Elsevier

Leukemia Research

Volume 28, Issue 4, April 2004, Pages 321-324
Leukemia Research

Review
Angiogenesis in acute and chronic lymphocytic leukemia

https://doi.org/10.1016/j.leukres.2003.08.001Get rights and content

Abstract

The bone marrow microenvironment plays a crucial role in leukemogenesis. Recent studies suggest that its vascularity changes significantly during this process and that angiogenic factors are of major importance in leukemia. This review summarizes the literature concerning the relationship between angiogenesis and the progression of acute and chronic lymphocytic leukemia. It is becoming increasingly evident that agents which interfere with angiogenesis also block tumor progression and anti-angiogenic management has become a prominent aspect of pre-clinical and clinical assessment. Recent applications of anti-angiogenic agents which interfere with or block leukemia progression are reviewed.

Introduction

Angiogenesis, i.e. the formation of new blood vessels from pre-existing ones plays a fundamental role in the neoplastic process and is essential for the local progression and metastasis spread of solid tumors [1]. Attention has recently been directed to the role of bone marrow vascularity and angiogenic factors in hematologic disorders [2].

Leukemias originate from hematopoietic stem cells (HSC) that lose the ability capacity to differentiate normally to mature blood cells at different stages of their maturation and differentiation. It is now well established that acute leukemias originate from immature HSC that undergo self-renewal, whereas less aggressive forms such as chronic leukemias seem to originate from more mature, committed HSC. B-cell chronic lymphocytic leukemia (B-cell CLL) is the most common leukemia of older adults and results from proliferation of mature B lymphocytes, mainly in the blood and bone marrow.

Section snippets

Angiogenesis in acute lymphocytic leukemia (ALL)

In a study of 51 children with ALL, bone marrow microvessel density was increased 6–7-fold compared with that of children evaluated for primary tumor. A computer-aided three-dimensional reconstruction of bone marrow vascularity showed complex microvessel arborization in leukemic specimens compared with the single, straight unbranched microvessels in the controls. Neoplastic cells formed cylindrical cords around new microvessels, as in solid tumors. A non-significant decrease in vessel density

Karyotype, CD38 expression and angiogenesis in B-cell CLL

Genomic aberrations are independent predictors of disease progression in early CLL [17]. Their correlation with microvessel area were studied in 28 patients. Thirteen (46.4%) with normal karyotype and 15 (53.6%) with aberrations: 8 had 13q (6 had deletion as a sole aberration, and 2 had 13q plus 12q trisomy), 6 patients displayed 12q trisomy as a sole aberration, and 2 patients 11q or 17p deletions. Patients were stratified into four groups according to major cytogenetic categories (normal

Role of matrix metalloproteinases in angiogenesis in B-cell CLL

Matrix metalloproteinase (MMP) production in vivo and in vitro is increased by angiogenic agents [21]. In cancer proteinase, activity is thought to be an integral part of both generalized tissue remodeling and angiogenesis [22]. MMPs are expressed in hematologic cells, including polymorphonuclear leukocytes, macrophages and lymphocytes. Tissue inhibitors of metalloproteinases (TIMP) are specific inhibitors that participate in controlling the local activities of MMP in tissues.

Hayashibara et al.

Role of stromal compartment in angiogenesis in B cell CLL

Tumor cells are surrounded by an infiltrate of inflammatory cells, namely lymphocytes, neutrophils, macrophages and mast cells (MC), which communicate via a complex network of intercellular signaling pathways mediated by surface adhesion molecules, cytokines and their receptors. MC density is highly correlated with the extent of both normal and pathological angiogenesis, such as that in chronic inflammatory diseases and tumors [28]. The mechanism of MC-mediated neovascularization has been

Anti-angiogenesis in leukemia

Anti-angiogenesis is a promising therapeutic approach in cancer. Pre-clinical studies with various angiogenesis inhibitors have produced remarkable anti-tumor effects in animal models and inhibitors are now the subject of trials for human cancers.

Leukemic cells release endothelial growth factors and activated endothelial cells release cytokines that stimulate leukemia cell growth. Targeting both tumor cells with conventional cytotoxic agents and endothelial cells with angiogenesis inhibitors

Acknowledgements

Supported in part by Associazione Italiana per la Ricerca sul Cancro (AIRC, Milan) and Ministry for Education, the Universities and Research (MIUR, “Molecular Engineering—C03” funds, Inter-university Funds for Basic Research (FIRB), Rome), Italy.

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