Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) in hematological malignancies

Outi Kuittinen

Department of Oncology and Radiotherapy, University of Oulu
University Hospital of Oulu

Abstract

Gelatinases (MMP-2 and MMP-9) play a key role during invasion and metastazising of malignant cells and they have been shown to be associated to invasive phenotype and poor prognosis in several solid tumours. However little is known about their role in hematological malignancies. In the present work, gelatinase expression and its clinicopathological correlations were studied with immunohistochemical staining in 10 cases representing normal bone marrow aspirate smears, 123 cases representing diagnostic bone marrow samples of patients with different leukaemias (35 AML, 7 CLL, 6 CML, 75 ALL), 67 diagnostic paraffin-embedded lymph node biopsies from patients with Hodgkin"s lymphoma and 57 biopsies from patients with non-Hodgkin"s lymphomas. The lymphoma samples were also stained with factor VIII antibody to evaluate the extent of new vessel formation and the non-Hodgkin"s lymphoma cases also with tissue inhibitor of metalloproteinases -1 (TIMP-1) antibody. CLL did not express either of the MMP enzymes, while CML in the chronic phase expressed strongly both of the enzymes. In ALL, gelatinase expression was weak and detectable in pediatric cases in only 12.7% and in the adults in 65% of the cases. In adult ALL, MMP-2 expression correlated strongly with an extramedullary and invasive pattern of disease presentation. In AML MMP-2 positivity had markedly favorable prognostic and predictive power. In lymphoma studies, no correlations could be detected between gelatinase expression and the clinical parameters of invasion. MMP-9 positivity was related to the presence of B symptoms, which difference was statistically significant in Hodgkin"s lymphoma. In Hodgkin"s lymphoma, strong MMP-9 expression also implicated decreased neovascularization. In both lymphoma types, strong MMP-9 expression correlated with unfavorable prognosis, which difference was statistically significant in non-Hodgkin"s lymphomas and remained as a tendency in Hodgkin"s lymphoma. MMP-2 had statistically significant association with a favorable prognosis in Hodgkin"s lymphoma. Combination of the results of both stainings further increased prognostic power. All together these findings implicate that gelatinases could be used as prognostic tools in AML and lymphomas albeit this needs to be verified in larger materials.

Dedication

To my parents Aune and Toivo Kuittinen and my daughters Siria, Aurora and Jasmiini Lemma

Table of Contents

Acknowledgements

Abbreviations

List of the original articles

1. Introduction

2. Review of the literature

2.1. Hematological malignancies

2.1.1. Acute myeloid leukemia
2.1.2. Acute lymphatic leukemia
2.1.3. Hodgkin´s lymphoma
2.1.4. Non-Hodgkin´s lymphoma

2.2. Gelatinases and their inhibitors

2.2.1. Matrix metalloproteinase gene family
2.2.2. Matrix metalloproteinase-2
2.2.3. Matrix metalloproteinase-9
2.2.4. Tissue inhibitor of metalloproteinases-1
2.2.5. Gelatinases and angiogenesis

2.3. Gelatinases in hematology

2.3.1. Hematopoietic stem cells
2.3.2. Granulocytes
2.3.3. Monocyte macrophage lineage
2.3.4. Lymphocytes
2.3.5. Platelets
2.3.6. Bone marrow stromal cells and dendritic cells
2.3.7. Gelatinases in AML
2.3.8. Gelatinases in ALL
2.3.9. Gelatinases in Hodgkin´s lymphoma
2.3.10. Gelatinases in Non-Hodgkin´s lymphomas

3. Aims of the present study

4. Materials and methods

4.1. Patients’ diagnostic work-up and treatment

4.2. Lymphoma patients´ diagnostic work-up and treatment

4.3. Preparation of smears for immunocytochemical staining

4.4. Preparation of paraffin-embedded tumor samples for immunohistochemistry

4.5. Staining procedure

4.6. Sample evaluation

4.6.1. Evaluation of MMP-2 and MMP-9 staining of bone marrow samples
4.6.2. Evaluation of MMP-2 and MMP-9 staining of paraffin-embedded tumor samples
4.6.3. Evaluation of factor VIII staining

4.7. Statistical analysis

5.1. Evaluation of gelatinases A and B and TIMP-1 expression in different hematological malignancies

5.1.1. Expression of gelatinases in normal bone marrow cells (I)
5.1.2. Expression of gelatinases in chronic leukemias (I)
5.1.3. Expression of gelatinases in AML (I)
5.1.4. Expression of gelatinases in ALL (II)
5.1.5. Expression of gelatinases in Hodgkin´s lymphoma (III)
5.1.6. Expression of gelatinases in non-Hodgkin´s lymphomas (IV)

5.2. Correlations of gelatinase expression with clinical disease presentation.

5.2.1. AML (I)
5.2.2. ALL (II)
5.2.3. Hodgkin´s lymphoma (III)
5.2.4. Non-Hodgkin´s lymphoma (IV)

5.3. Effect of MMP-2 or MMP-9 immunoreactive protein on survival in patients with leukemias and lymphomas

5.3.1. AML (I)
5.3.2. ALL (II)
5.3.3. Hodgkin´s lymphoma (III)
5.3.4. Non-Hodgkin´s lymphoma (IV)

5.4. Extent of neovascularization and its correlation with the expression of gelatinases in lymphomas (III and IV)

6. Discussion

6.1. Gelatinases in myeloid leukemia

6.2. Lymphoid malignancies in adult patients

6.2.1. Gelatinase expression in lymphoid malignancies
6.2.2. Impact of gelatinase expression on the invasion of malignant lymphoid tumors
6.2.3. Other clinicopathological correlations
6.2.4. Effects of the staining intensity of the MMP-9 immunoreactive protein on the survival of patients
6.2.5. Effects of the staining intensity of the MMP-2 immunoreactive protein on the survival of patients
6.2.6. Expression of TIMP-1 immunoreactive protein in non-Hodgkin´s lymphomas and its clinicopathological correlations

6.3. Gelatinases in a pediatric ALL

6.4. Angiogenesis and the expression of gelatinases in lymphoid tumors

7. Conclusions

List of Tables
1. Classification of acute myeloid leukemias
2. Known prognostic factors in AML
3. Most important recent publications dealing with clinical and biological prognostic factors in Hodgkin´s lymphoma.
4. Classification of non-Hodgkin´s lymphomas and lymphatic leukemias according to WHO II classification
5. Similarities and differences between two gelatinases
6. Current data in the literature dealing with the role of gelatinases in hematological malignancies.
7. Material of the present study
8. Correlation coefficients of gelatinase expression and various clinical disease characteristics in Hodgkin’s lymphoma.
9. Correlation coefficients of gelatinase expression and various clinical disease characteristics in non-Hodgkin’s lymphoma.
10. Major new findings presented in the current study that adds to the data existing so far from the role of gelatinases in hematological malignancies

List of Figures
1. Interactions of MMP-2, membrane type MMP and TIMP-2 during activation and inavtivation of pro MMP-2. TIMP-2 binding to pro MMP-2 is mandatory for Mt MMP binding and activation of pro MMP-2. Binding of a seconf TIMP-2 or TIMP-1 molecule to an activated MMP-2 inactivates the active MMP-2 enzyme.
2. Schematic presentation of differentiation of blood cells from common stem cells illustrating which cells are known to express gelatinases.

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