount of CD21 expressed on the B cells. B-CLL patients with swollen lymph nodes had higher amounts of CD21 high-expressing B cells, as well as CD21 low-expressing B cells, as compared to B-CLL patients without swollen lymph nodes.
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25
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Angiogenic factors in chronic lymphocytic leukemia. Leuk Res 2012; 36:1211-7. [PMID: 22727510 DOI: 10.1016/j.leukres.2012.05.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2012] [Revised: 03/28/2012] [Accepted: 05/21/2012] [Indexed: 01/12/2023]
Abstract
Angiogenesis is a complex process controlled by the balance of a large number of regulating factors, the pro- and anti-angiogenic factors. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks for cancer. Recent emphasis on the microenvironment's influence in chronic lymphocytic leukemia (CLL) progression and drug resistance nurtures the interest in angiogenesis. Researchers have already identified a variety of angiogenic factors involved in the CLL, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), angiopoietin-2(Ang-2), thrombospondin-1 (TSP-1), as well as extracellular proteinases such as matrix metalloproteinase-9 (MMP-9). Besides modulating neovascularization, angiogenic factors also participate in the regulation of pro-survival effects of CLL cells. However, the precise mechanism involved still needs to be elucidated further. At present, the levels of some angiogenic factors are regarded as prognostic markers of the progression of CLL, although it is not widely used. Several anti-VEGF agents are currently under clinical trial. Advances in the understanding of the bases of angiogenesis regulators will be benefit for the comprehension of CLL pathogenesis and help to conquer the disease.
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26
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Ugarte-Berzal E, Bailón E, Amigo-Jiménez I, Vituri CL, del Cerro MH, Terol MJ, Albar JP, Rivas G, García-Marco JA, García-Pardo A. A 17-residue sequence from the matrix metalloproteinase-9 (MMP-9) hemopexin domain binds α4β1 integrin and inhibits MMP-9-induced functions in chronic lymphocytic leukemia B cells. J Biol Chem 2012; 287:27601-13. [PMID: 22730324 DOI: 10.1074/jbc.m112.354670] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
We previously showed that pro-matrix metalloproteinase-9 (proMMP-9) binds to B chronic lymphocytic leukemia (B-CLL) cells and contributes to B-CLL progression by regulating cell migration and survival. Induction of cell survival involves a non-proteolytic mechanism and the proMMP-9 hemopexin domain (PEX9). To help design specific inhibitors of proMMP-9-cell binding, we have now characterized B-CLL cell interaction with the isolated PEX9. B-CLL cells bound soluble and immobilized GST-PEX9, but not GST, and binding was mediated by α4β1 integrin. The ability to recognize PEX9 was observed in all 20 primary samples studied irrespective of their clinical stage or prognostic marker phenotype. By preparing truncated forms of GST-PEX9 containing structural blades B1B2 or B3B4, we have identified B3B4 as the primary α4β1 integrin-interacting region within PEX9. Overlapping synthetic peptides spanning B3B4 were then tested in functional assays. Peptide P3 (FPGVPLDTHDVFQYREKAYFC), a sequence present in B4 or smaller versions of this sequence (peptides P3a/P3b), inhibited B-CLL cell adhesion to GST-PEX9 or proMMP-9, with IC(50) values of 138 and 279 μm, respectively. Mutating the two aspartate residues to alanine rendered the peptides inactive. An anti-P3 antibody also inhibited adhesion to GST-PEX9 and proMMP-9. GST-PEX9, GST-B3B4, and P3/P3a/P3b peptides inhibited B-CLL cell transendothelial migration, whereas the mutated peptide did not. B-CLL cell incubation with GST-PEX9 induced intracellular survival signals, namely Lyn phosphorylation and Mcl-1 up-regulation, and this was also prevented by the P3 peptides. The P3 sequence may, therefore, constitute an excellent target to prevent proMMP-9 contribution to B-CLL pathogenesis.
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Affiliation(s)
- Estefanía Ugarte-Berzal
- Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), 28040 Madrid, Spain
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27
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Cock-Rada AM, Medjkane S, Janski N, Yousfi N, Perichon M, Chaussepied M, Chluba J, Langsley G, Weitzman JB. SMYD3 promotes cancer invasion by epigenetic upregulation of the metalloproteinase MMP-9. Cancer Res 2011; 72:810-20. [PMID: 22194464 DOI: 10.1158/0008-5472.can-11-1052] [Citation(s) in RCA: 144] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Upregulation of the matrix metalloproteinase (MMP)-9 plays a central role in tumor progression and metastasis by stimulating cell migration, tumor invasion, and angiogenesis. To gain insights into MMP-9 expression, we investigated its epigenetic control in a reversible model of cancer that is initiated by infection with intracellular Theileria parasites. Gene induction by parasite infection was associated with trimethylation of histone H3K4 (H3K4me3) at the MMP-9 promoter. Notably, we found that the H3K4 methyltransferase SMYD3 was the only histone methyltransferase upregulated upon infection. SMYD3 is overexpressed in many types of cancer cells, but its contributions to malignant pathophysiology are unclear. We found that overexpression of SMYD3 was sufficient to induce MMP-9 expression in transformed leukocytes and fibrosarcoma cells and that proinflammatory phorbol esters further enhanced this effect. Furthermore, SMYD3 was sufficient to increase cell migration associated with MMP-9 expression. In contrast, RNA interference-mediated knockdown of SMYD3 decreased H3K4me3 modification of the MMP-9 promoter, reduced MMP-9 expression, and reduced tumor cell proliferation. Furthermore, SMYD3 knockdown also reduced cellular invasion in a zebrafish xenograft model of cancer. Together, our results define SMYD3 as an important new regulator of MMP-9 transcription, and they provide a molecular link between SMYD3 overexpression and metastatic cancer progression.
