Angiogenesis and antiangiogenic therapy in hematologic malignancies
Introduction
Angiogenesis, the generation of new blood capillaries from preexisting blood vessels, is tightly regulated in the adult organism. Physiologically, angiogenesis is fundamental to the female reproductive cycle, tissue repair and wound healing. Pathologic neovascularization has been observed in both non-malignant diseases and cancer [1]. Since it has been postulated that angiogenesis plays an important role in tumor development, progression and metastasis [2], accumulating studies support this so-called āangiogenic hypothesisā. Although angiogenesis has been found to be an adverse prognostic factor in several solid tumors [3], [4], increasing evidence indicates that angiogenesis also plays an important role in hematologic malignancies [5], [6], [7], [8].
In this review, we highlight the current literature on angiogenesis and antiangiogenic therapy in hematologic malignancies, and describe pitfalls and perspective in antiangiogenic treatment in clinical application.
According to the widely accepted angiogenic switch hypothesis, angiogenesis is tightly regulated by a delicate balance between angiogenic activators and inhibitors in tumorigenesis, this balance is derailed, thereby triggering tumor growth, invasion, and metastasis [9]. Pro- and anti-angiogenic factors arise from cancer cells, stromal cells, endothelial cells, inflammatory cells, the extracellular matrix (ECM), and blood. Importantly, the relative contribution of these factors is dependent on the tumor type and site, and their expression changes with tumor growth, regression, and relapse. Tumor growth is currently viewed as a phenomenon associated with neovascularization and sustained production of angiogenic factors, recent studies have emphasized that tumor angiogenesis is a process requiring a higher amount of angiogenic factors for its induction than maintenance [10].
Over the past three decades, a large number of pro- and anti-angiogenic factors have been identified. Table 1 shows a partial list of selected regulatory cytokines associated with the angiogenic process. Among the known angiogenic factors, vascular endothelial growth factor (VEGF) is the most important stimulator of the angiogenic process in physiological and pathological conditions. VEGF is overexpressed in most malignant diseases and correlates with poor prognosis. There is mounting evidence suggesting overexpression of angiogenic factors in particular VEGF in most hematologic malignancies, which may explain the increased angiogenesis found in these malignancies.
The VEGF family currently includes VEGF-A, -B, -C, -D, -E, -F and placenta growth factor (PlGF), that bind in a distinct pattern to three structurally related receptor tyrosine kinases, denoted VEGF receptor-1, -2, and -3 (VEGFR-1,2,3) [11]. VEGF-A, one of the most potent proangiogenic growth factors identified thus far, has been implicated in orchestrating the generation of neovessels in almost all types of pathological settings [12]. VEGF-C and VEGF-D also play a crucial role in the process of lymphangiogenesis [11]. VEGF not only promotes endothelial cell survival, proliferation and migration, but also increases vascular permeability and adhesion molecules on endothelial cells. It has recently been shown that VEGF mobilizes endothelial progenitor cells from the bone marrow to sites of neovascularization [13].
VEGF is upregulated by a variety of factors. A number of growth factors have been demonstrated to induce VEGF gene expression, including fibroblasts growth factors (FGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF) tumor necrosis factor (TNF), transforming growth factor-Ī² (TGF-Ī²) and interleukin-1 (IL-1) [14]. The most significant regulator of VEGF production is hypoxia. Hypoxic induction of VEGF appears to be a ubiquitous response, since a wide range of cultured cells have been observed to increase VEGF mRNA levels [15]. As a tumor increases in mass and becomes hypoxic, VEGF is induced and stimulates growth of new vessels. Transcription of VEGF mRNA is upregulated in hypoxia through transcription factors known as hypoxia-inducible factors (HIFs) that bind to the VEGF promoter [16].
The VEGFRs have been implicated in a variety of human diseases including tumor angiogenesis, tumor-dependent ascites formation, metastasis, inflammatory diseases such as rheumatoid arthritis and psoriasis, hyperthyroidism and atherosclerosis [17]. VEGFR-2 is a potent regulator of vascular endothelial cells and has been directly linked to tumor angiogenesis and blood vessel-dependent metastasis. VEGFR-1 may contribute to pathological vascularization directly by stimulating endothelial cell function and indirectly by mediating recruitment of bone marrow progenitor cells [18].
There are also data indicate that tumor cells may express VEGF receptors that, when stimulated, lead to tumor cell survival and proliferation [19]. Dysregulation of VEGF expression and signaling pathways therefore plays an important role in the pathogenesis and clinical features of hematologic malignancies. Direct and indirect targeting VEGF and its receptors may provide a potent novel therapeutic approach to overcome resistance to therapies and thereby improve patient outcome [20].
