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Recent Advances in Angiogenesis and Antiangiogenesis, 2009, 85-91 85 CHAPTER 10 Recent Advances in Angiogenesis and Antiangiogenesis: The Neuroblastoma Model Fabio Pastorino and Mirco Ponzoni Experimental Therapies Unit, Laboratory of Oncology, G. Gaslini Children’s Hospital, Genoa, Italy. Address correspondence to: Dr. Fabio Pastorino and Dr. Mirco Ponzon., Experimental Therapy Unit, Laboratory of Oncology, G. Gaslini Children’s Hospital, Largo G. Gaslini 5, 16148 Genoa, Italy; Tel.: +39-010-5636342; Fax: +39-010-3779820; Email: fabiopastorino@ospedale-gaslini.ge.it; mircoponzoni@ospedale-gaslini.ge.it Abstract: Promising novel antiangiogenic strategies are emerging for the treatment of cancer and the inhibition of angiogenesis might represent a powerful tool as adjuvant therapy of malignant tumors. Over the last fifteen years several reports have been published concerning the relationship between tumor progression and angiogenesis in neuroblastoma in experimental models in vitro and in vivo. Moreover, a high vascular index in neuroblastoma correlates with poor prognosis, suggesting dependence of aggressive tumor growth on active angiogenesis. Here, we present an overview of the most recent advances in antiangiogenesis in neuroblastoma, and describe tumor vascular-targeted preclinical results, as well as future perspectives. 1. ROLE OF ANGIOGENESIS IN NEUROBLASTOMA GROWTH Angiogenesis is the formation of new blood vessels from pre-existing ones and takes place in various physiological and pathological conditions, such as embryonic development, wound healing, the menstrual cycle, chronic inflammation and tumors [1, 2]. It is generally accepted that tumor growth is angiogenesisdependent and that every increment of tumor growth requires an increment of vascular growth [3]. Tumor angiogenesis is an uncontrolled and unlimited process essential for tumor growth, invasion and metastasis, regulated by the balanced interactions of numerous mediators and cytokines with pro-angiogenic and antiangiogenic activity. Tumors lacking angiogenesis remain dormant indefinitely. An expanding endothelial surface also gives tumor cells more opportunities to enter the circulation and metastasize. New vessels promote growth by conveying oxygen and nutrients and removing catabolites, whereas endothelial cells secrete growth factors for tumor cells and a variety of matrix-degrading proteinases that facilitate invasion. An expanding endothelial surface also gives tumor cells more opportunities to enter the circulation and metastasize, while release of antiangiogenic factors by the endothelial cells explains the control exerted by primary tumors over metastasis. These observations suggest that tumor angiogenesis is linked to a switch in the equilibrium between positive and negative regulators. In normal tissues, vascular quiescence is maintained by the dominant influence of Domenico Ribatti (Ed.) All rights reserved - © 2009 Bentham Science Publishers Ltd. endogenous angiogenesis inhibitors over angiogenic stimuli. Tumor angiogenesis, on the other hand, is induced by increased secretion of angiogenic factors and/or downregulation of angiogenesis inhibitors. Growth of solid and hematological tumors consists of an avascular and a subsequent vascular phase. Assuming that the latter process is dependent on angiogenesis and depends on the release of angiogenic factors, acquisition of angiogenic capability can be seen as an expression of progression from neoplastic transformation to tumor growth and metastasis. Angiogenic factors can be produced by a number of cells such as embryonic cells, adult resident and inflammatory cells (i.e. fibroblasts, macrophages, T cells, plasma cells, neutrophils, and eosinophils) and neoplastic cells. Several angiogenic factors have been identified, including vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), placenta growth factor (PlGF), basic fibroblast growth factor/fibroblast growth factor-2 (bFGF/FGF-2), transforming growth factor beta (TGF-β), hepatocyte growth factor (HGF), tumor necrosis factor alpha (TNF-α), interleukin-8 (IL-8), and angiopoietin-1 and –2. Except for cancers of hematologic origin and of the central nervous system (CNS), pediatric cancers frequently originate from mesenchymal structures, such as bone or muscle. Childhood malignancies tend to have short latency periods and are frequently rapidly growing and aggressively invasive. Unlike adult cancers, most pediatric malignancies have either spread locally or have metastasized at the time of pre-