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Affiliation(s)
- Alicia M Cock-Rada
- Université Paris Diderot, Sorbonne Paris Cité, CNRS UMR7216 Epigénétique et Destin Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Inserm U1016, Paris, France
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28
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Bauvois B. New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta Rev Cancer 2011; 1825:29-36. [PMID: 22020293 DOI: 10.1016/j.bbcan.2011.10.001] [Citation(s) in RCA: 249] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Revised: 10/03/2011] [Accepted: 10/04/2011] [Indexed: 12/14/2022]
Abstract
This review focuses on matrix metalloproteinases (MMPs)-2 (gelatinase A) and -9 (gelatinase B), both of which are cancer-associated, secreted, zinc-dependent endopeptidases. Gelatinases cleave many different targets (extracellular matrix, cytokines, growth factors, chemokines and cytokine/growth factor receptors) that in turn regulate key signaling pathways in cell growth, migration, invasion, inflammation and angiogenesis. Interactions with cell surface integral membrane proteins (CD44, αVβ/αβ1/αβ2 integrins and Ku protein) can occur through the gelatinases' active site or hemopexin-like C-terminal domain. This review evaluates the recent literature on the non-enzymatic, signal transduction roles of surface-bound gelatinases and their subsequent effects on cell survival, migration and angiogenesis. Gelatinases have long been drug targets. The current status of gelatinase inhibitors as anticancer agents and their failure in the clinic is discussed in light of these new data on the gelatinases' roles as cell surface transducers - data that may lead to the design and development of novel, gelatinase-targeting inhibitors.
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Affiliation(s)
- Brigitte Bauvois
- INSERM U872, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Université Paris Descartes, Paris, France.
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Merhi F, Auger J, Rendu F, Bauvois B. Allium compounds, dipropyl and dimethyl thiosulfinates as antiproliferative and differentiating agents of human acute myeloid leukemia cell lines. Biologics 2011; 2:885-95. [PMID: 19707466 PMCID: PMC2727902 DOI: 10.2147/btt.s3212] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Epidemiologic studies support the premise that Allium vegetables may lower the risk of cancers. The beneficial effects appear related to the organosulfur products generated upon processing of Allium. Leukemia cells from patients with acute myeloid leukemia (AML) display high proliferative capacity and have a reduced capacity of undergoing apoptosis and maturation. Whether the sulfur-containing molecules thiosulfinates (TS), diallyl TS (All(2)TS), dipropyl TS (Pr(2)TS) and dimethyl TS (Me(2)TS), are able to exert chemopreventative activity against AML is presently unknown. The present study was an evaluation of proliferation, cytotoxicity, differentiation and secretion of AML cell lines (U937, NB4, HL-60, MonoMac-6) in response to treatment with these TS and their related sulfides (diallylsulfide, diallyl disulfide, dipropyl disulfide, dimethyl disulfide). As assessed by flow cytometry, ELISA, gelatin zymogaphy and RT-PCR, we showed that Pr(2)TS and Me(2)TS, but not All(2)TS and sulfides, 1) inhibited cell proliferation in dose- and time-dependent manner and this process was neither due to cytotoxicity nor apoptosis, 2) induced macrophage maturation, and 3) inhibited the levels of secreted MMP-9 (protein and activity) and TNF-alpha protein, without altering mRNA levels. By establishing for the first time that Pr(2)TS and Me(2)TS affect proliferation, differentiation and secretion of leukemic cell lines, this study provides the opportunity to explore the potential efficiency of these molecules in AML.
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Affiliation(s)
- Faten Merhi
- UMR 7131 UPMC Paris Universitas/ CNRS, Groupe Hospitalier Broussais-HEGP, Paris, France
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30
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Balasubramanian S, Fan M, Messmer-Blust AF, Yang CH, Trendel JA, Jeyaratnam JA, Pfeffer LM, Vestal DJ. The interferon-gamma-induced GTPase, mGBP-2, inhibits tumor necrosis factor alpha (TNF-alpha) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-kappaB and Rac protein. J Biol Chem 2011; 286:20054-64. [PMID: 21502320 PMCID: PMC3103378 DOI: 10.1074/jbc.m111.249326] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2011] [Revised: 04/15/2011] [Indexed: 11/06/2022] Open
Abstract
Matrix metalloproteinase-9 (MMP-9) is important in numerous normal and pathological processes, including the angiogenic switch during tumor development and tumor metastasis. Whereas TNF-α and other cytokines up-regulate MMP-9 expression, interferons (IFNs) inhibit MMP-9 expression. We found that IFN-γ treatment or forced expression of the IFN-induced GTPase, mGBP-2, inhibit TNF-α-induced MMP-9 expression in NIH 3T3 fibroblasts, by inhibiting MMP-9 transcription. The NF-κB transcription factor is required for full induction of MMP-9 by TNF-α. Both IFN-γ and mGBP-2 inhibit the transcription of a NF-κB-dependent reporter construct, suggesting that mGBP-2 inhibits MMP-9 induction via inhibition of NF-κB-mediated transcription. Interestingly, mGBP-2 does not inhibit TNF-α-induced degradation of IκBα or p65/RelA translocation into the nucleus. However, mGBP-2 inhibits p65 binding to a κB oligonucleotide probe in gel shift assays and to the MMP-9 promoter in chromatin immunoprecipitation assays. In addition, TNF-α activation of NF-κB in NIH 3T3 cells is dependent on Rac activation, as evidenced by the inhibition of TNF-α induction of NF-κB-mediated transcription by a dominant inhibitory form of Rac1. A role for Rac in the inhibitory action of mGBP-2 on NF-κB is further shown by the findings that mGBP-2 inhibits TNF-α activation of endogenous Rac and constitutively activate Rac can restore NF-κB transcription in the presence of mGBP-2. This is a novel mechanism by which IFNs can inhibit the cytokine induction of MMP-9 expression.
