[Frontiers in Bioscience 10, 1581-1596, May 1, 2005]

THE ROLE OF THE TUMOR MICROENVIRONMENT IN HEMATOLOGICAL MALIGNANCIES AND IMPLICATION FOR THERAPY

Jianbiao Zhou, Katja Mauerer, Lucia Farina and John G Gribben

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Pathogenesis of microenvironment in hematological malignancies
3.1. Acute leukemia and myelodysplastic syndrome
3.1.1. Acute lymphoblastic leukemia
3.1.2. Acute myeloid leukemia and myelodysplastic syndrome
3.2. Lymphoma and chronic lymphocytic leukemia
3.2.1. Lymphoma
3.2.2. Chronic lymphocytic leukemia
3.3. Multiple myeloma
4. Novel therapeutic strategies targeting the microenvironment in hematological malignancies
4.1. Cytokines
4.2. Thalidomide and related analogues
4.3. Proteasome inhibitor
4.4. Arsenic trioxide
4.5. VEGF receptor tyrosine kinase inhibitors and anti-VEGF monoclonal antibodies
4.6. Matrix metalloprotease (MMP) inhibitors
4.7. Farnesyl transferase inhibitors (FTI)
4.8. TNP-470
5. Perspective
6. References

1. ABSTRACT

The tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion, and metastasis by providing survival signals and a sanctuary site for tumor cells, by secretion of growth factors, pro-angiogenesis factors and direct adhesion molecule interactions. Our knowledge of microenvironment is only now beginning to unfold. In this review, the morphological and molecular characteristics of microenvironment in various hematological malignancies including acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, lymphoma, chronic lymphocytic leukemia, and multiple myeloma are summarized and the molecular mechanisms of microenvironment contributing to leukemogenesis are elucidated. We also aim to discuss the encouraging preclinical and clinical trials for treatment of hematological malignancies by targeting the tumor microenvironment. Further understanding of the signal transduction pathways between tumor cells and microenvironment will lead to the development of novel targeted therapeutic agents and more effective combination of current drugs for fighting hematological malignancies.