The process of angiogenesis is inherently coupled to the induction of antiangiogenic mechanisms. Generation and release of antiangiogenic factors during the process of angiogenesis contributes to coordinated downregulation of the angiogenic process in physiologic angiogenesis but is insufficient to counteract the net effect of proangiogenic factors in the case of progressive tumors.
Multiple antiangiogenic molecules have been identified in recent years, including cytokines such as interferon-Ī± (IFN-Ī±) and IFN-Ī³ as well as several peptides generated by proteolytic cleavage of the basement membrane, and proteins of the fibrinolytic and clotting pathway (e.g. angiostatin, endostatin, maspin, tumstatin) [21], [22], [23], [24], [25].
There is increasing evidence of autocrine as well as paracrine angiogenic loops that are important for tumor growth and survival. For example, some tumor cells produce VEGF and at the same time express its receptors, promoting growth and survival through an autocrine loop. In this case, VEGF promotes tumor proliferation or survival directly by acting on the cell surface receptors. The endothelial and stromal cells, constituting the microenvironment, may express VEGF or VEGF receptors and respond to the tumor VEGF by proliferating to generate new vessels and secreting several mitogenic or angiogenic cytokines, which in a paracrine fashion stimulate the tumor cells to grow (Fig. 1) [26].
Section snippets
Angiogenesis in acute leukemia
Leukemias originate from hematopoietic stem cells (HSC) 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 the more mature, committed HSC. Increased expression of angiogenic activators such as VEGF and bFGF was revealed in most hematologic malignancies. Some recent studies are summarized in Table 2.
Interference with control of angiogenesis
Angiogenesis is required for tumor formation and growth inhibition of angiogenesis is a promising new approach in cancer therapy. Various angiogenesis inhibitors have been developed to target vascular endothelial cells and block tumor angiogenesis (Table 3).
Hypoxia activates HIF-1-dependent transcription in cancer cells that, in a paracrine fashion, drive tumor angiogenesis. UCN-01 is a protein kinase C inhibitor that exerts an antiangiogenic effect by blocking the response of cancer cells to
Pitfalls and perspective
Accumulating evidence suggests that increased angiogenesis in hematologic malignancies is not merely an epiphenomenon but a critical part of the disease pathogenesis. Studies have shown that angiogenesis has prognostic value in many of these malignancies. Inhibition of tumor angiogenesis suppresses tumor growth and metastatic spreading in many experimental models, suggesting that antiangiogenic drugs may be used to treat human cancer. A high number of drugs that target angiogenesis are under
Acknowledgements
This project was supported in part by grants of National Natural Science Foundation of China (30670900), Ministry of Education of China (20060023031), Ministry of Personnel of China (2006) and Tianjin Key Project for Basic Research (05YFJZJC01500, 06YFJZJC01800). The authors would like to thank Prof. Man-Chiu Poon (University of Calgary, Canada) for critical review of the manuscript.
Xunwei Dong received her medical doctoral degree in 1993 from Dalian Medical University, China. She is currently working as a Ph.D. fellow in the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Her research is focused on angiogenesis in oncology/hematology.
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Xunwei Dong received her medical doctoral degree in 1993 from Dalian Medical University, China. She is currently working as a Ph.D. fellow in the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Her research is focused on angiogenesis in oncology/hematology.
Dr. Zhong Chao Han graduated from Medical College in 1982, obtained his Master in Medical Sciences degree in 1984 and his Ph.D. degree in Life Science from Occidental Bretagne University School of Medicine of Brest, France in 1988. From 1990 to 1997, he was research scientist and laboratory chief of the Institut des Vaisseaux et du Sang, Paris and then professor associated with universities (Hematology) in Paris 7th University. From August 1997 to November 2004, he was the Director of the Institute of Hematology and Hospital of Blood diseases, Chinese Academy of Medical Sciences and Peking Union Medical College. Dr. Han is currently Director of the State Key Laboratory for Experimental Hematology, Director of the National Research Center for Stem Cell Engineering and Technology. Dr. Han has published approximately 100 papers in peer-review international journals and several books.
Renchi Yang graduated from Tongji Medical University in 1988 and from Peking Union Medical College with M.D. degree in 1995. He has engaged in clinical work in Department of Hematology, Institute of Hematology and Blood Diseases Hospital, CAMS and PUMC, China for 18 years and was at Institut des Vaisseaux et du Sang, Paris as visiting Scholar for 1 year. He is currently Professor of Hematology and Head of Department of Hemostasis and Thrombosis. Dr. Yang has published approximately 100 papers in peer-reviewed journals and several books.