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Affiliation(s)
- Sujata Balasubramanian
- From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606 and
| | - Meiyun Fan
- the Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38163
| | | | - Chuan H. Yang
- the Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38163
| | - Jill A. Trendel
- From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606 and
| | - Jonathan A. Jeyaratnam
- From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606 and
| | - Lawrence M. Pfeffer
- the Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38163
| | - Deborah J. Vestal
- From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606 and
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31
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Casabonne D, Reina O, Benavente Y, Becker N, Maynadié M, Foretová L, Cocco P, González-Neira A, Nieters A, Boffetta P, Middeldorp JM, de Sanjose S. Single nucleotide polymorphisms of matrix metalloproteinase 9 (MMP9) and tumor protein 73 (TP73) interact with Epstein-Barr virus in chronic lymphocytic leukemia: results from the European case-control study EpiLymph. Haematologica 2010; 96:323-7. [PMID: 21048031 DOI: 10.3324/haematol.2010.031161] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Using EpiLymph case-control data, we found that chronic lymphocytic leukemia patients were more likely to have abnormal reactive serological patterns to Epstein Barr virus than controls. Here, we aimed to assess whether this association is modified by genetic variants. We examined 1,305 Single Nucleotide Polymorphisms from 300 selected genes related to various pathways in 240 cases and 513 controls from five European centers. In a recessive model, patients positive to aberrant antibody pattern and homozygous for rare genotypes in rs8113877T>G or rs17576A>G of the MMP9 gene were at highest risk of chronic lymphocytic leukemia. In a dominant model, TP73 showed the highest risk in patients positive to aberrant antibody pattern and homozygous for the wild-type genotype in rs1885859G>C or rs3765701A>T. All interactions were additive and no main effect was observed. The strong interactions observed may be indicative of a specific pathway in cancer genesis. Confirmation of these results is warranted.
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Affiliation(s)
- Delphine Casabonne
- Unit of Infections and Cancer (UNIC), IDIBELL, Institut Català d’Oncologia, L’Hospitalet de Llobregat, Barcelona, Spain.
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Karroum A, Mirshahi P, Benabbou N, Faussat AM, Soria J, Therwath A, Mirshahi M, Hatmi M. Matrix metalloproteinase-9 is required for tubular network formation and migration of resistant breast cancer cells MCF-7 through PKC and ERK1/2 signalling pathways. Cancer Lett 2010; 295:242-251. [PMID: 20359813 DOI: 10.1016/j.canlet.2010.03.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2009] [Revised: 03/04/2010] [Accepted: 03/07/2010] [Indexed: 01/29/2023]
Abstract
Matrix metalloproteinase-9 (MMP-9) strongly influences tumor development and metastasis. Using resistant (rMCF-7) and sensitive (sMCF-7) breast cancer lines we investigated the role of MMP-9 in cell migration (CM) and tubular network (TN) formation, two processes implied in tumor growth and metastasis. Our data demonstrate that MMP-9 which is critical for CM is necessary but not sufficient for TN formation and suggest a link between MDR1/P-gp and constitutive MMP-9. Both TN formation and CM are dependent on PKC and ERK1/2 pathways. This study reinforces the logic of combining therefore MMP inhibitors in cancer therapy, especially in patients with chemoresistance and invasion/metastasis.
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33
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Lagarrigue F, Dupuis-Coronas S, Ramel D, Delsol G, Tronchère H, Payrastre B, Gaits-Iacovoni F. Matrix Metalloproteinase-9 Is Upregulated in Nucleophosmin-Anaplastic Lymphoma Kinase–Positive Anaplastic Lymphomas and Activated at the Cell Surface by the Chaperone Heat Shock Protein 90 to Promote Cell Invasion. Cancer Res 2010; 70:6978-87. [DOI: 10.1158/0008-5472.can-10-0861] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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34
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Redondo-Muñoz J, Ugarte-Berzal E, Terol MJ, Van den Steen PE, Hernández del Cerro M, Roderfeld M, Roeb E, Opdenakker G, García-Marco JA, García-Pardo A. Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain. Cancer Cell 2010; 17:160-72. [PMID: 20159608 DOI: 10.1016/j.ccr.2009.12.044] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2009] [Revised: 08/31/2009] [Accepted: 12/02/2009] [Indexed: 12/19/2022]
Abstract
Matrix metalloproteinase-9 (MMP-9) is the major MMP produced by B-CLL cells and contributes to their tissue infiltration by degrading extracellular and membrane-anchored substrates. Here we describe a different function for MMP-9 in B-CLL, which involves the hemopexin domain rather than its catalytic function. Binding of soluble or immobilized (pro)MMP-9, a catalytically inactive proMMP-9 mutant, or the MMP-9 hemopexin domain to its docking receptors alpha4beta1 integrin and CD44v, induces an intracellular signaling pathway that prevents B-CLL apoptosis. This pathway is induced in all B-CLL cases, is active in B-CLL lymphoid tissues, and consists of Lyn activation, STAT3 phosphorylation, and Mcl-1 upregulation. Our results establish that MMP/receptor binding induces intracellular survival signals and highlight the role of (pro)MMP-9 in B-CLL pathogenesis.
