Recent Advances in Angiogenesis and ... - Bentham Science

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Recent Advances in Angiogenesis and Antiangiogenesis Recent Advances in Angiogenesis and Antiangiogenesis, 2009 87 Recently, the use of VTAs, such as ligand-targeted liposomes and drug conjugates, has started to fulfill its promise [23]. This strategy builds on the clinical success of nanomedicines such as Caelyx ® , which are used to improved therapeutic outcome and/or minimized damage to normal tissues such as heart or bone marrow, thereby increasing the selective toxicity of chemotherapeutics in cancer [24]. Further increases in therapeutic activity can be achieved by using ligand-targeted nanomedicines that have surfaceconjugated, tumor-selective antibodies or peptides [25], particularly when targeting is by internalizing ligands that facilitate the delivery of the therapeutic contents to intracellular sites of activity via the endosome/lysosome pathway [25, 26]. Indeed, compared to normal blood vessels, tumor blood vessels have an abnormal wall structure, being highly disorganized and heterogeneous, with complex branching patterns and lack of hierarchy [27]. Moreover, endothelial cells in angiogenic vessels express several proteins that are absent or barely detectable in established blood vessels, including αv integrins [28], receptors for angiogenic growth factors [29], and other types of membrane-spanning molecules, such as the aminopeptidases N (CD13) and A (APA) [30, 31]. In vivo panning of phage libraries in tumor-bearing mice have proven useful for selecting peptides that bind to receptors that are either overexpressed or are selectively expressed on tumorassociated vessels and that home to neoplastic tissues [32]. Thus, it may be possible to develop ligandtargeted chemotherapy strategies, based on peptides that are selective for tumor vasculature. Among the various tumor-targeting ligands identified to date, peptides containing the asparagine-glycine-arginine (NGR) motif, which binds to CD13, have proven useful for delivering various anti-tumor compounds to tumor vasculature [33, 34]. Although there are several subpopulations of CD13 [35], relatively widely distributed in the body, only one isoform is believed to be the receptor for the NGR-containing peptides. This isoform has been shown to be expressed exclusively in angiogenic vessels, such as the neovasculature found in tumor tissues [36]. Consequently, since this CD13 isoform, recognized by NGR-containing peptides, is expressed on endothelial cells within most, if not all, solid tumors, an alternative strategy that has been pursued to increase the delivery of anti-cancer/antiangiogenic compounds (such as doxorubicin-DXR) to tumors was based on the use of vascular targeted liposomes. 3. TUMOR VASCULAR TARGETING TECHNOLOGY This strategy has been developed that might overcome problems of tumor cell heterogeneity by using vascular targeted liposomes to exploit the obvious advantages of anti-angiogenic therapies. Indeed, it has been shown that pronounced tumor regressions can be achieved in mice by systemic delivery of a liposomal anti-angiogenic chemotherapeutic drug that is targeted to the tumor vasculature [33]. There are several advantages of targeting chemotherapeutic agents to proliferating endothelial cells in the tumor vasculature rather than directly to tumour cells. First, acquired drug resistance, resulting from genetic and epigenetic mechanisms reduces the effectiveness of available drugs [37]. Anti-angiogenic therapy has the potential to overcome these problems or reduce their impact. This therapy targets the tumor vasculature, derived from local and circulating endothelial cells that are considered, although controversial, genetically stable. Second, the fact that a large number of cancer cells depend upon a small number of endothelial cells for their growth and survival might also amplify the therapeutic effect [38]. Third, anti-angiogenic therapies may also circumvent what may be a major mechanism of intrinsic drug resistance, namely insufficient drug penetration into the interior of a tumor mass due to high interstitial pressure gradients within tumors [39]. A strategy that targets both the tumor vasculature and the tumor cells themselves may be more effective than strategies that target only tumor vasculature, since this strategy can leave a cuff of unaffected tumor cells at the tumor periphery that can subsequently re-grow and kill the animals [40]. Fourth, oxygen consumption by neoplastic and endothelial cells, along with poor oxygen delivery, creates hypoxia within tumors. These characteristics of solid tumors compromise the delivery and effectiveness of conventional cytotoxic therapies as well as molecularly targeted therapies [38, 39]. Finally, the therapeutic target is partially independent of the type of solid tumor; killing of proliferating endothelial cells in the tumor microenvironment can be effective against a variety of malignancies. In order to better mimic physiological and pathological features of the tumor microenvironment observed in patients suffering with cancer and, consequently, to build novel and more specific tumorand vasculature-targeted therapies, the importance of choosing the correct animal models to be used, became mandatory. Most preclinical studies on tumor angiogenesis and anti-angiogenic therapy usually employ rapidly growing transplantable mouse tumors, or human tumor xenografts, which are grown as solid, localized tumors in the subcutaneous space. For several reasons this approach almost certainly exaggerates the anti-tumor responses. Principally, in such experimental situations, unlike in the clinic, distant metastases are usually not the focus of the treatment, but it is precisely such secondary tumors which are ultimately responsible for cancer's lethality.