86 Recent Advances in Angiogenesis and Antiangiogenesis, 2009 Pastorino and Mirco Ponzoni sentation and are not amenable to curative surgical excision. Among pediatric solid tumors, neuroblastoma (NB), most commonly occurring in the adrenal gland, is predominantly a tumor of infancy with 16% of children diagnosed within the first month of life and 41% diagnosed within the first 3 months of life. Several recent studies implicate angiogenesis in the regulation of NB growth and inhibition of angiogenesis is a promising approach in the treatment of NB because of the high degree of vascularity of these tumors. In 1994 Kleinman and co-workers published a paper in which they showed that human NB cells induce angiogenesis in nude mouse during tumorigenesis [4]. Meitar et al. (1996) evaluated the vascularity of primary untreated NB from 50 patients. They found that the vascularity of NB from patients with widely metastatic disease is significantly higher than in tumors from patients with local or regional disease [5]. Ribatti et al. (1998) investigated the angiogenic potential of two human NB cell lines demonstrating their capacity to induce in vitro human microvascular endothelial cells to proliferate and in vivo angiogenesis in the chick embryo chorioallantoic membrane assay [6]. Canete et al. (2000) in a retrospective study showed that tumor vascularity was not predictive of survival of NB patients and that neither disseminated nor local relapses were influenced by the angiogenic characteristics of the tumors [7]. Eggert et al. (2000) performed a systematic analysis of expression of angiogenic factors in 22 NB cell lines and in 37 tumor samples. They found that high expression levels of seven angiogenic factors correlated strongly with the advanced stage of NB and this suggests that several angiogenic peptides set in concert in the regulation of neovascularization [8]. Ara et al. (1998) found that increased expression of MMP-2, but not of MMP-9, in stromal tissues of NB had significant association with advanced clinical stages [9]. Sarakibara et al. (1999) have demonstrated that the higher gelatinases activation ratio resulting from high espression of a novel membrane-type matrix metalloproteinase-1 (MT-MMP-1) on NB specimens is associated significantly with advanced stage and unfavorable outcome [10]. Ribatti et al. (2001) showed that the extent of angiogenesis and the expression of the MMP-2 and MMP-9 were upregulated in advanced stages of NB [11]. MYC-N may regulate the growth of NB vessels, because its amplification or overexpression is associated with angiogenesis in experimental [12] and clinical settings [5]. Amplification of MYC-N is a frequent event in advanced stages of human NB. MYC-N amplification correlates with poor prognosis and enhanced vascularization of human NB, suggesting that the MYC-N oncogene could stimulate tumor angiogenesis and thereby allow NB progression [13]. Erdreich-Epstein et al. (2000) demostrated by immunohistochemical analysis that ανβ3 integrin was expressed by 61% of microvessels in high-risk NB, but only by 18 % of microvessels in low-risk tumors [14]. It has been reported a very low tumor vascularity in Schwannian stroma-rich/stroma-dominant NB tumors and that Schwann cells produce angiogenesis inhibitors, such as tissue inhibitor of metalloproteinase-2 (TIMP-2) and pigment epithelium-derived factor (PEDF), that are capable of inducing endothelial cell apoptosis [15, 16]. Chlenski et al. (2002) isolated an angiogenic inhibitor in Schwann cell conditioned medium, identified as SPARC, which expression is inversely correlated with the degree of malignant progression in NB tumors. Furthermore, SPARC inhibited angiogenesis in vivo and impaired NB tumor growth [17]. Leali et al. (2003) demonstrated that FGF-2 causes osteopontin (OPN)-upregulation in endothelial cells, in vitro and in vivo, resulting in the recruitment of proangiogenic monocytes [18]. Takahashi et al. (2002) demonstrated that OPN-transfected murine NB cells significantly increased neovascularization in mice [19]. Enforced expression of OPN in NB cells significantly stimulated endothelial cells migration and induced angiogenesis in mice, as evaluated by dorsal air sac assay. 2. ANGIOGENESIS AS THERAPEUTIC TARGET It is exhaustively reported in the literature that a functional blood supply is essential to meet the oxygen and nutrient demands of growing solid tumors [20]. Moreover, since the neovasculature that arises from the normal host vessels by the process of angiogenesis also is the principal vehicle for metastatic spread [21], we can conclude that tumor neo-vasculature is a potential therapeutic target [22] for all solid tumors, including neuroblastoma. There are two major approaches in controlling tumor vasculature. One strategy is to prevent the development of tumor blood vessels by inhibiting the angiogenesis process (AIAs, angiogenesis inhibiting agents); the other strategy acts by compromising the function of established tumor blood vessels (VTAs/VDAs, vascular targeting/vascular disrupting agents). The latter strategy has been shown to disrupt established tumor vasculature causing rapid and sustained inhibition of tumor blood flow. By depriving tumors of the nutrients necessary to growth and survive, VTAs/VDAs induce necrosis, particularly within the core of the tumor.
Page 2 and 3: Recent Advances in Angiogenesis and
Page 4 and 5: FOREWORD It has been known for a ve
Page 6 and 7: single proangiogenic protein. Howev
Page 8 and 9: v Vito Pistoia Head, Laboratory of
Page 10 and 11: 2 Recent Advances in Angiogenesis a
Page 12 and 13: 10 Recent Advances in Angiogenesis
Page 16 and 17: The Role of Mesenchymal Stem Cells
Page 22 and 23: Thymus and Angiogenesis Recent Adva
Page 32 and 33: Role of Thymidine Recent Advances i
Page 34 and 35: Role of Stromal Cells Recent Advanc
Page 40 and 41: Tumor Targeting with Transgenic End
Page 44 and 45: Tumor Vascular Disrupting Agents Re
Page 50 and 51: Tumour Vascular Disrupting Agents R
Page 52: Index Recent Advances in Angiogenes

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