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MESH Headings
- Apoptosis
- B-Lymphocytes/metabolism
- B-Lymphocytes/pathology
- Cell Adhesion
- Cells, Cultured
- Gene Expression Regulation, Leukemic
- Humans
- Integrin alpha4beta1/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Matrix Metalloproteinase 9/chemistry
- Matrix Metalloproteinase 9/metabolism
- Matrix Metalloproteinase 9/physiology
- Mitochondria/metabolism
- Mitochondria/ultrastructure
- Myeloid Cell Leukemia Sequence 1 Protein
- Phosphorylation
- Protein Structure, Tertiary
- Proto-Oncogene Proteins c-bcl-2/genetics
- Proto-Oncogene Proteins c-bcl-2/metabolism
- STAT3 Transcription Factor/metabolism
- Signal Transduction
- src-Family Kinases/metabolism
- src-Family Kinases/physiology
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VEGF/VEGFR2 interaction down-regulates matrix metalloproteinase-9 via STAT1 activation and inhibits B chronic lymphocytic leukemia cell migration. Blood 2009; 115:846-9. [PMID: 19965686 DOI: 10.1182/blood-2009-08-239426] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
B-cell chronic lymphocytic leukemia (B-CLL) migration involves several molecules, including matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF). We have studied whether VEGF regulates MMP-9. VEGF significantly reduced MMP-9 protein expression in a dose-dependent manner, measured by gelatin zymography. Blocking the VEGFR2 receptor restored MMP-9 levels, implicating this receptor in the observed effect. Down-regulation of MMP-9 by VEGF resulted in significant inhibition of B-CLL cell migration through Matrigel or human umbilical vein endothelial cells, confirming the crucial role of MMP-9 in these processes. Reverse-transcription polymerase chain reaction analyses revealed that VEGF regulated MMP-9 at the transcriptional level. Indeed, VEGF induced STAT1 tyrosine phosphorylation, and this was blocked by inhibiting VEGFR2. STAT1 was responsible for MMP-9 down-regulation, as STAT1 gene silencing restored MMP-9 production and B-CLL cell migration in the presence of VEGF. Thus, the levels of VEGF and MMP-9 influence B-CLL cell expansion and both molecules could constitute therapeutic targets for this disease.
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36
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Does adiponectin act as an antiangiogenic factor in B-cell chronic lymphocytic leukemia? Adv Hematol 2009; 2009:287974. [PMID: 19960063 PMCID: PMC2778818 DOI: 10.1155/2009/287974] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2009] [Accepted: 05/21/2009] [Indexed: 11/17/2022] Open
Abstract
Angiogenesis is involved in the pathogenesis of B-cell chronic lymphocytic leukemia (CLL), and high microvascular density has been found in CLL to be associated with a poor prognosis. In this study, we assessed serum levels of adiponectin in 69 patients with Binet stage A B-CLL, and these values were retrospectively correlated with bone marrow (BM) microvessel area and serum levels of vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), angiogenin, PECAM-1 (CD31), matrix metalloproteinase-9 (MMP-9), interleukin-8 (IL-8), syndecan-1, and the percentage of CD38+ or ZAP-70+ CLL cells. The positive correlation between serum levels of adiponectin and VEGF (P = .03) does not translate into an increase of the extent of BM angiogenesis (P = .404), FGF-2 (P = .348), angiogenin (P = .402), and CD31 (P = .248) serum concentrations. Accordingly, IL-8 (P = .175), syndecan-1 (P = .06), and MMP-9 (P = .144) circulating levels were not likely to reflect adiponectin concentration. Furthermore, patients with higher levels of adiponectin had a more favorable biological profile as defined by a lower number of both CD38− (r = −0.294; P = .02) and ZAP-70+ (r = −0.285; P = .04). Finally, we evaluated the presence of adiponectin in B-CLL cells at gene expression level. RMA intensity values for adiponectin gene transcript denote a homogeneous low expression in B-CLL cells, whereas VEGF transcript was highly expressed with a degree of interpatient variability. Overall, these data seem to indicate that adiponectin could be involved as an antiangiogenic factor in B-CLL.
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37
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Wong MLH, Prawira A, Kaye AH, Hovens CM. Tumour angiogenesis: its mechanism and therapeutic implications in malignant gliomas. J Clin Neurosci 2009; 16:1119-30. [PMID: 19556134 DOI: 10.1016/j.jocn.2009.02.009] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2008] [Revised: 01/31/2009] [Accepted: 02/03/2009] [Indexed: 12/15/2022]
Abstract
Angiogenesis is a key event in the progression of malignant gliomas. The presence of microvascular proliferation leads to the histological diagnosis of glioblastoma multiforme. Tumour angiogenesis involves multiple cellular processes including endothelial cell proliferation, migration, reorganisation of extracellular matrix and tube formation. These processes are regulated by numerous pro-angiogenic and anti-angiogenic growth factors. Angiogenesis inhibitors have been developed to interrupt the angiogenic process at the growth factor, receptor tyrosine kinase and intracellular kinase levels. Other anti-angiogenic therapies alter the immune response and endogeneous angiogenesis inhibitor levels. Most anti-angiogenic therapies for malignant gliomas are in Phase I/II trials and only modest efficacies are reported for monotherapies. The greatest potential for angiogenesis inhibitors may lie in their ability to combine safely with chemotherapy and radiotherapy.
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Affiliation(s)
- Michael L H Wong
- Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.