92 Recent Advances in Angiogenesis and Antiangiogenesis, 2009, 92-100 Tumor Targeting with Transgenic Endothelial Cells Gerold Untergasser and Eberhard Gunsilius Domenico Ribatti (Ed.) All rights reserved - © 2009 Bentham Science Publishers Ltd. CHAPTER 11 Tumor Biology & Angiogenesis Lab, Department of Internal Medicine V, Medical University Innsbruck, TILAK & Oncotyrol, Innrain 66, 6020 Innsbruck, Austria Correspondence to: Prof. Eberhard Gunsilius Tumor Biology & Angiogenesis Lab, Department of Internal Medicine V, Medical University Innsbruck, TILAK & Oncotyrol, Innrain 66, 6020 Innsbruck, Austria. Tel: 0043.512.50423255; Fax: 0043.51252199214778; Email: eberhard.gunsilius@i-med.ac.at 1. INTRODUCTION Abstract: The formation of tumor supporting vessels can be accomplished by the sprouting of preexisting vessels, i.e. the proliferation of resident endothelial cells (angiogenesis) or by vasculogenesis, i.e. the de novo formation of vessels by circulating endothelial progenitor cells (EPC) presumably deriving from the bone marrow. Cytokines and chemokines released by tumors and inflamed tissue have been shown to recruit EPC and other progenitor cells from the circulation to home to sites of active vessel and tumor growth. Therefore, EPC-based therapies might be used to target specifically malignant tumors. Incorporated autologous cells thereby function as “Trojan horses” and deliver enzymes for activation of cytotoxic agents or release antiangiogenic proteins. However, the extent of EPC incorporation and the precise mechanisms by which EPC contribute to neovessels or migrate and invade tumor tissue are still under investigation. Furthermore, cells used for therapeutic purposes, regardless of their origin, have to be produced under Good Manufacturing Practice (GMP) conditions and should be at least homogenous and unequivocally characterized to minimize potential risks of malignant transformation in individuals after transplantation. Thus, this review will summarize the current knowledge on EPC, their ex-vivo propagation, genetic modification and homing to tumors in preclinical trials. Tumors need sufficient nutrients and oxygen supply, otherwise tumor cells get acidic, hypoxic and necrotic. Thus, tumor growth is strongly dependent on the generation of new blood vessels [1]. Tumour blood vessels are generated by various mechanisms, such as cooption of the existing vascular network, expansion of the host vascular network by budding of endothelial sprouts (sprouting angiogenesis), remodelling and expansion of vessels by the insertion of interstitial tissue columns into the lumen of pre-existing vessels (intussusceptive angiogenesis) and homing of endothelial cell precursors (EPC; CEPs, angioblastlike cells) from the bone marrow or peripheral blood into the endothelial lining of neovessels (vasculogenesis) [2,3]. Bone marrow derived progenitor cells contribute significantly to neovascularization in a variety of tumors [4-6]. Despite significant contributions in animal systems the extent of incorporated EPCs into neovessels of malignant human tumors is still under investigation and strongly depending on the tumor-type studied [7]. EPCs might represent an ideal shuttle for a cell-based therapy targeting the expanding tumor, i.e. areas of hypoxia and inflammation. Specific targeting of tumors should be achieved since bone marrow mononuclear cells and EPCs are mobilized and attracted from the circulation by a released cocktail of tumor-derived cytokines and chemokines. In particular VEGF [8] and SDF1 [9] produced under ischemic conditions can mobilize EPCs from the bone marrow and circulation to sites of active neovascularization. Genetically-modified EPCs can be used to deliver therapeutic proteins, such as secreted antiangiogenic proteins or enzymes for activation of cytotoxic agents into neovessels of the tumor [10,11]. Hitherto, this therapeutic attempt has been shown as proof of principle in different preclinical studies making use of murine tumor models or human tumor xenografts transplanted into immunocompromised mice [11-15]. Despite these promising results in preclinical animal models, we are still far away from a safe and specific cell-based therapy that can be used in a clinical setting. There are still stringent prerequisites for EPC based therapies in humans that need be reached or established, such as (i) a well characterized terminally differentiating cell-type that can be produced under GMP-conditions, (ii) a cell-type with high proliferative capacity for propagation and genetic modification, (iii) a save genetic modification system not causing transformation of cells and not inducing immune responses in the host, (iv) a genetic modification system allowing permanent and high expression of the target gene (v), a cell-type that can be

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