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38
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Types I and II interferons upregulate the costimulatory CD80 molecule in monocytes via interferon regulatory factor-1. Biochem Pharmacol 2009; 78:514-22. [PMID: 19433065 DOI: 10.1016/j.bcp.2009.05.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2009] [Revised: 04/30/2009] [Accepted: 05/04/2009] [Indexed: 11/20/2022]
Abstract
CD80/B7.1 expressed on monocytes plays a prominent role in the activation of T cell-mediated immunity and its level is reduced in monocytes from cancer patients. Type I (alpha/beta) and type II (gamma) IFNs are widely administered as adjuvant therapy. We show here that both classes of IFNs upregulate CD80 mRNA and protein in primary monocytes ex vivo. The stimulatory action of IFN-alpha/beta on CD80 is accompanied by the activation of both interferon regulatory factors IRF-1 and IRF-7, whereas IFN-gamma stimulating effect is associated only with IRF-1 induction. IFNs concomitantly upregulate the transcription of CD40 costimulatory molecule whose activation is known to require IRF-1. In monocytic U937 cells, IRF-1 is activated by IFN-gamma but not by IFN-alpha/beta, whereas it is the reverse for IRF-7; in the latter cells, only IFN-gamma is capable of stimulating CD80 transcription emphasizing the essential role of IRF-1. Moreover, siRNA against IRF-1 prevents IFN-gamma-mediated CD80 activation. In AML cells, IFNs upregulate CD40, CD80 and IRF-1 in the FAB-M4/M5 subtypes but not in the less differentiated M1/M2 subtypes. Monitoring the expression of CD80 on AML cells and its modulation by IFNs could help to predict the patients more susceptible to benefit from therapeutic strategies aimed at eliciting specific T cell responses to leukemia-associated antigens.
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39
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Bozkurt C, Ertem U, Oksal A, Sahin G, Yüksek N, Birgen D. Expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in tissues with a diagnosis of childhood lymphoma. Pediatr Hematol Oncol 2008; 25:621-9. [PMID: 18850474 DOI: 10.1080/08880010802313657] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Matrix metalloproteinases (MMP) are enzymes involved in the reconfiguration of the microenvironment by means of degrading the extracellular matrix and have more than 20 subgroups containing zinc. Proteins that serve as the inhibitors of these enzymes are called tissue inhibitors of matrix metalloproteinase (TIMP). These enzymes have been shown to be active in a wide range of processes, from wound recovery to fetus development, heart diseases, and spread of malignant diseases. The aim of this study was to investigate whether there is a relationship between the type, stage, and prognosis of childhood lymphoma subjects and matrix metalloproteinase type-9 (MMP-9) and its inhibitor, tissue inhibitor of matrix metalloproteinase type-1 (TIMP-1). Paraffin blocks of childhood patients diagnosed with non-Hodgkin lymphoma (n = 23), Hodgkin lymphoma (n = 14), or reactive lymphadenopathy (n = 12) were retrospectively immunohistochemically stained with MMP-9 and TIMP-1 stains and whether there was a relationship between the degree of staining and the type, tumor stage, and prognosis of the disease was investigated. Moderate and high degrees of MMP-9 staining were detected in 94.6% of the lymphoma patient tissues and a slight TIMP-1 staining was detected in 21.6% of the lymphoma patient tissues. No relationship was observed between the degree of these staining patterns and the type, tumor stage, and prognosis of the disease. This study indicates that the equilibrium between MMP-9 and TIMP-1 is important in lymphomas in addition to all the physiological and pathologic events although MMP-9 and the TIMP-1 staining patterns are not related to the tumor stage, prognosis, and type of the disease. Larger series of patients are needed to determine the prognostic value of MMP-9 and TIMP-1 in childhood lymphoma.
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Affiliation(s)
- Ceyhun Bozkurt
- Department of Pediatric Oncology and Pathology, Dr. Sami Ulus Children's Hospital, Ankara, Turkey.
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40
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Alpha4beta1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells. Blood 2008; 112:169-78. [PMID: 18326820 DOI: 10.1182/blood-2007-08-109249] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
As B-cell chronic lymphocytic leukemia (B-CLL) progresses, malignant cells extravasate and infiltrate lymphoid tissues. Several molecules, including gelatinase B/MMP-9, contribute to these processes. Although mainly a secreted protease, some MMP-9 is present at the B-CLL cell surface and the function, mode of anchoring, and interactions of this MMP-9 are unknown. Here we show that anti-MMP-9 antibodies immunoprecipitated a 190-kDa CD44v isoform and alpha4beta1 integrin from B-CLL cells, but not from normal B cells. Function-blocking antibodies to alpha4beta1 or CD44, or transfection with specific siRNAs, decreased cell-associated proMMP-9 and increased the secreted form. B-CLL cells attached to and bound proMMP-9 and active MMP-9, and this was inhibited by blocking the expression or function of alpha4beta1 or CD44. The MMP-9 hemopexin domain was critical in these interactions. alpha4beta1 and 190-kDa CD44v (but not CD44H) formed a complex at the cell surface, since they both coimmunoprecipitated with anti-alpha4, anti-beta1, or anti-CD44 antibodies. Immunofluorescence analyses confirmed that alpha4beta1 and CD44v colocalized with MMP-9. Binding of proMMP-9 inhibited B-CLL cell migration, and this required MMP-9 proteolytic activity. Thus, we have identified alpha4beta1 and CD44v as a novel proMMP-9 cell surface docking complex and show that cell-associated MMP-9 may regulate B-CLL cell migration and arrest.
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41
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Redondo-Muñoz J, José Terol M, García-Marco JA, García-Pardo A. Matrix metalloproteinase-9 is up-regulated by CCL21/CCR7 interaction via extracellular signal-regulated kinase-1/2 signaling and is involved in CCL21-driven B-cell chronic lymphocytic leukemia cell invasion and migration. Blood 2008; 111:383-6. [PMID: 17890452 DOI: 10.1182/blood-2007-08-107300] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
B-cell chronic lymphocytic leukemia (B-CLL) progression is frequently accompanied by clinical lymphadenopathy, and the CCL21 chemokine may play an important role in this process. Indeed, CCR7 (the CCL21 receptor), as well as matrix metalloproteinase-9 (MMP-9), are overexpressed in infiltrating B-CLL cells. We have studied whether MMP-9 is regulated by CCL21 and participates in CCL21-dependent migration. CCL21 significantly increased B-CLL MMP-9 production, measured by gelatin zymography. This was inhibited by blocking extracellular signal-regulated kinase-1/2 (ERK1/2) activity or by cell transfection with CCR7-siRNA. Accordingly, CCL21/CCR7 interaction activated the ERK1/2/c-Fos pathway and increased MMP-9 mRNA. CCL21-driven B-CLL cell migration through Matrigel or human umbilical vein endothelial cells (HUVEC) was blocked by anti-CCR7 antibodies, CCR7-siRNA transfection, or the ERK1/2 inhibitor U0126, as well as by anti-MMP-9 antibodies or tissue inhibitor of metalloproteinase 1 (TIMP-1). These results strongly suggest that MMP-9 is involved in B-CLL nodal infiltration and expand the roles of MMP-9 and CCR7 in B-CLL progression. Both molecules could thus constitute therapeutic targets for this disease.
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Affiliation(s)
- Javier Redondo-Muñoz
- Departamento de Fisiopatología Celular y Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid
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Aref S, Salama O, Shamaa S, El-Refaie M, Mourkos H. Angiogenesis factor pattern differs in acute lymphoblastic leukemia and chronic lymphocytic leukemia. ACTA ACUST UNITED AC 2007; 12:319-24. [PMID: 17654059 DOI: 10.1080/10245330701340759] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Angiogenesis is an important event in the survival and progression of solid tumors. The angiogenic status and the exact role of the angiogenic cytokines in lymphoid leukemia has not been fully elucidated. We have investigated the profile of the systemic components of angiogenic regulation in B-lineage acute lymphoblastic leukemia (B-ALL) and B-chronic lymphocytic leukemia (B-CLL), namely vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-alpha), endostatin and matrix metalloproteinase-9 (MMP-9) using enzyme-linked immunosorbent assay (ELISA). In B-ALL patients, sVEGF, and MMP-9 were significantly lower than control levels at diagnosis (p < 0.001) and increased to near control levels in remission (p>0.05). Both serum TNF-alpha and endostatin levels showed no significant difference at diagnosis (p>0.05) and in remission (p>0.05) compared to control levels. VEGF, TNF-alpha, MMP-9 and endostatin levels were not significantly correlated with peripheral white cell count or bone marrow blast cell count, but were positively correlated with platelet count. In B-CLL patients, serum VEGF, MMP-9 and TNF-alpha were significantly higher (p < 0.001 = 0.009, 0.007, respectively) and decreased to near control levels in remission (p>0.05 for all). Serum endostatin levels showed no significant difference at diagnosis and in remission compared to control levels (p>0.05). A significant positive correlation between VEGF, TNF-alpha, MMP-9 and peripheral white cell counts, bone marrow lymphocytic count and platelets count were found. In conclusion, our data suggest that the driving forces of angiogenic factors (VEGF, TNF-alpha and MMP-9) in adult B-ALL appears different from that in B-CLL patients.
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Affiliation(s)
- Salah Aref
- Hematology Unit, Clinical Pathology Department, Mansoura Faculty of Medicine, Mansoura, Egypt.
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43
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El Houda Agueznay N, Badoual C, Hans S, Gey A, Vingert B, Peyrard S, Quintin-Colonna F, Ravel P, Bruneval P, Roncelin S, Lelongt B, Bertoglio J, Fridman WH, Brasnu D, Tartour E. Soluble interleukin-2 receptor and metalloproteinase-9 expression in head and neck cancer: prognostic value and analysis of their relationships. Clin Exp Immunol 2007; 150:114-23. [PMID: 17680822 PMCID: PMC2219282 DOI: 10.1111/j.1365-2249.2007.03464.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
In a series of 84 head and neck patients, a statistically significant correlation was observed between high serum soluble interleukin (IL)-2 receptor alpha (sIL-2Ralpha) (P = 0.034) and metalloproteinase-9 (MMP-9) concentrations (P = 0.036) at diagnosis and a shorter survival of these patients. As MMP-9 has been shown to mediate cleavage of IL-2Ralpha (CD25) by preactivated T cells, we looked for a relationship between MMP-9 expression and soluble IL-2Ralpha serum concentrations in these cancer patients. We did not find any correlation between intratumoral expression of MMP-9 or serum MMP-9 concentrations and serum sIL-2Ralpha levels. These results led us to reassess the role of MMP-9 in the release of sIL-2Ralpha. Treatment of Kit225 leukaemic cells with recombinant MMP-9 slightly decreased membrane CD25 expression and was associated with an increased concentration of sIL-2Ralpha in the supernatants. However, using a selective inhibitor of MMP-9 we did not succeed in specifically inhibiting the release of sIL-2Ralpha by the Kit225 cell line or by phytohaemagglutinin (PHA)-activated peripheral blood mononuclear cells. In addition, in a preclinical mouse model, basal serum sIL-2Ralpha concentrations and sIL-2Ralpha production by activated cells were not altered in MMP-9-deficient mice compared to wild-type mice. Interestingly, a broad spectrum metalloproteinase inhibitor inhibited the release of sIL-2Ralpha by PHA-activated peripheral blood mononuclear cells, suggesting that in contrast with current views concerning the major role of MMP-9 in the cleavage of membrane IL-2Ralpha, other proteases are involved in the shedding of sIL-2Ralpha. MMP-9 and sIL-2Ralpha appear therefore as independent prognostic markers in head and neck cancers.
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Affiliation(s)
- N El Houda Agueznay
- EA 4054 Université Paris Descartes, Ecole Nationale Vétérinaire d'Alfort, Paris, France
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Olszewski MA, Gray J, Vestal DJ. In silico genomic analysis of the human and murine guanylate-binding protein (GBP) gene clusters. J Interferon Cytokine Res 2007; 26:328-52. [PMID: 16689661 DOI: 10.1089/jir.2006.26.328] [Citation(s) in RCA: 124] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The guanylate-binding proteins (GBPs) were among the first interferon (IFN)-stimulated genes (ISGs) discovered, but until recently, little was known about their functions and even less about the composition of the gene family. Analysis of the promoter of human GBP-1 contributed significantly toward the understanding of Jak-Stat signaling and the delineation of the IFN-gamma activation site (GAS) and IFN-stimulated response element (ISRE) promoter elements. In this study, we have examined the genomic arrangement and composition of the GBPs in both mouse and humans. There are seven GBP paralogs in humans and at least one pseudogene, all of which are located in a cluster of genes on chromosome 1. Five of the six MuGBPs and a GBP pseudogene are clustered in a syntenic region on chromosome 3. The sixth MuGBP, MuGBP-4, and three GBP pseudogenes are located on chromosome 5. As might be expected, the GBPs share similar genomic organizations of introns and exons. Five of the MuGBPs had previously been shown to be coordinately induced by IFNs, and as expected, all of the MuGBPs have GAS and ISRE elements in their promoters. Interestingly, not all of the HuGBPs have GAS and ISRE elements, suggesting that not all GBPs are IFN responsive in humans.
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Affiliation(s)
- Maureen A Olszewski
- Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA
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Molica S, Vacca A, Mirabelli R, Ria R, Ribatti D. Angiogenesis in Chronic Lymphocytic Leukemia: An Emerging Target. ACTA ACUST UNITED AC 2006. [DOI: 10.3816/clk.2006.n.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Letilovic T, Vrhovac R, Verstovsek S, Jaksic B, Ferrajoli A. Role of angiogenesis in chronic lymphocytic leukemia. Cancer 2006; 107:925-34. [PMID: 16832815 DOI: 10.1002/cncr.22086] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Angiogenesis is a physiologic process of new blood vessels formation mediated by various cytokines called angiogenic and angiostatic factors. Although its potential pathophysiologic role in solid tumors has been extensively studied for more than 3 decades, enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematological disorders has been recognized more recently. An increased level of angiogenesis has been documented by various experimental methods both in bone marrow and lymph nodes of patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease remains to be fully elucidated, experimental data suggest that several angiogenic factors play a role in the disease progression. Biologic markers of angiogenesis were also shown to be of prognostic relevance in CLL. The current findings provide the rationale for investigating antiangiogenic agents in CLL. In the current review angiogenesis in CLL is discussed and its potential diagnostic and therapeutic applications.
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MESH Headings
- Angiogenesis Inducing Agents/analysis
- Angiogenesis Inhibitors/therapeutic use
- Cytokines/physiology
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Matrix Metalloproteinases/metabolism
- Models, Biological
- Neovascularization, Pathologic
- Prognosis
- Receptors, Vascular Endothelial Growth Factor/metabolism
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Trocme C, Leroy V, Sturm N, Hilleret MN, Bottari S, Morel F, Zarski JP. Longitudinal evaluation of a fibrosis index combining MMP-1 and PIIINP compared with MMP-9, TIMP-1 and hyaluronic acid in patients with chronic hepatitis C treated by interferon-alpha and ribavirin. J Viral Hepat 2006; 13:643-51. [PMID: 16970595 DOI: 10.1111/j.1365-2893.2006.00730.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
We have recently described a fibrosis index combining serum procollagen type III N-terminal peptide (PIIINP) and matrix metalloproteinase 1 (MMP-1) concentrations for evaluating the amount of liver fibrosis in chronic hepatitis C patients. The aims of the present study were to validate this score in another cohort of patients and to assess its variations along those of TIMP-1, hyaluronic acid (HA) and MMP-9 during antiviral treatment. Seventy-nine patients treated by interferon-alpha and ribavirin for 24 or 48 weeks were included. A liver biopsy was performed within the 6 months before the start of treatment. Serum markers were measured in serum collected the day of the liver biopsy, at start of treatment, and every 3 months during treatment and a 6-month follow-up period. The PIIINP/MMP-1 index was significantly correlated to the METAVIR fibrosis (r = 0.68, P < 0.001). Its overall diagnostic value defined by the area under the receiver operating characteristics curves was 0.77 for discriminating F1 vs F2F3F4, and 0.81 for discriminating F1F2 vs F3F4, and was better than that observed for HA and TIMP-1. At the end of follow-up, the PIIINP/MMP-1 index significantly decreased in responders and remained stable in nonresponder patients. This decrease occurred early and continued regularly during the treatment period. This variation was because of both a decrease of PIIINP and an increase of MMP-1 concentrations. HA and TIMP-1 serum concentrations were also significantly lower at the end of follow-up in responder patients, but early changes were minimal and not influenced by the response to treatment. Our study shows that a noninvasive index combining PIIINP and MMP-1 is a useful tool to follow-up fibrosis change during and after antiviral therapy chronic hepatitis C patients.
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Affiliation(s)
- C Trocme
- Laboratoire d'Enzymologie, DBPC, GREPI EA 2938, France
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Sick building syndrome (SBS) and exposure to water-damaged buildings: time series study, clinical trial and mechanisms. Neurotoxicol Teratol 2006; 28:573-88. [PMID: 17010568 DOI: 10.1016/j.ntt.2006.07.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2006] [Revised: 06/27/2006] [Accepted: 07/31/2006] [Indexed: 10/24/2022]
Abstract
Occupants of water-damaged buildings (WDBs) with evidence of microbial amplification often describe a syndrome involving multiple organ systems, commonly referred to as "sick building syndrome" (SBS), following chronic exposure to the indoor air. Studies have demonstrated that the indoor air of WDBs often contains a complex mixture of fungi, mycotoxins, bacteria, endotoxins, antigens, lipopolysaccharides, and biologically produced volatile compounds. A case-series study with medical assessments at five time points was conducted to characterize the syndrome after a double-blinded, placebo-controlled clinical trial conducted among a group of study participants investigated the efficacy of cholestyramine (CSM) therapy. The general hypothesis of the time series study was that chronic exposure to the indoor air of WDBs is associated with SBS. Consecutive clinical patients were screened for diagnosis of SBS using criteria of exposure potential, symptoms involving at least five organ systems, and the absence of confounding factors. Twenty-eight cases signed voluntary consent forms for participation in the time-series study and provided samples of microbial contaminants from water-damaged areas in the buildings they occupied. Twenty-six participants with a group-mean duration of illness of 11 months completed examinations at all five study time points. Thirteen of those participants also agreed to complete a double-blinded, placebo-controlled clinical trial. Data from Time Point 1 indicated a group-mean of 23 out of 37 symptoms evaluated; and visual contrast sensitivity (VCS), an indicator of neurological function, was abnormally low in all participants. Measurements of matrix metalloproteinase 9 (MMP9), leptin, alpha melanocyte stimulating hormone (MSH), vascular endothelial growth factor (VEGF), immunoglobulin E (IgE), and pulmonary function were abnormal in 22, 13, 25, 14, 1, and 7 participants, respectively. Following 2 weeks of CSM therapy to enhance toxin elimination rates, measurements at Time Point 2 indicated group-means of 4 symptoms with 65% improvement in VCS at mid-spatial frequency-both statistically significant improvements relative to Time Point 1. Moderate improvements were seen in MMP9, leptin, and VEGF serum levels. The improvements in health status were maintained at Time Point 3 following a 2-week period during which CSM therapy was suspended and the participants avoid re-exposure to the WDBs. Participants reoccupied the respective WDBs for 3 days without CSM therapy, and all participants reported relapse at Time Point 4. The group-mean number of symptoms increased from 4 at Time Point 2 to 15 and VCS at mid-spatial frequency declined by 42%, both statistically significant differences relative to Time Point 2. Statistically significant differences in the group-mean levels of MMP9 and leptin relative to Time Point 2 were also observed. CSM therapy was reinstated for 2 weeks prior to assessments at Time Point 5. Measurements at Time Point 5 indicated group-means of 3 symptoms and a 69% increase in VCS, both results statistically different from those at Time Points 1 and 4. Optically corrected Snellen Distance Equivalent visual acuity scores did not vary significantly over the course of the study. Group-mean levels of MMP9 and leptin showed statistically significant improvement at Time Point 5 relative to Time Points 1 and 4, and the proportion of participants with abnormal VEGF levels was significantly lower at Time Point 5 than at Time Point 1. The number of participants at Time Point 5 with abnormal levels of MMP9, leptin, VEGF, and pulmonary function were 10, 10, 9, and 7, respectively. The level of IgE was not re-measured because of the low incidence of abnormality at Time Point 1, and MSH was not re-measured because previously published data indicated a long time course for MSH improvement. The results from the time series study supported the general study hypothesis that exposure to the indoor air of WDBs is associated with SBS. High levels of MMP9 indicated that exposure to the complex mixture of substances in the indoor air of the WDBs triggered a pro-inflammatory cytokine response. A model describing modes of action along a pathway leading to biotoxin-associated illness is presented to organize current knowledge into testable hypotheses. The model links an inflammatory response with tissue hypoxia, as indicated by abnormal levels of VEGF, and disruption of the proopiomelanocortin pathway in the hypothalamus, as evidenced by abnormalities in leptin and MSH levels. Results from the clinical trial on CSM efficacy indicated highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline in the 7 participants randomly assigned to receive 2 weeks of CSM therapy, but no improvement in the 6 participants assigned placebo therapy during that time interval. However, those 6 participants also showed a highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline following a subsequent 2-week period of CSM therapy. Because the only known benefit of CSM therapy is to enhance the elimination rates of substances that accumulate in bile by preventing re-absorption during enterohepatic re-circulation, results from the clinical trial also supported the general study hypothesis that SBS is associated with exposure to WDBs because the only relevant function of CSM is to bind and remove toxigenic compounds. Only research that focuses on the signs, symptoms, and biochemical markers of patients with persistent illness following acute and/or chronic exposure to WDBs can further the development of the model describing modes of action in the biotoxin-associated pathway and guide the development of innovative and efficacious therapeutic interventions.
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Redondo-Muñoz J, Escobar-Díaz E, Samaniego R, Terol MJ, García-Marco JA, García-Pardo A. 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. Blood 2006; 108:3143-51. [PMID: 16840734 DOI: 10.1182/blood-2006-03-007294] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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.
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Affiliation(s)
- Javier Redondo-Muñoz
- Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
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